Biochemistry (Lippincott Illustrated Reviews Series), 6th edition

Lippincott Illustrated Reviews: Biochemistry
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De naturatio n o f pro te ins. P rote in de na tura tion re s ults in the unfolding a nd dis orga niza tion of a prote ins s e conda ry a nd te rtia ry s tructure s without the hydrolys is of pe ptide bonds. De na tura tion ma y, unde r ide a l conditions , be re ve rs ible , s uch tha t the prote in re folds into its origina l na tive s tructure whe n the de na turing a ge nt is re move d.

Howe ve r, mos t prote ins , once de na ture d, re ma in pe rma ne ntly dis orde re d. De na ture d prote ins a re ofte n ins oluble a nd pre cipita te from s olution. The informa tion ne e de d for corre ct prote in folding is conta ine d in the prima ry s tructure of the polype ptide. Howe ve r, mos t prote ins whe n de na ture d do not re s ume the ir na tive conforma tions e ve n unde r fa vora ble e nvironme nta l conditions. This is be ca us e , for ma ny prote ins , folding is a fa cilita te d proce s s tha t re quire s a s pe cia lize d group of prote ins , re fe rre d to a s mole cula r cha pe rone s , a nd a de nos ine triphos pha te hydrolys is.

The cha pe rone s , a ls o known a s he a t s hock prote ins Hs p , inte ra ct with a polype ptide a t va rious sta ge s during the folding proce s s. S ome cha pe rone s bind hydrophobic re gions of a n e xte nde d polype ptide a nd a re importa nt in ke e ping the prote in unfolde d until its s ynthe s is is comple te d for e xa mple , Hs p Othe rs form ca ge -like ma cromole cula r s tructure s compos e d of two s ta cke d rings.

The pa rtia lly folde d prote in e nte rs the ca ge , binds the ce ntra l ca vity through hydrophobic inte ra ctions , folds , a nd is re le a s e d for e xa mple , mitochondria l Hs p Howe ve r, othe rs ma y cons is t of two or more polype ptide cha ins tha t ma y be s tructura lly ide ntica l or tota lly unre la te d. The a rra nge me nt of the s e polype ptide s ubunits is ca lle d the qua te rna ry s tructure of the prote in. S ubunits a re he ld toge the r prima rily by non-. P rote in Mis folding cova le nt inte ra ctions for e xa mple , hydroge n bonds , ionic bonds , a nd hydrophobic inte ra ctions.

S ubunits ma y e ithe r function inde pe nde ntly of e a ch othe r or ma y work coope ra tive ly, a s in he moglobin, in which the binding of oxyge n to one s ubunit of the te tra me r incre a s e s the a ffinity of the othe r s ubunits for oxyge n s e e p. Is oforms a re prote ins tha t pe rform the s a me function but ha ve diffe re nt prima ry s tructure s.

The y ca n a ris e from diffe re nt ge ne s or from tis s ue -s pe cific proce s s ing of the product of a s ingle ge ne. B Prote in folding is a comple x proce s s tha t ca n s ome time s re s ult in imprope rly folde d mole cule s. Howe ve r, this qua lity control s ys te m is not pe rfe ct, a nd intra ce llula r or e xtra cellula r a ggre ga te s of mis folde d prote ins ca n a ccumula te , pa rticula rly a s individua ls a ge.

Amylo id dis e as e s Mis folding of prote ins ma y occur s ponta ne ous ly or be ca us e d by a muta tion in a pa rticula r ge ne , which the n produce s a n a lte re d prote in. In a ddition, s ome a ppa re ntly norma l prote ins ca n, a fte r a bnorma l prote olytic cle a va ge , ta ke on a unique conforma tiona l s ta te tha t le a ds to the forma tion of long, fibrilla r prote in a s s e mblie s cons is ting of -ple a te d s he e ts. Accumula tion of the s e ins oluble , sponta ne ous ly a ggre ga ting prote ins , ca lle d a myloids , ha s be e n implica te d in de ge ne ra tive dis e a s e s s uch a s P a rkins on a nd Huntington a nd pa rticula rly in the a ge -re la te d ne urode ge ne ra tive dis orde r, Alzhe ime r dis e a s e.

