Đang tải... (xem toàn văn)
(BQ) Part 1 book The big picture: Medical biochemistry presents the following contents: Amino acids and proteins, carbohydrates, lipids, nucleosides, nucleotides, DNA, and RNA; integrated usmle style questions and answer, enzymes and amino acid protein metabolism, carbohydrate metabolism, lipid metabolism, membranes, DNA/RNA function and protein synthesis.
Notice Medi ci ne i s a n ever-cha ngi ng s ci ence As new res ea rch a nd cl i ni ca l experi ence broa den our knowl edge, cha nges i n trea tment a nd drug thera py a re requi red The a uthors a nd the publ i s her of thi s work ve checked wi th s ources bel i eved to be rel i a bl e i n thei r efforts to provi de i nforma ti on tha t i s compl ete a nd genera l l y i n a ccord wi th the s ta nda rds a ccepted a t the ti me of publ i ca ti on However, i n vi ew of the pos s i bi l i ty of huma n error or cha nges i n medi ca l s ci ences , nei ther the a uthors nor the publ i s her nor a ny other pa rty who s been i nvol ved i n the prepa ti on or publ i ca ti on of thi s work wa rra nts tha t the i nforma ti on conta i ned herei n i s i n every res pect a ccura te or compl ete, a nd they di s cl a i m a l l res pons i bi l i ty for a ny errors or omi s s i ons or for the res ul ts obta i ned from us e of the i nforma ti on conta i ned i n thi s work Rea ders a re encoura ged to confi rm the i nforma ti on conta i ned herei n wi th other s ources For exa mpl e a nd i n pa rti cul a r, rea ders a re a dvi s ed to check the product i nforma ti on s heet i ncl uded i n the pa cka ge of ea ch drug they pl a n to a dmi ni s ter to be certa i n tha t the i nforma ti on conta i ned i n thi s work i s a ccura te a nd tha t cha nges ve not been ma de i n the recommended dos e or i n the contra i ndi ca ti ons for a dmi ni s tra ti on Thi s recommenda ti on i s of pa rti cul a r i mporta nce i n connecti on wi th new or i nfrequentl y us ed drugs Copyri ght © 2012 by The McGra w-Hi l l Compa ni es , Inc Al l ri ghts res erved Except a s permi tted under the Uni ted Sta tes Copyri ght Act of 1976, no pa rt of thi s publ i ca ti on ma y be reproduced or di s tri buted i n a ny form or by a ny mea ns , or s tored i n a da ta ba s e or retri eva l s ys tem, wi thout the pri or wri tten permi s s i on of the publ i s her ISBN: 978-0-07-163792-3 MHID: 0-07-163792-3 The ma teri a l i n thi s eBook a l s o a ppea rs i n the pri nt vers i on of thi s ti tl e: ISBN: 978-0-07-163791-6, MHID: 0-07-163791-5 Al l tra dema rks a re tra dema rks of thei r res pecti ve owners Ra ther tha n put a tra dema rk s ymbol a fter every occurrence of a tra dema rked na me, we us e na mes i n a n edi tori a l fa s hi on onl y, a nd to the benefi t of the tra dema rk owner, wi th no i ntenti on of i nfri ngement of the tra dema rk Where s uch des i gna ti ons a ppea r i n thi s book, they ve been pri nted wi th i ni ti a l ca ps McGra w-Hi l l eBooks a re a va i l a bl e a t s peci a l qua nti ty di s counts to us e a s premi ums a nd s a l es promoti ons , or for us e i n corpora te tra i ni ng progra ms To conta ct a repres enta ti ve pl ea s e e-ma i l us a t bul ks a l es @mcgra w-hi l l com TERMS OF USE Thi s i s a copyri ghted work a nd The McGra w-Hi l l Compa ni es , Inc (“McGra w-Hi l l ”) a nd i ts l i cens ors res erve a l l ri ghts i n a nd to the work Us e of thi s work i s s ubject to thes e terms Except a s permi tted under the Copyri ght Act of 1976 a nd the ri ght to s tore a nd retri eve one copy of the work, you ma y not decompi l e, di s a s s embl e, revers e engi neer, reproduce, modi fy, crea te deri va ti ve works ba s ed upon, tra ns mi t, di s tri bute, di s s emi na te, s el l , publ i s h or s ubl i cens e the work or a ny pa rt of i t wi thout McGra w-Hi l l ’s pri or cons ent You ma y us e the work for your own noncommerci a l a nd pers ona l us e; a ny other us e of the work i s s tri ctl y prohi bi ted Your ri ght to us e the work ma y be termi na ted i f you fa i l to compl y wi th thes e terms THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE McGra w-Hi l l a nd i ts l i cens ors not wa rra nt or gua ntee tha t the functi ons conta i ned i n the work wi l l meet your requi rements or tha t i ts opera ti on wi l l be uni nterrupted or error free Nei ther McGra w-Hi l l nor i ts l i cens ors s l l be l i a bl e to you or a nyone el s e for a ny i na ccura cy, error or omi s s i on, rega rdl es s of ca us e, i n the work or for a ny da ma ges res ul ti ng therefrom McGra w-Hi l l s no res pons i bi l i ty for the content of a ny i nforma ti on a cces s ed through the work Under no ci rcums ta nces s l l McGra w-Hi l l a nd/or i ts l i cens ors be l i a bl e for a ny i ndi rect, i nci denta l , s peci a l , puni ti ve, cons equenti a l or s i mi l a r da ma ges tha t res ul t from the us e of or i na bi l i ty to us e the work, even i f a ny of them s been a dvi s ed of the pos s i bi l i ty of s uch da ma ges Thi s l i mi ta ti on of l i a bi l i ty s l l a ppl y to a ny cl a i m or ca us e wha ts oever whether s uch cl a i m or ca us e a ri s es i n contra ct, tort or otherwi s e CONTENTS Dedications Acknowledgements About the Authors SECTION I: THE BASIC MOLECULES OF LIFE CHAPTER Ami no Aci ds a nd Protei ns Overvi ew Ami no Aci ds —Structure a nd Functi ona l Groups Es s enti a l a nd Non-Es s enti a l Ba s i c Structure Cha cteri s ti cs of R-Groups Ba s i c Protei n Structure Level s of Protei n Structure Ca tegori es of Protei ns Ami no Aci d a nd Pepti de-Deri ved Hormones a nd Neurotra ns mi tters Enzymes Structura l Protei ns Motor Protei ns Tra ns port/Cha nnel Protei ns Revi ew Ques ti ons CHAPTER Ca rbohydra tes Overvi ew Ba s i c Ca rbohydra te Structure a nd Functi on Monos a ccha ri des a nd Di s a ccha ri des Gl ycogen a nd Sta rches Gl ycoprotei ns Gl ycos a mi nogl yca ns Revi ew Ques ti ons CHAPTER Li pi ds Overvi ew Ba s i c Li pi d Functi ons Ba s i c Membra ne Li pi d Structure Compl ex Li pi ds Gl ycol i pi ds /Sphi ngol i pi ds Ei cos a noi ds Chol es terol Li poprotei ns Bi l e Sa l ts Li pi d-Deri ved Hormones /Vi ta mi n D Corti cos teroi ds (Adrena l Gl a nd) Androgens (Tes tes ) a nd Es trogens (Ova ri es ) Vi ta mi n D Revi ew Ques ti ons CHAPTER Nucl eos i des , Nucl eoti des , DNA, a nd RNA Overvi ew Nucl eos i des a nd Nucl eoti des Components of Nucl eos i des a nd Nucl eoti des Synthes i s of Puri ne Nucl eos i des a nd Nucl eoti des Synthes i s of Pyri mi di ne Nucl eos i des a nd Nucl eoti des Forma ti on of Deoxy Nucl eos i des a nd Nucl eoti des Brea kdown of Puri nes a nd Pyri mi di nes RNA a nd DNA—Ba s i c Structure a nd Functi on RNA DNA Revi ew Ques ti ons SECTION I: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers Ques ti ons Ans wers SECTION II: FUNCTIONAL BIOCHEMISTRY CHAPTER Enzymes a nd Ami no Aci d/Protei n Meta bol i s m Overvi ew Enzymes Enzyme Rea cti ons Cofa ctors Regul a ti on Ami no Aci d Meta bol i s m Ami no Aci d Synthes i s Ami no Aci d Degra da ti on The Urea Cycl e Revi ew Ques ti ons CHAPTER Ca rbohydra te Meta bol i s m Overvi ew Gl ycol ys i s Ci tri c Aci d Cycl e Oxi da ti ve Phos phoryl a ti on Gl uconeogenes i s The Pentos e Phos pha te Pa thwa y Gl ycogen Synthes i s Gl ycogen Brea kdown Modi fi ed Ca rbohydra tes (Gl ycoprotei ns , GAGs ) Revi ew Ques ti ons CHAPTER Li pi d Meta bol i s m Overvi ew Fa tty Aci d Meta bol i s m Fa tty Aci d Synthes i s Fa tty Aci d Degra da ti on Meta bol i s m of Compl ex Li pi ds Tri a cyl gl ycerol Synthes i s Phos phogl yceri de Synthes i s Ketone Body Synthes i s Cera mi de/Sphi ngol i pi ds Synthes i s Chol es terol Synthes i s Revi ew Ques ti ons CHAPTER Membra nes Overvi ew Membra ne Structure Li pi ds Protei ns Membra ne Functi ons Membra ne Cha nnel s Membra ne Si gna l i ng Revi ew Ques ti ons CHAPTER DNA/RNA Functi on a nd Protei n Synthes i s Overvi ew Structure of the Nucl eus Hi s tones Nucl ea r Ma tri x/Sca ffol d Nucl eol us a nd Ri bos ome Synthes i s DNA Repl i ca ti on a nd Tra ns cri pti on DNA Repl i ca ti on Tra ns cri pti on Protei n Synthes i s Pos ttra ns l a ti ona l Tra ffi cki ng/Modi fi ca ti on Control of Gene Expres s i on Muta ti ons a nd Repa i r Mecha ni s ms Regul a ti on of Cel l Growth a nd Di fferenti a ti on Revi ew Ques ti ons SECTION II: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers Ques ti ons Ans wers SECTION III: APPLIED BIOCHEMISTRY CHAPTER 10 Meta bol i s m a nd Vi ta mi ns /Mi nera l s Co-authors/Editors: Maria L Valencik and Cynthia C Mastick Overvi ew Meta bol i c Rol es of Ma jor Bi ochemi ca l Mol ecul es Integra ti on a nd Regul a ti on of Meta bol i s m Gl ucos e-6-phos pha te Pyruva te Acetyl -CoA Hormona l Control of Meta bol i s m Ins ul i n Gl uca gon Ca techol a mi nes Gl ucocorti coi ds Di a betes Mel l i tus (DM) Vi ta mi ns a nd Mi nera l s Vi ta mi ns Mi nera l s Revi ew Ques ti ons CHAPTER 11 The Di ges ti ve Sys tem Editor: Kshama Jaiswal Overvi ew Summa ry of the Di ges ti ve Sys tem Mouth Stoma ch Li ver Li pi d Meta bol i s m i n the Li ver Ga l l Bl a dder Pa ncrea s Sma l l Intes ti ne (Duodenum, Jejunum, a nd Il eum) La rge Intes ti ne/Anus Revi ew Ques ti ons CHAPTER 12 Mus cl es a nd Moti l i ty Co-author/Editor: Darren Campbell Overvi ew The Ba s i c Components of Mus cl e Acti n Tropomyos i n–Troponi ns Myos i n Myos i n Li ght Cha i ns Acti n-Bi ndi ng Protei ns Exci ta ti on–Contra cti on Coupl i ng Skel eta l Mus cl e Structure a nd Genera l Overvi ew Skel eta l Mus cl e Types Ca rdi a c Mus cl e Smooth Mus cl e Energy Producti on a nd Us e i n Mus cl es Mi crotubul e-Ba s ed Moti l i ty Intermedi a te Fi l a ments Nonmus cl e Cel l s Revi ew Ques ti ons CHAPTER 13 Connecti ve Ti s s ue a nd Bone Editor: Jacques Kerr, BSc, MB, BS, FRCS, FCEM Overvi ew Connecti ve Ti s s ue Components of Bone Bone Growth a nd Remodel i ng Regul a ti on of Ca l ci um Level s Ma rkers of Bone Forma ti on a nd Res orpti on Revi ew Ques ti ons CHAPTER 14 Bl ood Co-authors/Editors: Matthew Porteus, MD, PhD and Tina Mantanona Overvi ew Ba s i c Components of Bl ood Red Bl ood Cel l (RBC) Functi ons Di s ea s es As s oci a ted wi th Ina dequa te Synthes i s of Hemogl obi n Components Oxygen Bi ndi ng Tens e a nd Rel a xed Hgb Al l os teri c Bi ndi ng of O2 by Hgb Regul a ti on of O2 Bi ndi ng Phys i ol ogi c Res pons e to Ina dequa te O2 Del i very Si ckl e Cel l Di s ea s e (SCD) Iron Iron Meta bol i s m Tra ns ferri n Ferri ti n Regul a ti on of Iron Ava i l a bi l i ty by Hepci di n Cl otti ng Pl a tel et Pl ug Forma ti on Cons i s ts of Adhes i on, Aggrega ti on, a nd Acti va ti on of Pl a tel ets The Cl otti ng Ca s ca de The Fi bri n Mes hwork Di fference between Pl a tel et Pl ug Forma ti on a nd Cl ot Forma ti on Regul a ti on of Cl ot Forma ti on Pl a s mi n a nd Cl ot Di s s ol uti on Revi ew Ques ti ons CHAPTER 15 The Immune Sys tem Editor: Eric L Greidinger, MD Overvi ew Overvi ew of the Immune Sys tem Anti gen Anti body Cel l s As s oci a ted wi th the Immune Sys tem T Lymphocytes B Lymphocytes /Pl a s ma Cel l s Na tura l Ki l l er (NK) Cel l s Monocytes a nd Ma cropha ges Neutrophi l s Eos i nophi l s Ba s ophi l s Dendri ti c Cel l s (DCs ) Cytoki nes Inna te Immuni ty Compl ement s ys tem Hypers ens i ti vi ty Rea cti ons Revi ew Ques ti ons CHAPTER 16 The Ca rdi ova s cul a r Sys tem Editor: Ralph V Shohet, MD Overvi ew Ca rdi a c Mus cl e Structure a nd Functi on Si noa tri a l a nd Atri oventri cul a r Nodes The Ca rdi a c Cycl e Bl ood Ves s el s Endogenous Chol es terol /Li poprotei n Meta bol i s m a nd Tra ns port VLDL Intermedi a te-Dens i ty Li poprotei n (IDL) a nd LDL HDL Atheros cl eros i s Bi ochemi ca l Mecha ni s ms As s oci a ted wi th