The domina nt compone nt of the a myloid pla que tha t a ccumula te s in Alzhe ime r dis e a s e is a myloid A , a n e xtra ce llula r pe ptide conta ining a mino a cid re s idue s. X-ra y crys ta llogra phy a nd infra re d s pe ctros copy de mons tra te a cha ra cte ris tic -ple a te d s he e t conforma tion in nonbra nching fibrils. This pe ptide , whe n a ggre ga te d in a -ple a te d s he e t configura tion, is ne urotoxic a nd is the ce ntra l pa thoge nic e ve nt le a ding to the cognitive impa irme nt cha ra cte ris tic of the dis e a s e.

The A pe ptide s a ggre ga te , ge ne ra ting the a myloid tha t is found in the bra in pa re nchyma a nd a round blood ve s s e ls. A s e cond biologic fa ctor involve d in the de ve lopme nt of Alzhe ime r dis e a s e is the a ccumula tion of ne urofibrilla ry ta ngle s ins ide ne urons. A ke y compone nt of the s e ta ngle d fibe rs is a n a bnorma l form hype rphos phoryla te d a nd ins oluble of the ta u prote in, which, in its he a lthy ve rs ion, he lps in the a s s e mbly of the microtubula r s tructure.

The de fe ctive a ppe a rs to block the a ctions of its norma l counte rpa rt. Inte rac tio n o f the infe c tio us PrP mo le c ule with a no rmal PrP c aus e s the no rmal fo rm to fo ld into the infe c tio us fo rm. The s e two mo le c ule s dis s o c iate and c o nve rt two additio nal no ninfe c tio us PrP mo le c ule s to the infe c tio us fo rm.

The prion prote in P rP ha s be e n s trongly implica ted a s the ca us a tive a ge nt of tra ns mis s ible s pongiform e nce pha lopa thie s TSEs , including Cre utzfe ldt-J a kob dis e a s e in huma ns , s cra pie in s he ep, a nd bovine spongiform e nce pha lopa thy in ca ttle popula rly ca lle d ma d cow dis e a s e. Afte r a n e xte ns ive s e rie s of purifica tion proce dure s , s cie ntis ts we re s urpris e d to find tha t the infe ctivity of the a ge nt ca us ing s cra pie in s he e p wa s a s s ocia te d with a s ingle prote in s pe cie s tha t wa s not comple xe d with de te cta ble nucle ic a cid.

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It is highly re s is ta nt to prote olytic de gra da tion a nd te nds to form ins oluble a ggre ga te s of fibrils , s imilar to the a myloid found in s ome othe r dis e a s e s of the bra in. No prima ry s tructure diffe re nce s or a lte rna te pos ttra ns la tiona l modifica tions ha ve be e n found be twe e n the norma l a nd the infe ctious forms of the prote in. The ke y to be coming infe ctious a ppare ntly lie s in cha nge s in the thre e -dime ns iona l conforma tion of P rP C. It ha s be e n obs e rve d tha t a numbe r of -he lice s pre s e nt in noninfe ctious P rP C a re re pla ce d by -s he e ts in the infe ctious form Figure 2.

It is presuma bly this conforma tiona l diffe re nce tha t confe rs re la tive re sis ta nce to prote olytic de gra da tion of infe ctious prions a nd pe rmits the m to be distinguis he d from the norma l P rP C in infe cte d tis s ue. The infe ctive a ge nt is , thus , a n a lte re d ve rs ion of a norma l prote in, which a cts a s a te mpla te for conve rting the norma l prote in to the pa thoge nic conforma tion. The TSEs a re inva ria bly fata l, a nd no tre a tme nt is curre ntly a va ila ble tha t ca n a lte r this outcome.

Ce ntra l to unde rs ta nding prote in s tructure is the conce pt of the native co nformation Figure 2. The unique three-dimensional structure of the native conformation is determined by its primary s tructure, that is, its amino acid sequence. Interactions between the amino acid side chains guide the folding of the polypeptide chain to form s econdary, tertiary, and sometimes quaternary structures, which cooperate in stabilizing the native conformation of the protein.

In addition, a s pe cia lize d group of prote ins na me d c hape ro ne s is re quire d for the proper folding of many species of proteins. Protein denaturation results in the unfolding and disorganization of the proteins structure, which are not accompanied by hydrolysis of peptide bonds. Denaturation may be reversible or, more commonly, irreversible.

Disease can occur when an apparently normal protein assumes a conformation that is cytotoxic, as in the case of Alzheimer disease and the trans mis s ible s pongiform encephalo pathie s TS Es , including Cre utzfe ldt-Jako b dis e as e. In Alzhe ime r dis eas e, normal proteins, after abnormal chemical processing, take on a unique conformational state that leads to the formation of neurotoxic amyloid peptide A assemblies consisting of -pleated sheets.

In TSEs, the infective agent is an altered version of a normal prion protein that acts as a template for converting normal protein to the pathogenic conformation. Secondary is regular arrangements contributes to of amino acids located near each other in primary structure. Te rtiary is the thre e contribute s to dime ns iona l s ha pe of the folde d cha in. Quate rnary is the a rra nge me nt may contribute to of polype ptide s ubunits in the prote in. Alzhe ime r dis e as e the mos t common ca us e of de me ntia in olde r a dults. P rote ins cons is ting of one polype ptide ha ve qua te rna ry s tructure tha t is s ta bilize d by cova le nt bonds.

The pe ptide bonds tha t link a mino a cids in a prote in mos t commonly occur in the cis configura tion. The de na tura tion of prote ins le a ds to irre ve rs ible los s of s e conda ry s tructura l e le me nts s uch a s the -he lix. The prima ry driving force for prote in folding is the hydrophobic e ffe ct. The mos t like ly cha nge in the prima ry s tructure of the muta nt prote in is : A. It ma y be found in typica l globula r prote ins.

It is s ta bilize d by inte rcha in hydroge n bonds. It ma y be found in s upe rs e conda ry s tructure s. His fa mily re porte d progre s s ive dis orie nta tion a nd me mory los s ove r the la s t 6 months. The re is no fa mily his tory of de me ntia. The pa tie nt wa s te ntative ly dia gnos e d with Alzhe ime r dis e a s e.

Which one of the following be s t de s cribe s Alzhe ime r dis e a s e? It re s ults from a ccumula tion of de na ture d prote ins tha t ha ve ra ndom conforma tions. It is a s s ocia te d with the a ccumula tion of a myloid pre curs or prote in. It is a s s ocia te d with the de pos ition of ne urotoxic a myloid pe ptide a ggre ga te s. It is a n e nvironme nta lly produce d dis e a s e not influe nce d by the ge ne tics of the individua l.

It is ca use d by the infe ctious -she e t form of a hostce ll prote in. The hydrophobic e ffe ct, or the te nde ncy of nonpola r e ntitie s to a s s ocia te in a pola r e nvironme nt, is the driving force of prote in folding. Qua te rna ry s tructure re quire s more tha n one polype ptide , a nd, whe n pre s e nt, it is s ta bilize d prima rily by noncova le nt bonds. The pe ptide bond is a lmos t a lwa ys tra ns.

Lippincott biochemistry 6th edition

The two cys te ine re s idue s pa rticipa ting in dis ulfide bond forma tion ma y be a gre a t dis ta nce a pa rt in the a mino a cid s e que nce of a polype ptide or on two s e pa ra te polype ptide s but a re brought into clos e proximity by the thre e -dime ns iona l folding of the polype ptide. De na tura tion ma y be re ve rs ible or irre ve rs ible.

P roline , be ca us e of its s e conda ry a mino group, is incompa tible with a n -he lix. Cha rge d a nd bra nche d bulky a mino a cids ma y dis rupt a n -he lix. The -she e t is sta bilize d by inte rcha in hydroge n bonds forme d be twe e n se pa ra te polype ptide cha ins a nd by intra cha in hydroge n bonds forme d be twe e n re gions of a s ingle polype ptide.

The -he lix, howe ve r, is s ta bilize d only by intra cha in hydroge n bonds. S ta te me nts A, B, D, a nd E a re true for both of the se s e conda ry structural e le me nts. The a ccumula te d a lte re d prote in occurs in a -ple a te d s he e t configura tion tha t is ne urotoxic. The a myloid tha t is de pos ite d in the bra in in Alzhe ime r dis e a s e is de rive d by prote olytic cle a va ge s from the la rge r a myloid pre curs or prote in, a s ingle tra ns me mbra ne prote in e xpre s s e d on the ce ll s urfa ce in the bra in a nd othe r tis s ue s.