Hea rt Atta ck Revi ew Ques ti ons CHAPTER 17 The Res pi tory Sys tem Editor: Howard J Huang, MD Overvi ew Ba s i c Ana tomy a nd Devel opment Pul mona ry Surfa cta nt a nd the Devel opi ng Lung O2 –CO2 Excha nge i n the Lung a nd Aci d–Ba s e Ba l a nce Noni nfecti ve Di s ea s es of the Res pi tory Sys tem Obs tructi ve Di s ea s es —Emphys ema Obs tructi ve Di s ea s es —Bronchi ti s Obs tructi ve Di s ea s es —As thma Bi ochemi ca l Ba s i s of As thma Medi ca ti ons Res tri cti ve Di s ea s es —Acute Res pi tory Di s ea s e Syndrome Res tri cti ve Di s ea s es —Occupa ti ona l Expos ures Res tri cti ve Di s ea s es —Inters ti ti a l Lung Di s ea s es Infecti ve Di s ea s es of the Res pi tory Sys tem Revi ew Ques ti ons CHAPTER 18 The Uri na ry Sys tem Editor: Armando J Lorenzo, MD, MSc, FRCSC, FAAP Overvi ew Ba s i c Ana tomy a nd Phys i ol ogy Rena l Fi l tra ti on The Rena l Corpus cl e Nephron Inul i n/Crea ti ni ne Cl ea nce Reni n–Angi otens i n–Al dos terone Sys tem (RAAS) Reni n a nd Bl ood Pres s ure Ma cul a Dens a a nd Bl ood Fl ow/Os mol a ri ty Angi otens i nogen/Angi otens i n I a nd II Al dos terone Va s opres s i n Atri a l Na tri ureti c Pepti de (ANP) Aci d–Ba s e Ba l a nce NH a nd Aci d–Ba s e Ba l a nce Syntheti c Functi ons Synthes i s of Erythropoi eti n Rol e i n Vi ta mi n D Synthes i s Revi ew Ques ti ons CHAPTER 19 The Nervous Sys tem Editor: Kathryn Beck-Yoo, MD Overvi ew Components of the Nervous Sys tem Nerve Impul s e Conducti on Neuron a t Res t Nerve Impul s e Repol a ri za ti on Autonomi c Nervous Sys tem Sympa theti c Nervous Sys tem Pa s ympa theti c Nervous Sys tem Neurotra ns mi tters Dopa mi ne NE/Epi nephri ne Serotoni n Acetyl chol i ne (Ach) Regul a ti on of Ca techol a mi nes Gl yci ne, Gl uta ma te, a nd GABA Neuropepti des Bi ochemi s try of Vi s i on Anes thes i a Revi ew Ques ti ons CHAPTER 20 The Reproducti ve Sys tem Editor: Catrina Bubier, MD Overvi ew Ba s i c Ana tomy a nd Devel opment Fema l e Reproducti ve Sys tem GnRH FSH LH Es trogens Proges terone hCG The Mens trua l Cycl e Mens trua ti on (Da ys 1–4) Fol l i cul a r/Prol i fera ti ve Pha s e (Da ys 5–13) The Lutea l /Secretory Pha s e (Da ys 15–28) Ferti l i za ti on Brea s t Devel opment a nd La cta ti on Oxytoci n Prol a cti n Ma l e Reproducti ve Sys tem Tes tos terone FSH a nd LH Revi ew Ques ti ons SECTION III: Integra ted USMLE-Styl e Ques ti ons a nd Ans wers Ques ti ons Ans wers SECTION IV: APPENDICES APPENDIX I: Bi ochemi ca l Ba s i s of Di s ea s es Contributing Editor: Harold Cross, MD, PhD Ami no Aci d Synthes i s /Degra da ti on Ami no Aci d Tra ns port Urea Cycl e Di s orders Structura l Protei ns Ca rbohydra tes Gl ycogen Stora ge Mi tochondri a l Enzymes (Excl udi ng Urea Cycl e a nd Fa tty Aci d Oxi da ti on) Li pi ds a nd Fa tty Aci d Oxi da ti on Errors Nucl eoti de Meta bol i s m Defecti ve DNA Bi l i rubi n Meta bol i s m Bl ood Cl otti ng Fa ctor Defects Steroi d Hormone Synthes i s Vi ta mi ns /Mi nera l s a nd El ectrol ytes APPENDIX II: Bi ochemi ca l Methods Pol ya cryl a mi de Gel El ectrophores i s (PAGE) [Sodi um Dodecyl Sul fa te (SDS)/Non-SDS] Immunoa s s a ys RIA ELISA or EIA Chroma togra phy Thi n La yer (Pa per) Chroma togra phy (TLC) Col umn Chroma togra phy Gel Fi l tra ti on Chroma togra phy Ion-Excha nge Chroma togra phy Affi ni ty Chroma togra phy Hi gh-Performa nce/Pres s ure Li qui d Chroma togra phy (HPLC) Protei n a nd Deoxyri bonucl ei c Aci d (DNA)/Ri bonucl ei c Aci d (RNA) Preci pi ta ti on DNA a nd RNA Sequenci ng Southern, Northern, a nd Wes tern Bl ots Southern Bl otti ng Northern Bl otti ng Wes tern Bl otti ng PCR Cl oni ng deoxyri bonucl ei c a ci d; mRNA, mes s enger ri bonucl ei c a ci d [Ada pted wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] Reverse Transcriptase and Retroviral Therapy: Severa l types of vi rus es , i ncl udi ng thos e tha t ca us e huma n i mmunodefi ci ency vi rus (HIV)/a cqui red i mmune defi ci ency s yndrome, ve the a bi l i ty to tra ns cri be thei r RNA i nto DNA a s pa rt of the proces s of i nfecti ng a hos t cel l a nd uti l i zi ng tha t cel l ’s repl i ca ti on ma chi nery The vi l enzyme tha t performs thi s RNA to DNA repl i ca ti on i s known a s reverse transcriptase Cl i ni ci a ns ca n uti l i ze thi s uni que a bi l i ty of vi rus es a ga i ns t them by us i ng a cl a s s of medi ca ti ons known a s reverse transcriptase inhibitors, commonl y ca l l ed retrovirals One s uch retrovi l i s Zidovudine or Azidothymidine (AZT), a n a na l og of thymi di ne (s ee fi gure bel ow) Beca us e revers e tra ns cri pta s e enzymes a re onl y found i n thes e vi rus es a nd the thymi -di ne a na l og i s 100 ti mes l es s s peci fi c for the pa ti ent’s huma n DNA pol ymera s es , the medi ca ti on preferenti a l l y bl ocks vi rus repl i ca ti on The a zi group a l s o s a hydrophobi c qua l i ty tha t a l l ows AZT to cros s through the pl a s ma membra ne for ea s y del i very to i nfected cel l s , a fter whi ch i nterna l cel l ul a r enzymes convert the AZT mol ecul e i nto a n a cti ve 5′-tri phos pha te form tha t ca n i ncorpora te i nto a nd termi na te revers e tra ns cri pti on PROTEIN SYNTHESIS Protei ns a re cha i ns of AAs connected by pepti de bonds formed between the ca rboxyl i c a ci d (COOH) group of one AA a nd the a mi no group (NH ) of the s econd AA (Cha pter 1, Fi gure 1-4A) Beca us e ea ch protei n s a s peci fi c AA s equence, mRNA copi ed from the DNA gene templ a te for tha t s peci fi c protei n provi des the nucl eoti de s equence/codon (Cha pter 4) i ns tructi ons to l i nk the proper AAs together Enzymes bri ng together the RNA a nd the neces s a ry s ubs tra tes a l ong wi th a n energy s ource, ATP, for effi ci ent producti on of protei ns Thi s proces s , ca l l ed “translation,” i s bri efl y des cri bed bel ow a nd s umma ri zed i n Fi gure 9-5 Figure 9-5 A Formation of the Ribosome Complex for “Translation.” The components of protei n s ynthes i s i ncl ude the 60S a nd 40S ri bos oma l s ubuni ts , mRNA, a nd tRNA–AA mol ecul es , the fi rs t of whi ch codes for methi oni ne (AUG mRNA s equence wi th a na l ogous UAC tRNA s equence) Severa l i ni ti a ti on fa ctors (IFs ) a nd el onga ti on fa ctors (EFs ) a re i nvol ved i n the forma ti on of the a cti ve 80S ri bos oma l compl ex B Protein Synthesis (“Translation”) Si mpl i fi ed model of protei n s ynthes i s The fi rs t tRNA–AA i s bound to the P-s i te fol l owed by bi ndi ng of the s econd tRNA–AA to the A-s i te [a i ded by el onga ti on fa ctor 1α(eEF 1α)] A pepti de bond i s formed between the two AAs , a nd the mRNA moves down the ri bos ome [a i ded by el onga ti on fa ctor (eEF )], rel ea s i ng the fi rs t tRNA mol ecul e a nd freei ng the A-s i te, s o a nother tRNA–AA ma y bi nd Thi s proces s i s repea ted unti l a nons ens e codon i s rea ched i n the mRNA s equence, s i gna l i ng the end of the protei n Termi na ti on i s fol l owed by di s s oci a ti on of the ri bos oma l compl ex (a i ded by eRF) a nd rel ea s e of the new pepti de AA, a mi no a ci d; GTP, gua nos i ne tri phos pha te; mRNA, mes s enger ri bonucl ei c a ci d; tRNA, tra ns fer ri bonucl ei c a ci d [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] Protei n s ynthes i s requi res the concerted i ntera cti on of mRNA, tRNA, s evera l a cces s ory protei ns , ca l l ed initiation factor (IF) a nd elongation (EF) factor, a nd ribosomes The mRNA mol ecul e i s copi ed from the DNA gene a nd conta i ns the copy of the nucl eoti de s equence for the chos en protei n Indi vi dua l tRNA mol ecul es ca n bi nd to onl y one s peci fi c type of AA Thi s tRNA–AA bi nds to the mRNA mol ecul e vi a anticodons us i ng the s a me bi ndi ng rul es a s DNA doubl e s tra nds (e.g., a tRNA tha t bi nds the s ta rti ng mRNA codon AUG s a n a nti codon s equence of UAC), i ns uri ng the s peci fi c order of AAs requi red for proper producti on of the protei n The IF a nd EF a cces s ory protei ns s erve a number of rol es , i ncl udi ng ena bl i ng bi ndi ng of the mRNA mol ecul e to the ri bos ome, movement of the mRNA a l ong the ri bos ome to the s ta rt poi nt of the s ynthes i s , docki ng of the tRNA–AA, joi ni ng of the 60S s ubuni t to the 40S–mRNA compl ex (Fi gure 9-5A), a nd movement of the mRNA a nd growi ng pepti de cha i n (Fi gure 9-5B), a s wel l a s a ccura cy a s s ura nce IF a nd EF rol es wi l l not be di s cus s ed further Elongation Factors, Bacteria, and Disease: Corynebacteria diptheriae ca us es the di s ea s e diphtheria, whi ch, unti l effecti ve i mmuni za ti on wa s a va i l a bl e, ca us ed up to 15,000 dea ths a yea r, ma i nl y i n chi l dren a nd ol der a dul ts The ba cteri a Pseudomonas aeruginosa ca us es frequent i nfecti ons of burns , wounds , a nd medi ca l devi ces (ca theters , venti l a tors , etc.), a s wel l a s s eri ous probl ems i n i mmunocompromi s ed pers ons Rotaviruses ca us e mi l l i ons of chi l dhood dea ths ea ch yea r from s eri ous di a rrhea Al l three of thes e i nfecti ve a gents work by mi mi cki ng huma n a cces s ory protei ns a nd bi ndi ng to el onga ti on fa ctors Al though the two ba cteri a i nhi bi t a n el onga ti on fa ctor, rota vi rus es a ctua l l y “hi ja ck” the fa ctor a nd us e the hos t’s protei n s ynthes i s ma chi nery for reproducti on a nd further i nfecti on The ri bos ome i s a two-pa rt s tructure compos ed of protei ns a nd four s tra nds of rRNA The fi rs t pa rt of the ri bos ome i s a 40S s ubuni t (“S” s ta nds for “Svedberg,” a uni t of mol ecul a r s i ze) a l ong wi th one rRNA, whi ch hel ps i n es ta bl i s hi ng the proper AUG codon s ta rt s i te on the mRNA The 40S s ubuni t a l s o conta i ns the bi ndi ng s i tes for the mRNA s tra nd a nd two bi ndi ng s i tes for i ncomi ng AAs —the “P-site” (na med for the pepti de cha i n tha t grows a t thi s s i te) a nd the “A-site” (na med beca us e new AAs bi nd here) The s econd pa rt of the ri bos ome i s a 60S s ubuni t wi th three rRNA mol ecul es , whi ch hel p i n s ta bi l i za ti on of the enti re ri bos ome, pepti de bond forma ti on, a nd movement of the ri bo-s ome, a l ong the mRNA s tra nd The 60S s ubuni t bi nds to the 40S s ubuni t onl y a fter the mRNA i s i n pl a ce, the fi rs t tRNA–AA i s bound a t the P-s i te, a nd the AUG s ta rt codon i s found a nd correctl y a l i gned As s embl y of thi s compl ex rel i es on the energy obta i ned from GTP Fol l owi ng the forma ti on of the mRNA–fi rs t tRNA–AA–ri bos ome compl ex, a s econd tRNA wi th i ts s peci fi c, bound AA bi nds to the A-s i te A pepti de bond i s formed between the two AAs a nd the ri bos ome moves down the mRNA (a proces s tha t uti l i zes ATP energy), the P-s i te tRNA i s rel ea s ed, a nd the proces s repea ts i ts el f unti l the end of the protei n i s rea ched Macrolides and the Machinery of Protein Synthesis: The cl a s s of drugs ca l l ed ma crol i des i ncl udes the a nti bi oti cs azithromycin, clarithromycin, erythromycin, a nd roxithromycin (us ed for ma ny res pi tory, uri na ry, a nd s oft-ti s s ue i nfecti ons ), a nd the i mmunos uppres s a nt drugs tacrolimus a nd sirolimus (us ed a fter orga n tra ns pl a nts to reduce orga n rejecti on) Thes e medi ca ti ons bl ock the movement of the ri bos ome a l ong the mRNA mol ecul e Ma crol i des ta ke a dva nta ge of the di fferent 50S ri bos oma l s ubuni t found i n ba cteri a a nd not a ffect the huma n 60S s ubuni t Ma crol i des a l s o tend to concentra te i n whi te bl ood cel l s a nd a re, therefore, conveni entl y tra ns ported to the s peci fi c s i tes of i nfecti on As a res ul t, ma crol i des s el ecti vel y a nd effi ci entl y trea t ba cteri a l i nfecti