The pre vious cha pte r de s cribe d the type s of s e conda ry a nd te rtia ry s tructure s tha t a re the bricks a nd morta r of prote in a rchite cture. By a rra nging the s e funda me nta l s tructura l e le me nts in diffe re nt combina tions , wide ly dive rs e prote ins ca n be cons tructe d tha t a re ca pa ble of va rious s pe cia lize d functions.

This cha pte r e xa mine s the re la tions hip be twe e n s tructure a nd function for the clinica lly importa nt globula r he me prote ins. Fibrous s tructura l prote ins a re dis cus s e d in Cha pte r 4. The role of the he me group is dicta te d by the e nvironme nt cre a te d by the thre e -dime ns iona l s tructure of the prote in. For e xa mple , the he me group of a cytochrome functions a s a n e le ctron ca rrie r tha t is a lte rna te ly oxidize d a nd re duce d s e e p.

In contra s t, the he me group of the e nzyme ca ta la s e is pa rt of the a ctive s ite of the e nzyme tha t ca ta lyze s the bre a kdown of hydroge n pe roxide s e e p. In he moglobin a nd myoglobin, the two mos t a bunda nt he me prote ins in huma ns , the he me group s e rve s to re ve rs ibly bind oxyge n. The iron is he ld in the ce nte r of the he me mole cule by bonds to the four nitroge ns of the porphyrin ring. In myoglobin a nd he moglobin, one of the s e pos itions is coordina te d to the s ide cha in of a his tidine re s idue of the globin mole cule , whe re a s the othe r pos ition is a va ila ble to bind oxyge n Figure 3.

B Iro n c an fo rm s ix bo nds : fo ur with po rphyrin nitro g e ns , plus two additio nal bo nds , o ne abo ve and o ne be lo w the planar po rphyrin ring. Fig ure 3.

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Biochemistry (Lippincott Illustrated Reviews Series) Sixth, North American Edition . by Ferrier PhD, Denise R. There is a newer edition of this item: Lippincott. Lippincott Illustrated Reviews Biochemistry/lahocybu.gar (Series editor lahocybu.ga) . Kanchan Kamila. Lippincott's Illustrated Reviews: Biochemistr Sixth Edition.

Mode l of myoglobin s howing he lice s A to H. S che ma tic dia gra m of the oxyge n-binding s ite of myoglobin. S truc ture and func tio n o f myo g lo bin Myoglobin, a he me prote in pre s e nt in he a rt a nd s ke le ta l mus cle , functions both a s a re s e rvoir for oxyge n a nd a s a n oxyge n ca rrie r tha t incre a s e s the ra te of tra ns port of oxyge n within the mus cle ce ll. This homology ma ke s myoglobin a us e ful mode l for inte rpre ting s ome of the more comple x prope rtie s of he moglobin. Lo c atio n o f po lar and no npo lar amino ac id re s idue s : The inte rior.

The y a re pa cke d clos e ly toge the r, forming a s tructure s ta bilize d by hydrophobic inte ra ctions be twe e n the s e clus te re d re s idue s s e e p. In contra s t, pola r a mino a cids a re loca te d a lmos t e xclus ive ly on the s urfa ce , whe re the y ca n form hydroge n bonds , both with e a ch othe r a nd with wa te r.

Binding o f the he me g ro up: The he me group of the myoglobin. Nota ble e xce ptions a re two his tidine re s idue s Figure 3.

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Blood obtaine d for analysis was brown colored. This re fle cts the fa ct tha t myoglobin re ve rs ibly binds a s ingle mole cule of oxyge n. De ficie ncy in die ta ry vita min C De ficie ncy of 1 -a ntitryps in De ficie ncy of prolyl hydroxyla s e De cre a s e d e la s ta s e a ctivity Incre a s e d colla ge na s e a ctivity. The y a re pa cke d clos e ly toge the r, forming a s tructure s ta bilize d by hydrophobic inte ra ctions be twe e n the s e clus te re d re s idue s s e e p. The polyme r tha t a ccumula te s in the live r ma y re s ult in cirrhos is s ca rring of the live r.

One , the proxima l his tidine F8 , binds dire ctly to the iron of he me. The s e cond, or dis ta l his tidine E7 , doe s not dire ctly inte ra ct with the he me group but he lps s ta bilize the binding of oxyge n to the fe rrous iron. The prote in, or globin, portion of myoglobin thus cre a te s a s pe cia l microe nvironme nt for the he me tha t pe rmits the re ve rs ible binding of one oxyge n mole cule oxyge na tion. The s imulta ne ous los s of e le ctrons by the fe rrous iron oxida tion to the fe rric form occurs only ra re ly. S tructure of he moglobin s howing the polype ptide ba ckbone.

S implifie d dra wing s howing the he lice s. S truc ture and func tio n o f he mo g lo bin He moglobin is found e xclus ive ly in re d blood ce lls RBC , whe re its ma in function is to tra ns port oxyge n O 2 from the lungs to the ca pilla rie s of the tis s ue s. He moglobin A, the ma jor he moglobin in a dults , is compos e d of four polype ptide cha ins two cha ins a nd two cha ins he ld toge the r by noncova le nt inte ra ctions Figure 3.

Ea ch cha in s ubunit ha s s tre tche s of -he lica l s tructure a nd a hydrophobic he me -binding pocke t s imila r to tha t de s cribe d for myoglobin. Howe ve r, the te tra me ric he moglobin mole cule is s tructura lly a nd functiona lly more comple x tha n myoglobin. Furthe rmore , the oxyge n-binding prope rtie s of he moglobin a re re gula te d by inte ra ction with a llos te ric e ffe ctors s e e p. Obta ining O 2 from the a tmos phe re s ole ly by diffus ion gre a tly limits the s ize of orga nis ms.

Circula tory s ys te ms ove rcome this , but tra ns port mole cule s s uch a s he moglobin a re a ls o re quire d be ca us e O 2 is only s lightly s oluble in a que ous s olutions s uch a s blood. The two polype ptide cha ins within e a ch dime r a re he ld tightly toge the r prima rily by hydrophobic inte ra ctions Figure 3. Multiple inte rcha in hydrophobic inte ra ctions form s trong a s s ocia tions be twe e n -s ubunits a nd -s ubunits in the dime rs. S tro ng inte rac tio ns , primarily hydro pho bic , be twe e n and c hains fo rm s table dime rs.

S che ma tic dia gra m s howing s tructura l cha nge s re s ulting from oxyge na tion a nd de oxyge na. The we a ke r inte ra ctions be twe e n the dime rs a llows the m to move with re s pe ct to one othe r. This move me nt re s ults in the two dime rs occupying diffe re nt re la tive pos itions in de oxyhe moglobin a s compa re d with oxyhe moglobin s e e Figure 3. Be ca use the iron is a ls o linke d to the proxima l his tidine F8 , the re is move me nt of the globin cha ins tha t a lte rs the inte rfa ce be twe e n the dime rs.

T fo rm: The de oxy form of he moglobin is ca lle d the T, or ta ut. In the T form, the two dime rs inte ra ct through a ne twork of ionic bonds a nd hydroge n bonds tha t cons tra in the move me nt of the polype ptide cha ins. The T conforma tion is the low-oxyge n-a ffinity form of he moglobin. R fo rm: The binding of O 2 to he moglobin ca us e s the rupture. This le a ds to a s tructure ca lle d the R, or re la xe d form s e e Figure 3. The R conforma tion is the high-oxyge na ffinity form of he moglobin.

Binding o f o xyg e n to myo g lo bin and he mo g lo bin Myoglobin ca n bind only one mole cule of O 2 , be ca us e it conta ins only one he me group. In contra s t, he moglobin ca n bind four O 2 mole cule s , one a t e a ch of its four he me groups. This gra ph illus tra te s tha t myoglobin ha s a highe r oxyge n a ffinity a t a ll pO 2 va lue s tha n doe s he moglobin.

The pa rtia l pre s s ure of oxyge n ne e de d to a chie ve ha lf-s a tura tion of the binding s ite s P 50 is a pproxima te ly 1 mm Hg for myoglobin a nd 26 mm Hg for he moglobin. The highe r the oxyge n a ffinity tha t is , the more tightly oxyge n binds , the lowe r the P Myo g lo bin: The oxyge n-dis s ocia tion curve for myoglobin ha s.