ons wi thout rm to the pa ti ent Ma ny other cl a s s es of a nti bi oti cs ta ke a dva nta ge of the di fferences i n huma n a nd ba cteri a l protei n tra ns l a ti on for thei r s el ecti ve a cti ons POSTTRANSLATIONAL TRAFFICKING/ MODIFICATION Inherent i n the proces s of protei n s ynthes i s /tra ns l a ti on i s the producti on of a s tri ng of AAs , the pri ma ry protei n s tructure, whi ch mus t fol d i nto the correct s econda ry, terti a ry, a nd qua terna ry s tructures to produce a functi oni ng fi na l protei n a nd/ or protei n compl ex (Cha pter 1) Al though s ome s ma l l er protei ns a re a bl e to s i mpl y fol d a s tra ns l a ti on occurs a nd the AA s equence i s genera ted, mos t of the l a rger a nd/or more compl ex protei ns requi re s peci a l i zed protei ns , known a s chaperones Thes e cha perones a s s i s t i n the res ul ti ng fol di ng a nd unfol di ng of s i ngl e, s equence protei ns (i e., s econda ry a nd terti a ry s tructures ) a nd the a s s embl y of mul ti pl e protei ns (qua terna ry s tructure) Some cha perone protei ns a re known a s “heat shock” proteins beca us e they a re s ometi mes preferenti a l l y uti l i zed to s ta bi l i ze protei n fol di ng a t ti mes of cel l ul a r s tres s es s uch a s a n i ncrea s e i n tempera ture In fa ct, a ma jor rol e of cha perones i s to tempora ri l y s ta bi l i ze the newl y s ynthes i zed AA cha i n, es peci a l l y i n a cytopl a s m a l rea dy fi l l ed wi th other protei ns , s o i t does not ndoml y a ggrega te i nto a nonfuncti ona l s tructure Other cha perones a re di rectl y i nvol ved i n the a ctua l fol di ng, di s s oci a ti ng from thei r a s s oci a ted protei n a fter the fi na l s tructure i s a chi eved Sti l l other cha perone protei ns a re i nvol ved i n s ome membra ne tra ns port a nd even the brea kdown of certa i n protei ns Beca us e of thei r cl os e a s s oci a ti on wi th protei n tra ns l a ti on, cha perones a re often found i n or nea r the ER Protein trafficking or targeting di rects a protei n ma de for a pa rti cul a r l oca ti on (e.g., nucl eus , cytopl a s m, membra nes , orga nel l es , or extra cel l ul a r) to i ts correct des ti na ti on Thi s proces s rel i es on signal sequences norma l l y conta i ned i n the fi rs t 20–30 AAs of the protei n Excepti ons i ncl ude protei ns bound for the nucl eus , whi ch ve s i gna l s throughout thei r enti re s equence, s ome peroxi s ome-bound protei ns wi th a s i gna l s equence i n the l a s t three AAs , a nd mi tochondri a l protei ns , whi ch ve two s i gna l s equences to di rect them to ei ther the mi tochondri a l ma tri x or the i ntermembra ne s pa ce In a ddi ti on, protei n s ynthes i s for cytopl a s mi c-, nucl eus -, a nd mi tochondri a -bound protei ns us ua l l y ta kes pl a ce on free ribosomes, wherea s extra cel l ul a r-, peroxi s ome-, a nd membra ne-bound protei ns a re us ua l l y s ynthes i zed on ERbound ribosomes Acces s ory protei ns ca l l ed sequence recognition particles (SRPs) a nd SRP docking protein a l s o hel p to di rect protei ns ta rgeted for s ecreti on/ peroxi s ome/membra nes to the ER a nd then the Gol gi a ppa tus for further s orti ng a nd routi ng The fi na l s tep i n the s ynthes i s of ma ny protei ns i s post-translational modification, the a ddi ti on or remova l of AAs (e.g., s i gna l s equence a nd i ni ti a ti on methi oni ne), ca rbohydra tes (e.g., s peci fi c ca rbohydra te s equences for gl ycoprotei ns /gl ycos a mi nogl yca ns ), or chemi ca l modi fi ca ti ons (e.g., a ddi ti on of l i pi ds , phos pha te, hydroxyl or methyl groups , a nd/ or cys tei ne–cys tei ne di s ul fi de bondi ng) Thes e cha nges us ua l l y i nvol ve extra cel l ul a r or membra ne-bound protei ns a nd, thus , genera l l y occur i n the ER a nd/or Gol gi a ppa tus Proenzymes (Cha pter 5) ca n a l s o be converted to thei r a cti ve form a t thi s ti me Protein Folding, Chaperones, and Mad Cow Disease: Mad cow disease/Bovine spongioform encephalopathy a nd i ts huma n equi va l ent Creutzfeldt–Jakob disease res ul t from i nfecti ous , mi s fol ded protei ns known a s prions (protei na ceous a nd infecti ous vi ri ons) Al though current res ea rch i s s ti l l ongoi ng a nd i s often very controvers i a l , pri ons a re fel t to i nfect thei r hos t a s a norma l l y fol ded protei n, whi ch then repl i ca tes a nd mi s fol ds i nto a ti ghtl y pa cked s tructure of β-s heets , referred to a s a n “a myl oi d fol d.” Thes e protei ns a ggrega te i nto s tructures known a s a myl oi d pl a ques , whi ch crea te “hol es ” i n the norma l bra i n ti s s ue a nd a res ul ti ng “s pongi oform” a ppea nce tha t i s typi ca l of the di s ea s e (s ee pi cture bel ow) Pri ons a ffect the bra i n/nervous ti s s ue l ea di ng to detri menta l a nd fa ta l neurol ogi ca l s ymptoms , i ncl udi ng dementi a , memory/s peech/movement/ba l a nce probl ems , ma rked pers ona l i ty cha nges , l l uci na ti ons , a nd s ei zures Some res ea rchers a re l ooki ng i nto the pos s i bl e rol e of cha perone protei ns i n the preventi on a nd/or trea tment of thi s di s ea s e Courtes y of Dr Denni s K Burns , Depa rtment of Pa thol ogy, Uni vers i ty of Texa s Southwes tern Medi ca l Center CONTROL OF GENE EXPRESSION The a bi l i ty of the body to control the expres s i on of genes a nd thei r res ul ti ng mRNAs a nd protei ns a l l ows the s el ecti ve i ni ti a ti on a nd ces s a ti on of the va ri ous bi ol ogi ca l rea cti ons tha t a l l ow l i fe Beca us e cons erva ti on of res ources i s i mporta nt, mos t regul a ti on occurs a t the l evel of gene tra ns cri pti on, a l though tra ns l a ti ona l control a s wel l a s pos ttra ns l a ti ona l a cti va ti on vi a protei n modi fi ca ti ons a l s o pl a ys a n i mporta nt pa rt i n the overa l l regul a ti on Tra ns cri pti ona l control (DNA → RNA) rel i es on promoter regi ons of DNA, us ua l l y, but not a l wa ys , l oca ted cl os e to the s ta rti ng poi nt of the tra ns cri pti on Thes e promoter regi ons a l l ow bi ndi ng of the RNA pol ymera s e a nd regul a tory transcription factor a nd enhancer protei ns DNA s equences tha t a ppea r i n s evera l di fferent promoter regi ons ve been i denti fi ed, s uch a s the TATA box, a n ei ght ba s e-pa i r s equence often excl us i vel y cons i s ti ng of a deni ne a nd thymi ne nucl eoti des Ma ny tra ns cri pti on fa ctors a l s o s re cons erved s econda ry a nd terti a ry protei n s tructures tha t a l l ow them to bi nd to pa rti cul a r pa rts of the DNA s equence; exa mpl es a re s hown i n Ta bl e 9-1) The bi ndi ng of di fferent tra ns cri pti on fa ctors a nd/ or enha ncers to thes e s equences a re es s enti a l for tra ns cri pti on a nd ca n i ncrea s e or decrea s e the tra ns cri pti on of a s peci fi c gene Steroid hormones (Cha pter 3) a re s peci fi c type of tra ns cri pti on fa ctors tha t bi nd often to uni que receptors (cytopl a s mi c or nucl ea r) Thes e s teroi d receptors s ubs equentl y bi nd to s peci fi c DNA s equences ca l l ed steroid response elements for s teroi d a cti va ti on of pa rti cul a r genes Steroi d receptors a l wa ys conta i n a n a rea for s teroi d bi ndi ng, a modi fi ed zi nc fi nger s tructure for DNA bi ndi ng, a s equence tha t a cti va tes tra ns cri pti on, a nd a n a rea tha t a l l ows receptor di meri za ti on Exa mpl es of s teroi ds a nd thei r a cti on wi l l be covered i n Secti on III TABLE 9-1 Exa mpl es of Some Common DNA Bi ndi ng Moti fs Iron Response Element (IRE): IRE i s a s peci fi c s pa n of a pproxi ma tel y 25–30 nucl eoti des found i n the mRNA for protei ns s uch a s ferritin (res pons i bl e for control l ed i ron s tora ge) a nd transferrin (res pons i bl e for i ron tra ns port) Thes e nucl eoti des bi nd to form a s econda ry i rpi n s tructure, whi ch ca n then bi nd protei ns i nvol ved i n regul a ti on of i ron concentra ti on i n the huma n body Duri ng ti mes of l ow i ron concentra ti on, thes e protei ns bi nd to the IRE of ferri ti n a nd decrea s e i ts tra ns l a ti on to i ncrea s e the a va i l a bl e i ron by decrea s i ng i ts s tora ge Thes e s a me protei ns bi nd to res pons e el ements found i n tra ns ferri n, whi ch s ta bi l i zes the mRNA l ea di ng to i ncrea s ed tra ns l a ti on a nd, therefore, i ncrea s ed i ron a cqui s i ti on IREs , therefore, a l l ow regul a ti on a t the RNA l evel of concentra ti ons of free a nd s tored i ron Gene expres s i on i s a l s o control l ed by the revers i bl e a cetyl a ti on of hi s tone, l ys i ne AA res i dues i n nucl eos omes , ca rri ed out by s peci fi c enzymes known a s histone acetyl transferases (HATs) a nd histone deacetylases The a ddi ti on of a cetyl groups a l l ows a cces s of RNA pol ymera s es to the DNA, wherea s the remova l of the a cetyl groups bl ocks thi s a cces s Some tra ns cri pti on fa ctors or thei r a s s oci a ted protei ns a ctua l l y conta i n HAT a cti vi ty to a l l ow them a cces s to thei r ta rget genes In a s i mi l a r wa y, the a ddi ti on of methyl groups to cytos i ne nucl eoti de res i dues us ua l l y res ul ts i n decrea s ed tra ns cri pti ona l a cti vi ty, a nd the remova l of the methyl group i s us ua l l y requi red for expres s i on of tha t gene Fi na l l y, s evera l a l terna ti ve forms of gene expres s i on a re a l s o s een In s ome i ns ta nces , promoters onl y occur i n pa rti cul a r ti s s ue or cel l types Al terna ti ve s pl i ci ng/ remova l /rea nnea l i ng ca n a l s o occur, a ffecti ng mRNA mol ecul es tha t conta i n i ntrons tha t crea te s evera l di fferent rel a ted mRNAs / protei ns wi th di fferi ng regul a ti on (up to 30% of huma n genes ma y be a ffected by thi s proces s ) Dea cti va ti on of one a l l el e of a gene or even a n enti re chromos ome ca n a l s o occur a s i s s een by the i na cti va ti on of one of the X chromos omes i n fema l es duri ng i ni ti a l embryo devel opment MUTATIONS AND REPAIR MECHANISMS Acci denta l cha nges or “mutations” i n DNA or RNA s equence (Fi gure 9-6) a re es ti ma ted to occur a t a n a pproxi ma te te of 1000–1,000,000 per cel l per da y i n the huma n genome, a nd every new cel l i s bel i eved to conta i n a pproxi ma tel y 120 new muta ti ons One ki nd of muta ti on i s point mutation, whi ch i ncl udes two di fferent types (Fi gure 9-6B): transition occurs when a s i ngl e puri ne nucl eoti de i s cha nged to a di fferent puri ne (A ↔ G) or a pyri mi di ne nucl eoti de i s cha nged to a di fferent pyri mi di ne nucl eoti de [C ↔ T(U)] a nd transversion occurs when the ori enta ti on of a s i ngl e puri ne a nd pyri mi di ne nucl eoti de i s revers ed [A/G ↔ C/T(U)] Poi nt muta ti ons ca n be further cl a s s i fi ed a s silent (when the s a me AA i s coded), mis-sense (when a di fferent AA i s coded), neutral (when a n AA cha nge occurs but does not a ffect the protei n’s s tructure or functi on), or nonsense (when a s top codon res ul ts , termi na ti ng tra ns l a ti on a nd s horteni ng the res ul ti ng protei n) Insertion a nd deletion muta ti ons i nvol ve more tha n one nucl eoti de a nd ca n not onl y cha nge the tra ns l a ted protei n, but, i f not occurri ng i n mul ti pl es of three nucl eoti des , ca n a l s o cha nge the enti re rea di ng of the mRNA s equence (frameshift muta ti on) Chemi ca l -, di a ti on-, a nd even vi l -ca us ed muta ti ons ca n a l s o ca us e s i ngl e- or doubl e-strand breaks a nd/or nucl eoti de–nucl eoti de or nucl eoti de–protei n cros s -l i nki ng A common exa mpl e of cros s -l i nki ng occurs between a dja cent thymi di ne di mers whos e puri ne ba s es ca n form a cycl obuta ne ri ng when expos ed to ul tra vi ol et l i ght (Fi gure 9-6A–C) Figure 9-6 A-C DNA Mutations Overvi ew of muta ti ons a nd s ome of thei r cl i ni ca l i mpl i ca ti ons (A a nd B) a nd exa mpl e thymi di ne di mer (C) See text for further di s cus s i on DNA, deoxyri bonucl ei c a ci d [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] Al though s ome of thes e muta ti ons a re benefi ci a l , offeri ng res i s ta nce to di s ea s e or i mproved s tructure a nd/or functi on, they ca n often l ea d to di s ea s e a nd/or dea th of the cel l or orga ni s m The huma n body s , therefore, devel oped a va ri ety of repa i r mecha ni s ms to a ttempt to res tore the a l tered nucl eoti de s equence In the ca s e of s i ngl e-nucl eoti de muta ti ons , pa rti cul a r endonuclease enzymes s ens e a nd remove (excision) the i ncorrect ba s e a nd the correct nucl eoti de i s repl a ced by a pol ymera s e a nd l i ga s e A pa rti cul a r exa mpl e i s the endonucl ea s e s peci fi c for the repa i r of thymi ne di mers Stra nd brea ks a re repa i red by l i ga s es or, when compl ex, by exci s i on a nd s ubs equent retra ns l a ti on/l i ga ti on Cel l cycl e check poi nts (s ee bel ow) a l s o offer the body the cha nce to veri fy the a ccura cy of the DNA s equence pri or to commi tment to cel l repl i ca ti on a nd di vi s i on Thymidine Dimer Repair and Xeroderma Pigmentosum: Al though a rel a ti vel y uncommon di s order Xeroderma pigmentosa i s a di rect exa mpl e of how a n a utos oma l reces s i ve muta ti on i n the enzyme(s ) requi red for the repa i r of thymi di ne di mers ca n l ea d to a di s ea s e The l os s of thi s i mporta nt repa i r mecha ni s m res ul ts i n di s ea s es s uch a s basal cell carcinoma, squamous cell carcinoma, a nd malignant melanoma—a l l a s a res ul t of unrepa i red, ul tra vi ol et l i ght da ma ge The onl y trea tment for a ffected i ndi vi dua l s i s reduci ng the expos ure to s unl i ght a nd s upporti ve ca re, a l though mos t pa ti ents di e by the a ge of 20 yea rs REGULATION OF CELL GROWTH AND DIFFERENTIATION Cell cycle i s the ordered pa thwa y underta ken by a l l ma mma l i a n cel l s , whi ch defi nes not onl y ti mes of both cel l di vi s i on a nd repl i ca ti on, but a l s o thos e ti mes of cel l growth a nd functi ona l a cti vi ti es The cel l cycl e i s di vi ded i nto G1 (gap 1), S (synthesis), G2 (gap 2/interphase), a nd M (mitosis) pha s es Cel l s ca n a l s o enter a G0 (“resting”) pha s e The progres s i on through the cel l cycl e depends on a va ri ety of protei ns , whi ch i ns ure tha t a cel l i s rea dy for the next cel l cycl e pha s e (“checkpoi nts ”) Thes e protei ns i ncl ude two types , the cyclins a nd the cyclin-dependent kinase (CDKs), whi ch joi n i n di fferent heterodi mer combi na ti ons tha t regul a te va ri ous pa rts of the cel l cycl e The cycl i n component of thi s protei n compl ex regul a tes the functi on of the phos phoryl a ti on a cti vi ty of the bound CDK Di fferent concentra ti ons of cycl i ns duri ng the cel l cycl e, a s determi ned by regul a ti on of thei r protei n s ynthes i s i n res pons e to va ri ous mol ecul a r s i gna l s , l ea d to a cti va ti on or i nhi bi ti on of a CDK An overvi ew of the cel l cycl e a nd the rol e of cycl i ns a nd CDKs a re s hown i n Ta bl e 9-2 a nd Fi gure 9-7 TABLE 9-2 Overvi ew of the Cel l Cycl e Figure 9-7 Overview of Cell Cycle Control Revi ew of va ri ous s i gna l s tha t regul a te progres s i on through the cel l cycl e Checkpoi nts i ncl ude G –S a nd G –M tra ns i ti on poi nts where DNA da ma ge i s detected a nd repa i red, S-pha s e where compl eti on of repl i ca ti on i s a s s es s ed, a nd M-pha s e where the i ntegri ty of the s pi ndl e a ppa tus i s veri fi ed Cycl i ns A, D, E, CDK2, a nd CDK4 a nd the protei n regul a tors p16, p 27, a nd p53, a s wel l a s DNA i rra di a ti on da ma ge a nd extra cel l ul a r s i gna l s pl a y rol es a s i l l us tra ted Tra ns formi ng growth fa ctor-β a l s o i ncrea s es p27 i nhi bi tory a cti vi ty (not s hown) CDK, cycl i n-dependent ki na s e; DNA, deoxyri bonucl ei c a ci d [Ada pted wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] Microtubules in the Cell Cycle and Cancer Treatment Strategies: The growth of mi crotubul es duri ng G a nd thei r s ubs equent brea kdown duri ng M pha s es of the cel l cycl e ve l ed to va ryi ng s tra tegi es i n the trea tment of ca ncers One s uch ca ncer a gent i s vincristine, whi ch bi nds to tubul i n protei n a nd bl ocks mi crotubul e pol ymeri za ti on, s toppi ng mi tos i s a t meta pha s e Vi ncri s ti ne i s us ed i n non-Hodgkin’s lymphoma, Wilm’s tumor, a nd acute lymphoblastic leukemia trea tments a mong others Taxol i s a nother i mporta nt ca ncer trea tment medi ca ti on obta i ned from the Pa ci fi c yew tree a nd i s us ed for pa ti ents s ufferi ng from ca ncers of the brea s t, l ung, ova ri es , hea d a nd neck, a nd for Ka pos i ’s s a rcoma Ta xol works by s ta bi l i zi ng mi crotubul es , thereby i nhi bi ti ng the progres s i on of ca ncer cel l s undergoi ng s i s ter chroma ti d s epa ti on Vi ncri s ti ne a nd ta xol a l s o a ffect a pa ti ent’s hea l thy cel l s , but to a l es s er extent tha n the much fa s ter repl i ca ti ng a nd di vi di ng ca ncer cel l s Va ri ous i nhi bi tors ca n s top the cel l cycl e by i na cti va ti ng the cycl i n–CDK heterodi mer compl ex When DNA da ma ge i s pres ent, the tumor s uppres s or protei n p53 s ens es the probl em a nd a cti va tes the i nhi bi tor p21, whi ch bl ocks the cycl i n D–CDK4 compl ex a nd, s ubs equentl y, the G to S tra ns i ti on The i nhi bi tors p16 a nd p27, the l a tter a cti va ted by the growth i nhi bi tor tra ns formi ng growth fa ctor-β (not s hown i n fi gure), ca n a l s o i nhi bi t the cel l cycl e by i nhi bi ti ng the cycl i n D–CDK4 or cycl i n E–CDK2 compl ex, res pecti vel y The overa l l control of the cel l cycl e by cycl i ns a nd CDKs i s s hown i n Fi gure 9-7 REVIEW QUESTIONS Wha t a re Wha t a re Wha t a re Wha t a re the the the the ba s i c s tructura l components of the nucl eus a nd thei r rol es ? key events i nvol ved i n DNA repl i ca ti on a nd the rol e of rel eva nt protei ns a nd enzymes ? key events i nvol ved i n tra ns cri pti on a nd the rol e of rel eva nt protei ns a nd enzymes ? key events i nvol ved i n protei n s ynthes i s i ncl udi ng the rol es of mRNA, tRNA, a nd a cces s ory protei ns ? Wha t i s the rol e of cha perones ? Wha t i s the s i gni fi ca nce of protei n tra ffi cki ng? Wha t a re the key a s pects i n the control of gene expres s i on? Wha t a re the va ri ous types of muta ti ons a nd how repa i r mecha ni s ms rel a te to thes e muta ti ons ? Wha t a re the va ri ous pha s es of the cel l cycl e a nd thei r functi ons ? SECTION II INTEGRATED USMLE-STYLE QUESTIONS AND ANSWERS QUESTIONS II-1 A previ ous l y norma l 2-month-ol d fema l e pres ents wi th ji ttery s pel l s s evera l hours a fter mea l s She s l ow bl ood gl ucos e Phys i ca l exa m revea l s a l i ver edge cm bel ow the ri ght cos ta l ma rgi n Percus s i on of the ri ght ches t a nd a bdomen confi rms hepa tomega l y The i nfa nt i ncrea s es her bl ood gl ucos e a fter brea s tfeedi ng but i t i s not ma i nta i ned a t norma l l evel s upon fa s ti ng Whi ch of the fol l owi ng i s the mos t l i kel y di a gnos i s of thi s pa ti ent? A Fructos emi a wi th i na bi l i ty to l i bera te s ucros e from gl ucos e B Ga l a ctos emi a wi th i na bi l i ty to convert l a ctos e to gl ucos e C Gl ycogen s tora ge di s ea s e D Growth hormone defi ci ency wi th i na bi l i ty to ma i nta i n gl ucos e E Intes ti na l ma l a bs orpti on of l a ctos e II-2 A wel l , 2-yea r-ol d gi rl contra cted a vi l i l l nes s a t da y ca re wi th vomi ti ng, di a rrhea , a nd progres s i ve l etha rgy She pres ents to the cl i ni c wi th di s ori enta ti on, a ba rel y rous a bl e s ens ori um, cra cked l i ps , s unken eyes , l a ck of tea rs , fl a cci d s ki n wi th “tenti ng” wea k pul s e wi th l ow bl ood pres s ure, a nd i ncrea s ed deep tendon refl exes La bora tory tes ts s how l ow bl ood gl ucos e, norma l el ectrol ytes , el eva ted l i ver enzymes , a nd (on ches t X-ra y) a di l a ted hea rt Uri na l ys i s revea l s no i nfecti on a nd no ketones The chi l d i s hos pi ta l i zed a nd s ta bi l i zed wi th 10% gl ucos e i nfus i on Admi s s i on l a bora tori es s how el eva ted medi um-cha i n fa tty a cyl ca rni ti nes i n bl ood a nd 6–8 ca rbon di ca rboxyl i c a ci ds i n the uri ne Whi ch of the fol l owi ng a bnorma l i ti es i s the mos t l i kel y di a gnos i s i n thi s chi l d? A Ca rni ti ne defi ci ency B Defect of medi um-cha i n coenzyme A dehydrogena s e C Defect of medi um-cha i n fa tty a cyl s yntheta s e D Mi tochondri a l defect i n fa tty a ci d tra ns port E Mi tochondri a l defect i n the el ectron tra ns port cha i n II-3 Whi ch of the fol l owi ng i s the correct order of the fol l owi ng s teps i n protei n s ynthes i s ? A pepti de bond i s formed The s ma l l ri bos oma l s ubuni t i s l oa ded wi th i ni ti a ti on fa ctors , mes s enger ri bonucl ei c a ci d (mRNA), a nd i ni ti a ti on a mi noa cyl –tra ns fer RNA (tRNA) The i nta ct ri bos ome s l i des forwa rd three ba s es to rea d a new codon The pri med s ma l l ri bos oma l s ubuni t bi nds wi th the l a rge ri bos oma l s ubuni t El onga ti on fa ctors del i ver a mi noa cyl –tRNA to bi nd to the A s i te A 1, 2, 5, 4, B 2, 3, 4, 5, C 2, 4, 5, 1, D 3, 2, 4, 5, E 4, 5, 1, 2, II-4 A mi ddl e-Ea s tern fa mi l y pres ents for eva l ua ti on beca us e thei r i nfa nt s on di ed i n the nurs ery wi th s evere hemol ys i s a nd ja undi ce The coupl e d two pri or fema l e i nfa nts who a re a l i ve a nd wel l , a nd the wi fe rel a tes tha t s he l os t a brother i n i nfa ncy wi th s evere hemol ys i s i nduced a fter a vi l i nfecti on The phys i ci a n s us pects gl ucos e-6-phos pha te dehydrogena s e defi ci ency, i mpl yi ng defecti ve s ynthes i s of whi ch of the fol l owi ng compounds ? A Deoxyri bos e a nd ni coti na mi de a deni ne di nucl eoti de phos pha te (NADP) B Gl ucos e a nd l a cta te C La ctos e a nd NADPH D Ri bos e a nd NADPH E Sucros e a nd ni coti na mi de a deni ne di nucl eoti de II-5 Whi ch of the fol l owi ng i s a n i mporta nt i ntermedi a te i n the bi os ynthes i s of unes teri fi ed fa tty a ci ds ? A Ca rni ti ne B Chol es terol C Fa tty a cyl -coenzyme A (CoA) D Gl ucos e E Ma l onyl -CoA II-6 Severa l di s orders , s uch a s one form of α1 -a nti tryps i n defi ci ency, ca n res ul t from mi s ta rgeti ng of protei ns i nto the wrong cel l ul a r compa rtments New protei ns des ti ned for s ecreti on a re s ynthes i zed i n whi ch of the fol l owi ng? A Free pol ys omes B Gol gi a ppa tus C Nucl eus D Rough endopl a s mi c reti cul um E Smooth endopl a s mi c reti cul um II-7 Chi l dren wi th urea cycl e di s orders pres ent wi th el eva ted s erum a mmoni a a nd cons equent neurol ogi c s ymptoms i ncl udi ng a l tered res pi ti on, l etha rgy, a nd coma Severa l a mi no a ci ds a re i ntermedi a tes of the urea cycl e, vi ng s i de a mmoni a groups tha t joi n wi th free ca rbon di oxi de (CO2 ) a nd a mmoni a to produce net excreti on of a mmoni a a s urea (NH CONH ) Whi ch of the fol l owi ng a mi no a ci ds s a n a mmoni a group i n i ts s i de cha i n a nd i s thus l i kel y to be a n i ntermedi a te of the urea cycl e? A Argi ni ne B As pa rta te C Gl uta ma te D Methi oni ne E Phenyl a l a ni ne II-8 Chol era toxi n ca us es ma s s i ve a nd often fa ta l di a rrhea by ca us i ng the conti nua l s ynthes i s of cycl i c a denos i ne monophos pha te (cAMP) Whi ch of the fol l owi ng mecha ni s ms woul d a ccount for thi s effect? A Acti va ti on of G i protei n B Irrevers i bl y a cti va ti on of a denyl yl cycl a s e C Locki ng of G s protei n i nto a n i na cti ve form D Preventi on of gua nos i ne tri phos pha te (GTP) from i ntera cti ng wi th G q protei n E Ra pi d hydrol ys i s of G protei n GTP to gua nos i ne di phos pha te (GDP) II-9 Whi ch of the fol l owi ng events occur duri ng the forma ti on of phos phoenol pyruva te from pyruva te duri ng gl uconeogenes i s ? A Acetyl -CoA i s uti l i zed B Adenos i ne tri phos pha te (ATP) i s genera ted C CO2 i s requi red D GTP i s genera ted E Inorga ni c phos pha te i s cons umed II-10 Regul a ti on of whi ch of the fol l owi ng enzymes i s mos t i mporta nt i n control l i ng l i pogenes i s ? A Acetyl -CoA ca rboxyl a s e B Acyl -CoA s yntheta s e C Ca rni ti ne–a cyl ca rni ti ne tra ns l oca s e D Ca rni ti ne–pa l mi toyl tra ns fera s e E Fa tty a ci d s yntha s e II-11 The s equence of the templ a te deoxyri bonucl ei c a ci d (DNA) s tra nd i s 5′-GATATCCATTAGTGAC-3′ Wha t i s the s equence of the RNA produced? A 5′-CAGUGAUUACCUAUAG-3′ B 5′-CTATAGGTAATCACTG-3′ C 5′-CUAUAGGUAAUCACUG-3′ D 5′-GTCACTAATGGATATC-3′ E 5′-GUCACUAAUGGAUAUC-3′ II-12 Whi ch of the fol l owi ng i s a n enzyme tha t i s a cti va ted by hydrol ys i s of a proenzyme form? A Hepa ri n B Kera ti n C La cta s e D Peps i n E Phenyl a l a ni ne hydroxyl a s e II-13 Whi ch of the fol l owi ng i s a n a ccura te des cri pti on of s i gna l tra ns ducti on i n res pons e to a pepti de hormone? A Ca l ci um a cti va ti on of ca l modul i n-dependent ki na s e B Di a cyl gl ycerol (DAG) ca us i ng a n i ncrea s e of i ntra cel l ul a r Ca 2+ C Inos i tol tri s phos pha te (IP3 ) bi ndi ng to a nd a cti va ti ng protei n ki na s e B D Phos phol i pa s e A2 ca ta l yzi ng the cl ea va ge of membra ne phos phol i pi ds to rel ea s e DAG E Rel ea s e of pota s s i um i ons from the endopl a s mi c reti cul um II-14 Whi ch of the fol l owi ng i s a n energy-requi ri ng s tep of gl ycol ys i s ? A Hexoki na s e B Phos phoenol pyruva te ca rboxyki na s e C Phos phogl ycera te ki na s e D Pyruva te ca rboxyl a s e E Pyruva te ki na s e (PK) II-15 Whi ch of the fol l owi ng proces s es genera tes the mos t ATP? A Ci tri c a ci d cycl e B Fa tty a ci d oxi da ti on C Gl ycogenol ys i s D Gl ycol ys i s E Pentos e phos pha te pa thwa y II-16 Whi ch of the fol l owi ng s ta tements a ccura tel y des cri bes fea tures of ri bos omes ? A An i ntegra l pa rt of tra ns cri pti on B Bound together s o ti ghtl y they ca nnot di s s oci a te under phys i ol ogi c condi ti ons C Compos ed of RNA, DNA, a nd protei n D Compos ed of three s ubuni ts of unequa l s i ze E Found both free i n the cytopl a s m a nd bound to membra nes II-17 Chi l dren wi th cys ti nos i s ve growth del a y, photos ens i ti vi ty wi th crys ta l s i n the l ens of thei r eyes , a nd progres s i ve rena l fa i l ure beca us e of a ccumul a ti on of cys ti ne i n cel l ul a r l ys os omes The defect i nvol ves a s peci fi c l ys os oma l membra ne receptor tha t fa ci l i ta tes cys ti ne egres s , a nd a n effecti ve thera py s been found us i ng ora l cys tea mi ne, a compound s i mi l a r i n s tructure to cys ti ne Thi s thera py refl ects the genera l pri nci pl e tha t competi ti ve i nhi bi tors typi ca l l y res embl e the s tructure of whi ch of the fol l owi ng? A An a l l os teri c regul a tor of enzyme/receptor a cti vi ty B Enzyme or receptor protei n C Enzyme rea cti on products D Subs tra tes or l i ga nds tha t bi nd the enzyme/receptor E The cofa ctor II-18 Whi ch of the fol l owi ng ki na s es pl a ys a rol e i n s i gna l tra ns ducti on for growth hormone, l epti n, a nd prol a cti n? A Adenyl a te ki na s e B Ja nus ki na s e C Mi togen-a cti va ted protei n (MAP) ki na s e D Protei n ki na s e A E Pyruva te ki na s e (PK) II-19 A 2-month-ol d boy i s brought to the emergency depa rtment i n a coma a fter s l eepi ng through the ni ght a nd fa i l i ng to a wa ken i n the morni ng He i s gi ven i ntra venous gl ucos e a nd a wa kens Serum l evel s of pyruva te, l a cta te, a nd a l a ni ne a re el eva ted, wherea s a s pa rti c a ci d l evel s a re reduced A mus cl e bi ops y s hows no a bnorma l i ti es , a nd vi ta mi n s uppl ementa ti on i s i neffecti ve Whi ch of the fol l owi ng i s the mos t l i kel y di a gnos i s i n thi s pa ti ent? A Is oci tra te dehydrogena s e defi ci ency B Phos phofructoki na s e (PFK) defi ci ency C Pyruva te ca rboxyl a s e defi ci ency D Pyruva te dehydrogena s e (PDH) compl ex defi ci ency E Pyruva te ki na s e defi ci ency II-20 Whi ch of the fol l owi ng bes t expl a i ns why s ta ti n thera py i s effecti ve for i ndi vi dua l s wi th hyperchol es terol emi a ? A Bi nd to l ow-dens i ty l i poprotei n (LDL) receptor, di s pl a ci ng chol es terol a nd i nhi bi ti ng chol es terol s ynthes i s B Inhi bi t 3-hydroxy-3-methyl gl uta ryl (HMG)-CoA reducta s e, a key regul a tor of chol es terol s ynthes i s C Inhi bi t HMG-CoA s yntha s e, key s tep for s ynthes i s of meva l ona te tha t i nhi bi ts fa tty a ci d s ynthes i s D Sti mul a te s ynthes i s of trans-uns a tura ted fa tty a ci ds E Sti mul a te thi ol a s e, thus ma ki ng more ma l onyl -CoA for i nhi bi ti on of the tri ca rboxyl i c a ci d cycl e II-21 GTP i s requi red by whi ch of the fol l owi ng s teps i n protei n s ynthes i s ? A Ami noa cyl –tRNA s yntheta s e a cti va ti on of a mi no a ci ds B Atta chment of mRNA to ri bos omes C Atta chment of ri bos omes to endopl a s mi c reti cul um D Atta chment of s i gna l recogni ti on protei n to ri bos omes E Tra ns l oca ti on of tRNA–na s cent protei n compl ex from A to P s i tes II-22 Inheri ted defi ci ency of the enzyme methyl ma l onyl -CoA (MMA-CoA) muta s e ca us es s erum a nd uri ne a ccumul a ti on of methyl ma l oni c a ci d Recogni ti on tha t perni ci ous a nemi a (due to defi ci ency of vi ta mi n B 12 ) ca n i nvol ve a ccumul a ti on of methyl ma l oni c a ci d l ed to s ucces s ful trea tment of s ome pa ti ents wi th MMA-CoA muta s e defi ci ency us i ng exces s B 12 Studi es of puri fi ed MMA-CoA muta s e enzyme from norma l i ndi vi dua l s then s howed enha nced muta s e a cti vi ty when B 12 wa s a dded to the rea cti on mi xture Thes e fa cts a re bes t reconci l ed by whi ch of the fol l owi ng rol es for Vi ta mi n B 12 ? A Cofa ctor for the MMA- CoA muta s e enzyme B Competi ti ve i nhi bi tor of MMA-CoA muta s e enzyme C Cova l entl y a tta ched group for the enzyme methyl ma l oni c a ci d-CoA muta s e D Feedba ck i nhi bi tor of MMA-CoA muta s e enzyme E Precurs or for methyl ma l oni c a ci d s ynthes i s II-23 Whi ch of the fol l owi ng s ta tements des cri bes where i ntegra l protei ns a re l oca ted? A As s oci a ted wi th DNA i n the nucl eus B In the l umen of the endopl a s mi c reti cul um C In the mi tochondri a l ma tri x D Mos tl y i n the bl ood E Predomi na ntl y wi thi n cel l membra nes II-24 A 7-yea r-ol d boy a rri ves a t the emergency depa rtment a s l eep i n hi s fa ther’s a rms The boy’s mother expl a i ns tha t the boy s pent the ni ght throwi ng up a nd experi enci ng s evere di a rrhea She i s concerned a bout the vomi ti ng a nd hi s i na bi l i ty to s ta y a wa ke Hi s tory i ndi ca tes the boy wa s hea l thy yes terda y, but beca me i l l a t di nnerti me a fter s pendi ng ti me pl a yi ng i n the ba s ement of thei r a pa rtment compl ex tha t a fternoon Further i nqui ry revea l s tha t a n extermi na tor d been hi red to ta ke ca re of a t probl em i n the a pa rtment He d us ed a poi s on (Rotenone) tha t bl ocks compl ex I i n the res pi tory cha i n of oxi da ti ve phos phoryl a ti on The boy i s pa l e a nd not cya noti c An a na l ys i s of thi s pa ti ent’s meta bol i s m woul d l i kel y i ndi ca te i mpa i red functi on of whi ch of the fol l owi ng enzymes ? A Gl ucos e-6-phos pha te dehydrogena s e B PFK C Pyruva te ca rboxyl a s e D PDH compl ex E Succi na te dehydrogena s e II-25 A pri me di a gnos ti c i ndi ca tor for the fi rs t pres enta ti on of di a betes mel l i tus type i s the pres ence of ketonuri a a nd s evere a ci dos i s ; the a ci dos i s produces exa ggera ted a ttempts a t res pi tory compens a ti on known a s Kus s ma ul brea thi ng Whi ch of the fol l owi ng a re “ketone bodi es ” tha t woul d be el eva ted i n s erum a nd uri ne from a chi l d wi th di a beti c ketoa ci dos i s ? A Acetone a nd etha nol B Fuma te a nd s ucci na te C Oxa l oa ceta te a nd pyruva te D Pyruva te a nd l a cta te E β-Hydroxybutyra te a nd a cetoa ceta te II-26 Ami noa cyl –tRNA s yntheta s es mus t be ca pa bl e of recogni zi ng whi ch of the fol l owi ng? A A s peci fi c a mi no a ci d a nd the 40S ri bos oma l s ubuni t B A s peci fi c a mi no a ci d a nd the 60S ri bos oma l s ubuni t C A s peci fi c ri bos oma l RNA (rRNA) a nd a s peci fi c a mi no a ci d D A s peci fi c tRNA a nd a s peci fi c a mi no a ci d E A s peci fi c tRNA a nd the 40S ri bos oma l s ubuni t II-27 Your pa ti ent pres ents wi th a defi ci ency of the enzyme tha t ca ta l yzes s ynthes i s of N-a cetyl gl uta mi c a ci d Whi ch of the fol l owi ng woul d be a cons equence of thi s defi ci ency i n the pa ti ent? A Decrea s ed di ges ti on of di eta ry protei n B Decrea s ed excreti on of uri c a ci d C Increa s ed a mi no a ci ds i n the bl ood D Increa s ed fa tty a ci ds i n the bl ood E Increa s ed gl ucos e i n the bl ood II-28 A pa ti ent pres ents wi th a nemi a a nd hyperbi l i rubi nemi a , refl ecti ng exces s i ve red bl ood cel l hemol ys i s Her s ymptoms i ncl ude fa ti gue, pa l l or, a nd ja undi ce Further eva l ua ti on s hows a defect i n s pectri n of her red bl ood cel l membra nes Whi ch of the fol l owi ng i s the l i kel y di a gnos i s ? A Es s enti a l fa tty a ci d (EFA) defi ci ency B Pyruva te ki na s e defi ci ency C Spherocytos i s D Ta rui ’s di s ea s e E Zel l weger s yndrome II-29 Whi ch of the fol l owi ng des cri bes the ma l a te s huttl e s ys tem? A Ca rri es NADH from the cytopl a s m di rectl y i nto the mi tochondri a l ma tri x B Genera tes three mol ecul es of ATP i n mi tochondri a per ea ch NADH from gl ycol ys i s C Moves NADH from the mi tochondri a to the cytopl a s m D Rel i es on ma l a te dehydrogena s e i n the i nner mi tochondri a l membra ne E Requi res reducti on of pyruva te to l a cta te for oxi di zi ng NADH II-30 Whi ch of the fol l owi ng i s the fi na l pri ma ry product of the fa tty a ci d s yntha s e rea cti on i n a di pos e ti s s ue? A Acetyl -CoA B Ma l onyl -CoA C Pa l mi ti c a ci d D Pa l mi toyl -CoA E Propi oni c a ci d II-31 A muta ti on tha t res ul ts i n a va l i ne repl a cement for gl uta mi c a ci d a t pos i ti on of the β-cha i n of hemogl obi n S hi nders norma l hemogl obi n functi on a nd res ul ts i n s i ckl e cel l a nemi a when the pa ti ent i s homozygous for thi s muta ti on Thi s i s a n exa mpl e of whi ch of the fol l owi ng types of muta ti on? A Del eti on B Fra mes hi ft C Ins erti on D Mi s s ens e E Nons ens e II-32 In l i ver, whi ch of the fol l owi ng i nhi bi tory effects i s the key regul a tory event tha t ens ures newl y s ynthes i zed pa l mi toyl -CoA i s not i mmedi a tel y oxi di zed? A Acyl -CoA s yntheta s e by ma l onyl -CoA B Ca rni ti ne–a cyl ca rni ti ne tra ns l oca s e (CAT) by pa l mi toyl -CoA C Ca rni ti ne–pa l mi toyl tra ns fera s e-I (CPT-I) by ma l onyl -CoA D CPT-I by pa l mi toyl ca rni ti ne E Ca rni ti ne–pa l mi toyl tra ns fera s e-II (CPT-II) by a cetyl -CoA II-33 Some pa ti ents wi th fa mi l i a l hyperchol es terol emi a produce a trunca ted form of the LDL receptor, termed the “Leba nes e” a l l el e, whi ch l a cks three of the fi ve doma i ns of the protei n a nd ca us es i t to be reta i ned i n the endopl a s mi c reti cul um Ana l ys i s of the muta nt gene i ndi ca ted tha t the s equence of the protei n wa s norma l up to the poi nt where i t termi na ted The geneti c cha nge tha t produced the muta nt LDL receptor i n thes e ca s es ca n be cl a s s i fi ed a s whi ch type of muta ti on? A Del eti on B Ins erti on C Mi s s ens e D Nons ens e E Si l ent ANSWERS II-1 The answer is C Importa nt ca rbohydra tes i ncl ude the di s a ccha ri des ma l tos e (gl ucos e–gl ucos e), s ucros e (gl ucos e–fructos e), a nd l a ctos e (ga l a ctos e–gl ucos e), a nd the gl ucos e pol ymers s ta rch (cerea l s , pota toes , a nd vegeta bl es ) a nd gl ycogen (a ni ma l ti s s ues ) Huma ns mus t convert di eta ry ca rbohydra tes to s i mpl e s uga rs (ma i nl y gl ucos e) for fuel , empl oyi ng i ntes ti na l enzymes a nd tra ns port s ys tems for enzyma ti c di ges ti on a nd a bs orpti on Si mpl e s uga rs (ga l a ctos e a nd fructos e) a re converted to gl ucos e by l i ver enzymes , a nd the gl ucos e i s revers i bl y s tored a s gl ycogen Enzyma ti c defi ci enci es i n i ntes ti na l di ges ti on (e.g., l a cta s e defi ci ency i n thos e wi th l a ctos e i ntol era nce), i n s uga r to gl ucos e convers i on (e.g., ga l a ctos e to gl ucos e convers i on i n ga l a ctos emi a ), or i n gl ycogenes i s /gl ycogenol ys i s (e.g., i n thos e gl ycogen s tora ge di s ea s es ) res ul t i n gl ucos e defi ci enci es (l ow bl ood gl ucos e or hypogl ycemi a ) wi th potenti a l a ccumul a ti on a nd toxi ci ty to hepa ti c ti s s ues The i nfa nt d been norma l duri ng brea s tfeedi ng, excl udi ng l ow gl ucos e due to growth hormone defi ci ency, a nd coul d rea di l y di ges t brea s t mi l k l a ctos e wi th a bs orpti on a nd convers i on to gl ucos e Low gl ucos e duri ng fa s ti ng a nd l i ver enl a rgement i mpl i es a l tered regul a ti on of gl ycogen s ynthes i s / rel ea s e due to one of the enzyme defi ci enci es wi thi n the ca tegory of gl ycogen s tora ge di s ea s e The hepa tomega l y res ul ts from the a ccumul a ti on of exces s i ve a mounts of gl ycogen (Ta bl e 6-1; Fi gure 6-9) II-2 The answer is B Fa tty a ci d oxi da ti on i s a ma jor s ource of energy a fter gl ycogen i s depl eted duri ng fa s ti ng Fa tty a ci ds a re fi rs t coupl ed wi th CoA, tra ns ferred for mi tochondri a l i mport a s a cyl ca rni ti nes , a nd degra ded i n s teps tha t remove two ca rbons The fa tty a cyl -CoA dehydrogena s es , enoyl hydra ta s es , hydroxya cyl -CoA dehydrogena s es , a nd thi ol a s es tha t ca rry out ea ch oxi da ti on s tep a re pres ent i n three groups wi th s peci fi ci ti es for very l ong-/l ong-, medi um-, a nd s hort-cha i n fa tty a cyl es ters As woul d be expected, defi ci enci es of l ong-cha i n oxi di zi ng enzymes ve more s evere cons equences tha n thos e for s hort cha i ns beca us e they i mpa i r ma ny more cycl es of two-ca rbon remova l Long-cha i n defi ci enci es ma y be l etha l i n the newborn peri od, wherea s medi um- or s hort-cha i n defi ci enci es ma y be undetected unti l a chi l d goes wi thout food for a prol onged ti me a nd mus t res ort to extens i ve fa tty a ci d oxi da ti on for energy Medi um-cha i n CoA dehydrogena s e defi ci ency ca n be fa ta l i f not recogni zed, a nd s ometi mes pres ents a s s udden unexpl a i ned dea th s yndrome (us ua l l y a t ol der a ges tha n s udden i nfa nt dea th s yndrome, tha t i s , mos tl y from res pi tory probl ems ) The defi ci t of a cetyl CoA from fa tty a ci d oxi da ti on i mpa cts gl uconeogenes i s wi th hypogl ycemi a , a nd the energy defi ci t l ea ds to hea rt, l i ver, a nd mus cl e di s ea s e tha t ma y be l etha l Unl i ke mos t ca us es of hypogl ycemi a , the i mpa i red fa tty a ci d oxi da ti on does not produce ketones (nonketoti c hypogl ycemi a ) Ca rni ti ne i s ti ed up a s medi um-cha i n a cyl ca rni ti nes a nd i s s econda ri l y defi ci ent i n fa tty a ci d oxi da ti on di s orders Ra re pri ma ry ca rni ti ne defi ci enci es [a s i n a ns wer opti on (e)] i mpa i r oxi da ti on of a l l fa tty a ci ds beca us e they ca nnot be i mported i nto mi tochondri a II-3 The answer is C Des pi te s ome di fferences , protei n s ynthes i s i n proka ryotes a nd euka ryotes i s qui te s i mi l a r The s ma l l ri bos oma l s ubuni t i s 30S i n proka ryotes a nd 40S i n euka ryotes The l a rge ri bos oma l s ubuni t i s 50S i n proka ryotes a nd 60S i n euka ryotes The i nta ct ri bos ome i s cons equentl y l a rger i n euka ryotes (80S) a nd s ma l l er i n proka ryotes (70S) At the s ta rt of tra ns l a ti on, i ni ti a ti on fa ctors , mRNA, a nd i ni ti a ti on a mi noa cyl –tRNA bi nd to the di s s oci a ted s ma l l ri bos oma l s ubuni t The i ni ti a ti on tRNA i n proka ryotes i s N-formyl methi oni ne i n proka ryotes a nd s i mpl y methi oni ne i n euka ryotes Onl y a fter the s ma l l ri bos oma l s ubuni t i s pri med wi th mRNA a nd i ni ti a ti on a mi noa cyl –tRNA does the l a rge ri bos oma l s ubuni t bi nd to i t Once thi s ppens , el onga ti on fa ctors bri ng the fi rs t a mi noa cyl – tRNA of the na s cent protei n to the A s i te Then pepti dyl tra ns fera s e forges a pepti de bond between the i ni ti a ti on a mi no a ci d a nd the fi rs t a mi no a ci d of the formi ng pepti de Now uncha rged i ni ti a ti on tRNA l ea ves the P s i te a nd the pepti dyl –tRNA from the A s i te moves to the now va ca nt P s i te wi th the two a mi no a ci ds a tta ched The ri bos ome a dva nces three ba s es to rea d the next codon a nd the proces s repea ts When the s top s i gna l i s rea ched a fter the compl ete pol ypepti de s been s ynthes i zed, rel ea s i ng fa ctors bi nd to the s top s i gna l , ca us i ng pepti dyl tra ns fera s e to hydro-l yze the bond tha t joi ns the pol ypepti de a t the A s i te to the tRNA Fa ctors prevent the rea s s oci a ti on of ri bos oma l s ubuni ts i n the a bs ence of new i ni ti a ti on compl ex (Fi gure 9-5) II-4 The answer is D Gl ucos e-6-phos pha te dehydrogena s e (G6PD) i s the fi rs t enzyme of the pentos e phos pha te pa thwa y, a s i de pa thwa y for gl ucos e meta bol i s m whos e pri ma ry purpos e i s to produce ri bos e a nd NADPH Its defi ci ency i s the mos t common enzymopa thy, a ffecti ng 400 mi l l i on peopl e worl dwi de It contra s ts wi th gl ycol ys i s i n i ts us e of NADP ther tha n NAD for oxi da ti on, i ts producti on of CO2 , i ts producti on of pentos es (ri bos e, ri bul os e, a nd xyl ul os e), a nd i ts producti on of the hi gh-energy compound (5-phos phori bos yl -1pyrophos pha te) ther tha n ATP Producti on of NADPH by the pentos e phos pha te pa thwa y i s cruci a l for reducti on of gl uta thi one, whi ch i n turn removes hydrogen peroxi de vi a gl uta thi one peroxi da s e Erythrocytes a re pa rti cul a rl y s us cepti bl e to hydrogen peroxi de a ccumul a ti on, whi ch oxi di zes red bl ood cel l membra nes a nd produces hemol ys i s Stres s es s uch a s newborn a djus tment, i nfecti on, or certa i n drugs ca n i ncrea s e red bl ood cel l hemol ys i s i n G6PD-defi ci ent i ndi vi dua l s , l ea di ng to s evere a nemi a , ja undi ce, pl uggi ng of rena l tubul es wi th rel ea s ed hemogl obi n, rena l fa i l ure, hea rt fa i l ure, a nd dea th Beca us e the l ocus encodi ng G6PD i s on the X chromos ome, the defi ci ency exhi bi ts X-l i nked reces s i ve i nheri ta nce wi th s evere a ffl i cti on i n ma l es a nd tra ns mi s s i on through a s ymptoma ti c fema l e ca rri ers Ri bos e-5-phos pha te produced by the pentos e phos pha te pa thwa y i s a n i mporta nt precurs or for ri bonucl eoti de s ynthes i s , but a l terna ti ve routes from fructos e-6-phos pha te a l l ow ri bos e s ynthes i s i n ti s s ues wi thout the compl ete cohort of pentos e phos pha te enzymes or wi th G6PD defi ci ency The compl ete pentos e phos pha te pa thwa y i s a cti ve i n l i ver, a di pos e ti s s ue, a drena l cortex, thyroi d, erythrocytes , tes ti s , a nd l a cta ti ng ma mma ry gl a nd Skel eta l mus cl e s onl y l ow l evel s of s ome of the enzymes of the pa thwa y but i s s ti l l a bl e to s ynthes i ze ri bos e through fructos e-6-phos pha te (Fi gure 6-7) II-5 The answer is E Acetyl -CoA i s ca rboxyl a ted to form ma l onyl -CoA through the a ddi ti on of CO2 by a cetyl -CoA ca rboxyl a s e The a cetyl - a nd ma l onyl -CoA groups a re a dded to s ul fydryl groups of fa tty a ci d s yntha s e mul ti enzyme compl ex (one on ea ch s ubuni t) through tra ns a cyl a ti on rea cti ons Condens a ti on forms a cetoa cetyl -S-enzyme on one s ubuni t a nd a free s ul fhydryl group of the other s ubuni t—a s equence of enzyme rea cti ons then converts the a cetoa cetyl -S-enzyme to a cyl (a cetyl ) enzyme A s econd round of two-ca rbon a ddi ti on begi ns , a s a nother ma l onyl -CoA res i due di s pl a ces the a cyl -S-enzyme to the other s ul fhydryl group, a nd then condens es to extend the a cyl group by two ca rbons Fa tty a ci d s ynthes i s then proceeds by s ucces s i ve a ddi ti on of ma l onyl -CoA res i dues wi th condens a ti on, ca us i ng the a cyl cha i n to grow by two ca rbons wi th ea ch cycl e (Fi gure 7-1) II-6 The answer is D Protei n s ynthes i s occurs i n the cytopl a s m, on groups of free ri bos omes ca l l ed pol ys omes , a nd on ri bos omes a s s oci a ted wi th membra nes , termed the rough endopl a s mi c reti cul um However, protei ns des ti ned for s ecreti on a re onl y s ynthes i zed on ri bos omes of the endopl a s mi c reti cul um a nd a re s ynthes i zed i n s uch a ma nner tha t they end up i ns i de the l umen of the endopl a s mi c reti cul um From there, the s ecretory protei ns a re pa cka ged i n ves i cl es The Gol gi a ppa tus i s i nvol ved i n the O-gl ycos yl a ti on a nd pa cka gi ng of ma cromol ecul es i nto membra nes for s ecreti on II-7 The answer is A Argi ni ne i s a n a mi no a ci d us ed i n protei ns tha t i s a l s o pa rt of the urea cycl e Ci trul l i ne a nd orni thi ne a re a mi no a ci ds not us ed i n protei ns but i mporta nt a s urea cycl e i ntermedi a tes As pa rta te i s condens ed wi th ci trul l i ne to form a rgi ni nos ucci na te i n the urea cycl e, a nd a cetyl gl uta ma te i s a cofa ctor i n the joi ni ng of CO2 wi th a mmoni a to form ca rba moyl phos pha te a t the begi nni ng of the urea cycl e (Fi gure 5-9A; a l s o s ee Ta bl e 1-1) II-8 The answer is B Chol era toxi n i s a n 87-kDa protei n produced by Vibrio cholerae, a Gra m nega ti ve ba cteri um The toxi n enters i ntes ti na l mucos a l cel l s by bi ndi ng to G M1 ga ngl i os i de It i ntera cts wi th G s protei n, whi ch s ti mul a tes a denyl cycl a s e By ADP-ri bos yl a ti on of G s , the toxi n bl ocks i ts ca pa ci ty to hydrol yze bound GTP to GDP Thus , the G protei n i s l ocked i n a n a cti ve form, a nd a denyl cycl a s e s ta ys i rrevers i bl y a cti va ted Under norma l condi ti ons , i na cti va ted G protei n conta i ns GDP, whi ch i s produced by a phos pha ta s e ca ta l yzi ng the hydrol ys i s of GTP to GDP When GDP i s s o bound to the G protei n, the a denyl cycl a s e i s i na cti ve Upon hormone bi ndi ng to the receptor, GTP i s excha nged for GDP a nd the G protei n i s i n a n a cti ve s ta te, a l l owi ng a denyl cycl a s e to produce cAMP Beca us e chol era toxi n prevents the hydrol ys i s of GTP to GDP, the a denyl cycl a s e rema i ns i n a n i rrevers i bl y a cti ve s ta te, conti nuous l y produci ng cAMP i n the i ntes ti na l mucos a l cel l s Thi s l ea ds to a ma s s i ve l os s of body fl ui d i nto the i ntes ti ne wi thi n a few hours (Fi gures 8-8, 8-9A; Ta bl e 8-2) II-9 The answer is C In the forma ti on of phos phoenol pyruva te duri ng gl uconeogenes i s , oxa l oa ceta te i s a n i ntermedi a te In the fi rs t s tep, ca ta l yzed by pyruva te ca rboxyl a s e, pyruva te i s ca rboxyl a ted wi th the uti l i za ti on of one hi gh-energy ATP phos pha te bond: Pyruva te + ATP + CO2 → Oxa l oa ceta te + ADP + Pi The pyruva te i n gl uconeogenes i s i s deri ved mos tl y from l a cta te a nd to a l a rge extent from a l a ni ne, a s wel l a s to a l es s er extent from s ome other a mi no a ci ds In the s econd s tep, ca ta l yzed by phos phoenol pyruva te ca rboxyki na s e, a hi gh-energy phos pha te bond of GTP dri ves the deca rboxyl a ti on of oxa l oa ceta te: Oxa l oa ceta te + GTP → Phos phoenol pyruva te + GDP + CO2 In contra s t to gl uconeogenes i s , the forma ti on of pyruva te from phos phoenol pyruva te duri ng gl ycol ys i s requi res onl y PK, a nd ATP i s produced (Fi gure 6-6) II-10 The answer is A Acetyl -CoA ca rboxyl a s e ca ta l yzes the fi rs t s tep of l i pogenes i s i n whi ch a cetyl -CoA i s l i nked to ma l onyl -CoA Thi s enzyme i s a cti va ted by ci tra te vi a pol ymeri za ti on a nd i na cti va ted by pa l mi toyl -CoA tha t ca us es depol ymeri za ti on to the monomeri c form The monomeri c form ca n undergo phos phoryl a ti on by epi nephri ne or gl uca gon to put i t i nto a n i na cti ve conforma ti on tha t ca nnot rea di l y pol ymeri ze Ins ul i n a cti va ti on of a phos pha ta s e revers es thi s cova l ent modi fi ca ti on Acetyl -CoA does not rea di l y cros s the mi tochondri a l membra ne Ins tea d, ci tra te tra ns l oca tes to the cytos ol where i t i s cl ea ved to a cetyl -CoA a nd oxa l oa ce-ta te by ATP-ci tra te l ya s e Ci tra te i ncrea s es i n the fed s ta te a nd i ndi ca tes a n a bunda nt s uppl y of a cetyl -CoA for l i pogenes i s Al though fa tty a ci d s yntha s e i s i n the pa thwa y, i ts regul a ti on i s fa r l es s i mporta nt Acyl -CoA s yntheta s e i s not i n the l i pogenes i s pa thwa y per s e beca us e i t a cti va tes fa tty a ci ds to the fa tty a cyl -CoA form rega rdl es s of thei r s ource Ca rni ti ne–a cyl ca rni ti ne tra ns l oca s e a nd ca rni ti ne–pa l mi toyl tra ns fera s e a re both i nvol ved i n the proces s of fa tty a ci d degra da ti on (Fi gure 7-1) II-11 The answer is E The templ a te s tra nd refers to the DNA s tra nd tha t i s tra ns cri bed i nto mRNA As for DNA, mRNA i s s ynthes i zed i n the 5′ to 3′ di recti on The templ a te s tra nd i s a l wa ys rea d i n the 3′ to 5′ di recti on The oppos i te DNA s tra nd i s known a s the codi ng s tra nd a nd s the s a me s equence a s the mRNA tra ns cri pt, except tha t U repl a ces T i n mRNA Choi ces b a nd d a re DNAs , a s they conta i n T i ns tea d of U II-12 The answer is D Peps i n i s s ecreted i n a proenzyme form (peps i nogen) i n the s toma ch Unl i ke the ma jori ty of proenzymes , i t i s not a cti va ted by protea s e hydrol ys i s but i ns tea d by s ponta neous a ci d hydrol ys i s Hydrochl ori c a ci d s ecreted by the s toma ch l i ni ng crea tes the a ci d envi ronment Al l the enzymes s ecreted by the pa ncrea s exi s t a l s o i n a proenzyme form i ncl udi ng tryps i nogen, chymotryps i nogen, proca rboxypepti da s e, a nd proel a s ta s e La cta s e a nd phenyl a l a ni ne hydroxyl a s e a re a cti ve i n thei r na ti ve forms Hepa ri n a nd kera ti n a re not enzymes II-13 The answer is A Hormone s i gna l tra ns ducti on ul ti ma tel y l ea ds to the a cti va ti on of a va ri ety of ki na s es Some of thes e depend on ca l ci um for thei r a cti vi ty One of thes e i nvol ves ca l ci um fi rs t a tta chi ng to a ca l ci um-bi ndi ng protei n, ca l modul i n Hence, thi s ki na s e i s referred to a s ca l modul i n-dependent ki na s e Protei n ki na s e C depends on i ntera cti on wi th both ca l ci um a nd DAG for i ts ful l a cti vi ty The DAG i s genera ted by the cl ea va ge of membra ne phos phol i pi ds ca ta l yzed by the enzyme phos phol i pa s e C The other product of thi s cl ea va ge i s IP3 tha t ca us es the rel ea s e of ca l ci um from the endopl a s mi c reti cul um where i t i s s tored (Fi gure 8-9B) II-14 The answer is A Hexoki na s e ca ta l yzes the convers i on of gl ucos e to gl ucos e-6-phos pha te i n the energy-requi ri ng fi rs t s tep of gl ycol ys i s ATP i s a l s o requi red i n the convers i on of fructos e-6-phos pha te to fructos e 1,6-bi s phos pha te by PFK ATP i s genera ted i n the convers i on of 1,3-bi s phos phogl ycera te to 3-phos phogl ycera te by phos phogl ycera te ki na s e a nd i n the convers i on of phos phoenol pyruva te to pyruva te by PK Both phos phoenol pyruva te ca rboxyki na s e a nd pyruva te ca rboxyl a s e a re energy-requi ri ng rea cti ons except tha t thes e occur i n the gl uconeogenes i s pa thwa y (Fi gure 6-2) II-15 The answer is B The pentos e phos pha te pa thwa y does not genera te a ny ATP but i ns tea d forms NADPH a nd ri bos e phos pha te Gl ycol ys i s produces a net two ATP mol ecul es per gl ucos e The ci tri c a ci d cycl e produces a net 12 ATP per turn of the cycl e Fa tty a ci d oxi da ti on of pa l mi ta te res ul ts i n a tota l of 129 ATP El ectron tra ns port i n the res pi tory cha i n res ul ts i n fi ve ATP for ea ch of the fi rs t s even a cetyl -CoA produced by the oxi da ti on of pa l mi ta te for a tota l of 35 ATP Ea ch of the ei ght a cetyl -CoA mol ecul es produced from pa l mi ta te res ul ts i n 12 ATP from the ci tri c a ci d cycl e for 96 tota l ATP Thi s gi ves a tota l of 131 ATP per pa l mi ta te oxi di zed, mi nus two ATP for the i ni ti a l a cti va ti on of pa l mi ta te for a gra nd tota l of 129 ATP per pa l mi ta te II-16 The answer is E The two s ubuni ts of ri bos omes a re compos ed of protei ns a nd rRNA Ri bos omes a re found i n the cytopl a s m, mi tochondri a , a nd bound to the endopl a s mi c reti cul um Tra ns cri pti on refers to the s ynthes i s of RNA compl ementa ry to a DNA templ a te a nd s nothi ng i mmedi a tel y to wi th ri bos omes II-17 The answer is D Li ga nd–receptor a nd s ubs tra te–enzyme rea cti ons a re both s a tura bl e proces s es wi th s i mi l a r dependence of rea cti on te on l i ga nd/s ubs tra te a nd receptor/s ubs tra te concentra ti ons Competi ti ve i nhi bi tors functi on by bi ndi ng to the s ubs tra te or l i ga ndbi ndi ng porti on of the a cti ve s i te a nd thereby bl ock a cces s to the s ubs tra te (Fi gure 5-3) Thus , the s tructures of competi ti ve i nhi bi tors tend to res embl e the s tructures of the s ubs tra te a nd a re often ca l l ed s ubs tra te or l i ga nd a na l ogs The effects of competi ti ve i nhi bi tors ca n be overcome by i s i ng the concentra ti on of the s ubs tra te The a mount the s ubs tra te mus t be i ncrea s ed i s dependent on the concentra ti on of the i nhi bi tor, the a ffi ni ty of the i nhi bi tor for the enzyme, a nd the a ffi ni ty of the s ubs tra te for the enzyme For membra ne receptors s uch a s tha t i n the l ys os ome tha t i s defecti ve i n cys ti nos i s , the rea cti on ma y be one of membra ne tra ns port s uch tha t i nterna l s ubs tra te/l i ga nd i s i n equi l i bri um wi th externa l s ubs tra te/l i ga nd Thus , l ys os ome–i nterna l cys ti ne i s s ubs tra te a nd l ys os oma l –externa l cys ti ne a product, i n a s ens e, s uch tha t l ys os oma l –externa l cys tea mi ne wi l l effecti vel y decrea s e externa l cys ti ne concentra ti on a nd l ea d to egres s of l ys os oma l cys ti ne through i ts defecti ve tra ns porter II-18 The answer is B Ja nus ki na s e i s a s ol ubl e receptor-a s s oci a ted tyros i ne ki na s e tha t hel ps ful l y a cti va te the receptor a fter bi ndi ng of the a ppropri a te hormone (e.g., growth hormone, prol a cti n, a nd l epti n) Adenyl a te ki na s e ca ta l yzes the revers i bl e i nterconvers i on of ADP ↔ ATP + AMP MAP ki na s e i s a s s oci a ted wi th tra ns ducti on of s i gna l s from growth fa ctors (e.g., epi derma l growth fa ctor, fi brobl a s t growth fa ctor, i ns ul i n-l i ke growth fa ctor, a nd other cytoki nes a nd growth fa ctors ) but not from growth hormone, whi ch i s more s i mi l a r to the meta bol i c hormones tha n the growth fa ctors Protei n ki na s e A i s i nvol ved i n tra ns duci ng s i gna l s from hormones tha t a ct vi a G s protei n (e.g., ca techol a mi nes , gl uca gon, fol l i cl e-s ti mul a ti ng hormone, pa thyroi d hormone, a mong others ) PK i s the l a s t enzyme of the gl ycol yti c pa thwa y (Fi gure 8-9C; Ta bl e 8-1) II-19 The answer is C Defi ci enci es of PK a nd PFK a re rul ed out by the el eva ted s erum l a cta te l evel s , a s thes e a re gl ycol yti c enzymes The coma i s a s s oci a ted wi th a fa s ti ng hypogl ycemi a , whi ch i s i ndi ca ti ve of pyruva te ca rboxyl a s e defi ci ency The el eva ted l a cta te a nd a l a ni ne occurs beca us e the pyruva te requi red for pyruva te ca rboxyl a s e i n gl uconeogenes i s i s deri ved mos tl y from l a cta te a nd to a l a rge extent a l s o from a l a ni ne, a s wel l a s to a l es s er extent s ome other a mi no a ci ds The reducti on of a s pa rti c a ci d l evel s occurs beca us e there i s reduced forma ti on of oxa l oa ceta te, the product of the pyruva te ca rboxyl a s e rea cti on a nd oxa l oa ceta te provi des the ca rbon ba ckbone for s ynthes i s of a s pa rta te (Fi gure 6-6) II-20 The answer is B Chol es terol i s formed i n fi ve s teps The fi rs t s tep, bi os ynthes i s of meva l ona te, i s ca ta l yzed by three enzymes —a cetyl -CoA thi ol a s e, HMG-CoA s yntha s e, a nd HMG-CoA reducta s e Thi ol a s e ca ta l yzes the condens a ti on of two mol ecul es of a cetyl -CoA to form a cetoa cetyl -CoA HMG-CoA s yntha s e ca ta l yzes the a ddi ti on of a thi rd mol ecul e of a cetyl -CoA to form HMG-CoA Thi s compound i s reduced to meva l ona te by HMG-CoA reducta s e Thi s enzyme i s the pri nci pa l regul a tory s tep i n the pa thwa y In the s econd s tep of chol es terol s ynthes i s , meva l ona te i s phos phoryl a ted a nd deca rboxyl a ted to produce i s opentyl di phos pha te Si x of thes e i s oprenoi d uni ts a re condens ed to form s qua l ene i n the thi rd s tep La nos terol i s formed i n the fourth s tep a nd i s s ubs equentl y converted to chol es terol (Fi gure 7-9) II-21 The answer is E Two mol ecul es of GTP a re us ed i n the forma ti on of ea ch pepti de bond on the ri bos ome In the el onga ti on cycl e, bi ndi ng of a mi noa cyl –tRNA del i vered by EF-2 to the A s i te requi res hydrol ys i s of one GTP Pepti de bond forma ti on then occurs Tra ns l oca ti on of the na s cent pepti de cha i n on tRNA to the P s i te requi res hydrol ys i s of a s econd GTP The a cti va ti on of a mi no a ci ds wi th a mi noa cyl –tRNA s yntheta s e requi res hydrol ys i s of ATP to AMP pl us PPi II-22 The answer is A Sma l l mol ecul es ma y be i ntegra l (cova l entl y a tta ched) pa rts of enzymes (pros theti c groups ) or cofa ctors tha t pa rti ci pa te i n enzyme–s ubs tra te i ntera cti on or convers i on Pros theti c groups ca nnot be di s s oci a ted from the enzyme by di l uti on a nd thus wi l l not be obvi ous components of the enzyme rea cti on when recons ti tuted i n the tes t tube Cofa ctors , s uch a s vi ta mi n B 12 for MMA-CoA muta s e, a s s oci a te revers i bl y wi th enzymes or s ubs tra tes a nd ca n be a dded i n vi tro to obta i n enha ncement of the ca ta l yzed rea cti on(s ) Competi ti ve or feedba ck i nhi bi tors i ntera ct a t s ubs tra te or a l l os teri c bi ndi ng s i tes of the enzyme, reduci ng effecti ve s ubs tra te concentra ti on a nd rea cti on te or converti ng the enzyme to a l es s a cti ve conforma ti on Vi ta mi n B 12 (cya nocoba l a mi n) i s a cofa ctor for MMA-CoA muta s e, a ccel era ti ng the convers i on of methyl ma l oni c a ci d to s ucci nyl -CoA through a cti vi ty of i ts coba l t group Certa i n defects i n MMA-CoA muta s e ca n be a mel i ora ted by i ntra mus cul a r B 12 i njecti ons s o tha t effecti ve B 12 concentra ti on a nd muta s e a cti vi ty a re i ncrea s ed II-23 The answer is E Membra ne protei ns a re cl a s s i fi ed a s extrinsic—predomi na ntl y on the i nner or the outer s urfa ce of the membra ne bi l a yer —a nd intrinsic—predomi na ntl y wi thi n the membra ne Intri ns i c protei ns a re us ua l l y compos ed of uncha rged, hydrophobi c a mi no a ci ds s o they ca n enter a nd s ta y i n the hydrophobi c envi ronment of the l i pi d bi l a yer Intri ns i c protei ns s erve s evera l functi ons i ncl udi ng cha nnel s , “ca rri er protei ns ”—tra ns porti ng mol ecul es through the membra ne a s a “ca rri er protei n” or a s a s i gna l i ng protei n—cha ngi ng a porti on of thei r i nterna l cytopl a s mi c s tructure i n res pons e to a s i gna l a t a n expos ed externa l pa rt of thei r s tructure to a cti va te a ddi ti ona l , cl os el y a s s oci a ted mol ecul es l ea di ng to a res ul ti ng functi on (e.g., turni ng on a gene) (Fi gure 8-4) II-24 The answer is D Thi s pa ti ent exhi bi ts s evera l s i gns of a cute compl ex I poi s oni ng Beca us e compl ex I of oxi da ti ve phos phoryl a ti on i s a t l ea s t pa rti a l l y i nhi bi ted by the chi l d cons umi ng thi s poi s on, the a bi l i ty of mi tochondri a l NADH to be oxi di zed i s i mpa i red Cons equentl y, NAD wi l l become l i mi ti ng for the PDH compl ex (Cha pter 6) Al though gl ycol ys i s a l s o requi res regenera ti ng NAD, enzymes i n thi s pa thwa y ca n opera te norma l l y beca us e NADH ca n be oxi di zed by the convers i on of pyruva te to l a cta te Gl ucos e-6-phos pha te dehydrogena s e i n the pentos e phos pha te pa thwa y wi l l be una ffected beca us e i t us es NADP not NAD (Fi gure 6-7A) Li kel y pyruva te ca rboxyl a s e wi l l ve i ncrea s ed a cti vi ty beca us e pyruva te not us ed by the PDH compl ex coul d be proces s ed to oxa l oa ceta te Fi na l l y, s ucci na te dehydrogena s e wi l l be una ffected beca us e i t produces FADH ther tha n NADH Hence, i t feeds el ectrons i nto compl ex II i ns tea d of compl ex I of the res pi tory cha i n II-25 The answer is E The ketone bodi es , β-hydroxybutyra te a nd a cetoa ceta te, a re s ynthes i zed i n l i ver mi tochondri a from a cetyl -CoA The l i ver produces ketone bodi es under condi ti ons of fa s ti ng a s s oci a ted wi th hi gh tes of fa tty a ci d oxi da ti on The i na bi l i ty to get gl ucos e i nto extra hepa ti c cel l s beca us e of i ns ul i n defi ci ency i n di a betes a l s o i ncrea s es fa tty a ci d oxi da ti on a nd ketogenes i s The a ci d groups of βhydroxybutyra te a nd a cetoa ceta te ca us e a ci dos i s a nd a n a ni on ga p (s um of s erum s odi um a nd pota s s i um mi nus the s um of chl ori de a nd bi ca rbona te) tha t i s grea ter tha n norma l (over 8–15) In the ca s e of di a betes , the “hi dden a ni ons ” tha t a dd to bi ca rbona te i n ba l a nci ng the ca ti ons ca n be recogni zed a s ketones through uri ne ketos ti x tes ti ng In meta bol i c di s orders s uch a s methyl ma l oni c a ci duri a or fa tty a ci d oxi da ti on defects , there a re s ca nty a bnorma l or no ketones (i f fa t ca nnot be oxi di zed) s o the hi dden a ni ons mus t be i denti fi ed by pl a s ma a cyl ca rni ti ne or uri ne orga ni c a ci d profi l es Acetone i s a ketone body produced i n di a betes tha t produces a n a ci d brea th duri ng ketoa ci dos i s (Fi gure 7-8A) II-26 The answer is D Ami noa cyl –tRNA s yntheta s es a re res pons i bl e for cha rgi ng a tRNA wi th the a ppropri a te a mi no a ci d for tra ns l a ti on Cha rgi ng a tRNA i s a two-s tep rea cti on In the fi rs t s tep, the enzyme forms a n a mi noa cyl –AMP enzyme compl ex i n a rea cti on tha t requi res one ATP In the s econd s tep, the a cti va ted a mi no a ci d i s a tta ched to the a ppropri a te tRNA a nd the enzyme a nd AMP a re rel ea s ed II-27 The answer is C N-a cetyl gl uta mi c a ci d i s a s ti mul a nt of the urea cycl e A pa ti ent wi th a defi ci ency of the enzyme tha t ca ta l yzes i ts forma ti on woul d ve a decrea s ed a cti vi ty of the urea cycl e Beca us e the ni trogen for the cycl e l a rgel y comes from a mi no a ci ds , the bl ood concentra ti on of a mi no a ci ds woul d i ncrea s e A decrea s ed a bi l i ty to proces s thes e a mi no a ci ds i n fa s ti ng/s ta rva ti on for gl ucos e producti on coul d potenti a l l y l ea d to decrea s ed bl ood gl ucos e Fa tty a ci d us a ge woul d be una ffected Al though the urea cycl e proces s es the ni trogen from a mi no a ci ds deri ved from di eta ry protei ns , thei r di ges ti on woul d be una ffected Ins tea d, bl ood a mi no a ci ds woul d a l s o ri s e a fter a mea l Al though s ecreti on of urea woul d be di mi ni s hed, uri c a ci d i s deri ved from the degra da ti on of puri ne nucl eoti des a nd tha t woul d be una ffected II-28 The answer is C Di s ea s es of red bl ood cel l s often res ul t from cha nges i n l i pi d compos i ti on a nd/or defects i n protei ns a s s oci a ted wi th the red bl ood cel l membra ne Spherocytos i s i s one s uch di s ea s e tha t res ul ts from defects i n s pectri n, a nkyri n, or other red bl ood cel l membra ne protei ns i mporta nt i n the s ta bi l i za ti on of the norma l bi conca ve s pe of red bl ood cel l s Thi s uni que s pe i s requi red for red bl ood cel l s to tra vel ea s i l y a nd unda ma ged through bl ood ves s el s As the na me i mpl i es , red bl ood cel l s a ppea r a s s pheres a nd pa ti ents often s uffer from l ow red bl ood cel l numbers (a nemi a ) due to the res ul ti ng des tructi on of the a ffected cel l s EFA defi ci ency, PK defi ci ency, a nd Ta rui ’s di s ea s e (PFK defi ci ency) ca n a l l l ea d to a nemi a for va ri ous rea s ons EFA defi ci ency ca us es i ns ta bi l i ty of the red bl ood cel l membra ne a nd hence hemol ys i s Both PK a nd PFK defi ci enci es res ul t i n i ns uffi ci ent energy producti on to ma i nta i n red bl ood cel l membra ne i ntegri ty Al though Zel l weger s yndrome ca n l ea d to ja undi ce, thi s i s rel a ted to di mi ni s hed l i ver functi on a nd not to red bl ood cel l i s s ues II-29 The answer is B The rol e of the ma l a te s huttl e i s , under a erobi c condi ti ons , to oxi di ze cytos ol i c NADH produced duri ng gl ycol ys i s to regenera te NAD to keep the gl ycol yti c pa thwa y opera ti ng Beca us e there i s no tra ns porter to ca rry NADH i nto the mi tochondri a , the el ectrons retri eved duri ng the cytos ol i c oxi da ti on of NADH mus t be ca rri ed a cros s the mi tochondri a l i nner membra ne to the ma tri x a s ma l a te In the ma tri x, ma l a te dehydrogena s e i n the ci tri c a ci d cycl e (Fi gure 6-4) us es the ma l a te to produce NADH tha t i s s ubs equentl y proces s ed vi a oxi da ti ve phos phoryl a ti on (Fi gure 6-5) to produce three mol ecul es of ATP Under a na erobi c condi ti ons , NAD i s regenera ted for gl ycol ys i s by the reducti on of pyruva te to l a cta te II-30 The answer is C The pri ma ry fa tty a ci d tha t i s s tored for energy purpos es i s the 16-ca rbon pa l mi ti c a ci d The product of fa tty a ci d s yntha s e i s a l wa ys the free (unes teri fi ed) fa tty a ci d In a s ubs equent s tep ca ta l yzed by a cyl -CoA s yntheta s e, the fa tty a ci d i s a cti va ted to i ts fa tty a cyl -CoA form Acetyl -CoA i s a precurs or for the s ynthes i s of fa tty a ci ds , a nd ma l onyl -CoA i s a n i ntermedi a te i n the proces s Propi oni c a ci d i s a product of odd-cha i n fa tty a ci d degra da ti on (Fi gure 7-2) II-31 The answer is D Mi s s ens e muta ti ons a re thos e i n whi ch a s i ngl e ba s e cha nge (poi nt muta ti on) res ul ts i n a codon tha t encodes for a di fferent a mi no a ci d res i due The effects of thes e types of muta ti ons ca n nge from very mi nor or even undetecta bl e to ma jor, dependi ng on the i mporta nce of the a l tered res i due to protei n fol di ng a nd functi on Nons ens e muta ti ons a re a l s o poi nt muta ti ons i n whi ch the a ffected codon i s a l tered to a s top (nons ens e) codon, res ul ti ng i n a trunca ted protei n Fra mes hi ft muta ti ons a re due to one or two ba s e pa i r i ns erti ons or del eti ons s uch tha t the rea di ng fra me i s a l tered Thes e muta ti ons genera l l y l ea d to trunca ted protei ns a s wel l beca us e, i n mos t protei n codi ng regi ons , the unus ed rea di ng fra mes conta i n numerous s top codons II-32 The answer is C Ma l onyl -CoA i s a uni que i ntermedi a te i n the pa thwa y for fa tty a ci d s ynthes i s a nd wi l l onl y be hi gh i n concentra ti on i n the cel l when fa tty a ci d s ynthes i s i s a cti ve When the cel l i s s ynthes i zi ng fa tty a ci ds , i t woul d be energeti ca l l y i l l ogi ca l to i mmedi a tel y oxi di ze the newl y formed fa tty a ci d The s i mpl es t mea ns of s l owi ng fa tty a ci d oxi da ti on i s to prevent the forma ti on of the fa tty a cyl ca rni ti ne deri va ti ve tha t mus t be formed for tra ns port of the fa tty a ci d i nto the mi tochondri a l ma tri x for oxi da ti on Inhi bi ti on of a cyl CoA s yntheta s e woul d not work beca us e the fa tty a cyl -CoA form mus t be produced for es teri fi ca ti on of gl ycerol to form tri a cyl gl ycerol for s tora ge Any control by pa l mi toyl -CoA woul d be i neffecti ve beca us e thi s i s the s ubs tra te for fa tty a ci d oxi da ti on Inhi bi ti on of CAT woul d be i l l ogi ca l beca us e the fa tty a cyl ca rni ti ne deri va ti ves woul d a ccumul a te a nd be us el es s for a ny other functi on Inhi bi ti on of ca rni ti ne– pa l mi toyl tra ns fera s e-I by pa l mi toyl ca rni ti ne woul d be feedba ck i nhi bi ti on by i ts product a nd woul d not be effecti ve Inhi bi ti on of ca rni ti ne–pa l mi toyl tra ns fera s e-II by a cetyl -CoA woul d ca us e a ccumul a ti on of pa l mi toyl ca rni ti ne i n the mi tochondri a l ma tri x, l ea di ng to a depl eti on of ca rni ti ne (Fi gure 7-3) II-33 The answer is D Producti on of a trunca ted protei n i ndi ca tes tha t a muta ti on s occurred, but thi s phenomenon ma y ve a ri s en from a fra mes hi ft muta ti on (i ns erti on or del eti on) or by a nons ens e muta ti on The mos t l i kel y pos s i bi l i ty i s a nons ens e muta ti on beca us e s equence a na l ys i s of the trunca ted protei n s howed tha t i t d norma l (wi l d-type) s equence Ins erti on a nd del eti on events often produce a s tretch of ga rbl ed or a bnorma l protei n s equence a t the C-termi na l end of the trunca ted protei n a ri s i ng from out-of-fra me tra ns l a ti on of the mRNA downs trea m of the muta ti on unti l a s top codon i s encountered ... nka ges wi th the ni trogen from the a mi no group, the centra l ca rbon from the a mi no a ci d, a nd the ca rbon from the ca rboxyl i c a ci d formi ng the protei n “ba ckbone.” The pri ma ry... s ys tem, wi thout the pri or wri tten permi s s i on of the publ i s her ISBN: 978-0-07 -16 3792-3 MHID: 0-07 -16 3792-3 The ma teri a l i n thi s eBook a l s o a ppea rs i n the pri nt vers i on... on thems el ves wi th ea ch other a nd wi th other s i mi l a r a rea s of the fol ded protei n to keep thei r hydrophobi c a rea s a wa y from a nd thei r hydrophi l i c a rea s expos ed to the