This re fle cts the fa ct tha t myoglobin re ve rs ibly binds a s ingle mole cule of oxyge n. The oxyg e n-dis s oc iation c urve for Hb is s te e pe s t at the oxyge n c onc e ntratio ns that oc c ur in the tis s ue s. This pe rmits o xyg e n de live ry to re s po nd to s mall c hange s in pO2. The e quilibrium is s hifte d to the right or to the le ft a s oxyge n is a dde d to or re move d from the s ys te m. Myoglobin, in turn, re le a s e s oxyge n within the mus cle ce ll in re s pons e to oxyge n de ma nd. Coope ra tive binding of oxyge n by the four s ubunits of he moglobin me a ns tha t the binding of a n oxyge n mole cule a t one he me group incre a s e s the oxyge n a ffinity of the re ma ining he me groups in the s a me he moglobin te tra me r Figure 3.

Although it is more difficult for the firs t oxyge n mole cule to bind to he moglobin, the s ubs e que nt binding of oxyge n occurs with high a ffinity, a s s hown by the s te e p upwa rd curve in the re gion ne a r mm Hg s e e Figure 3. Allo s te ric e ffe c ts The a bility of he moglobin to re ve rs ibly bind oxyge n is a ffe cte d by the pO 2 through he me he me inte ra ctions a s de s cribe d a bove , the pH of the e nvironme nt, the pa rtia l pre s s ure of ca rbon dioxide pCO 2 a nd the a va ila bility of 2,3-bis phos phoglyce ra te.

The s e a re colle ctive ly ca lle d a llos te ric othe r s ite e ffe ctors , be ca us e the ir inte ra ction a t one s ite on the he moglobin mole cule a ffe cts the binding of oxyge n to he me groups a t othe r s ite s on the mole cule. The ne t e ffe ct is tha t the a ffinity of he moglobin for the la s t oxyge n bound is a pproxima te ly time s gre a te r tha n its a ffinity for the firs t oxyge n bound. Globula r P rote ins a. Lo ading and unlo ading o xyg e n: The coope ra tive binding of. For e xa mple , in the lung, the conce ntra tion of oxyge n is high, a nd he moglobin be come s virtua lly s a tura te d or loa de d with oxyge n.

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In contra s t, in the pe riphe ra l tis s ue s , oxyhe moglobin re le a s e s or unloa ds much of its oxyge n for us e in the oxida tive me ta bolis m of the tis s ue s Figure 3. A mole cule with a hype rbolic oxyge n-dis s ocia tion curve , s uch a s myoglobin, could not a chie ve the s a me de gre e of oxyge n re le a s e within this ra nge of pa rtia l pre s s ure s of oxyge n. Ins te a d, it would ha ve ma ximum a ffinity for oxyge n throughout this oxyge n pre s s ure ra nge a nd, the re fore , would de live r no oxyge n to the tis s ue s.

Protons a re a llos te ric e ffe ctors of he moglobin. Both re s ult in a de cre a s e d oxyge n a ffinity of he moglobin a nd, the re fore , a s hift to the right in the oxyge n-dis s ocia tion curve Figure 3. This cha nge in oxyge n binding is ca lle d the Bohr e ffe ct. Conve rs e ly, ra is ing the pH or lowe ring the conce ntra tion of CO 2 re s ults in a gre a te r a ffinity for oxyge n, a s hift to the le ft in the oxyge n-dis s ocia tion curve , a nd s ta biliza tion of the R oxy form.

S o urc e o f the pro to ns that lo we r the pH: The conce ntra tion. This diffe re ntia l pH gra die nt tha t is , lungs ha ving a highe r pH a nd tis s ue s a lowe r pH fa vors the unloa ding of oxyge n in the pe riphe ra l tis s ue s a nd the loa ding of oxyge n in the lung. Thus , the oxyge n a ffinity of the he moglobin mole cule re s ponds to s ma ll s hifts in pH be twe e n the lungs a nd oxyge n-cons uming tis s ue s , ma king he moglobin a more e fficie nt tra ns porte r of oxyge n.

This e ffe ct is ca us e d by ioniza ble groups s uch a s s pe cific his tidine s ide cha ins that ha ve a highe r pKa in de oxyhe moglobin tha n in oxyhe moglobin. The re fore , a n increa s e in the conce ntra tion of protons re s ulting in a de cre a s e in pH ca us e s the s e groups to be come protona te d cha rge d a nd a ble to form ionic bonds s a lt bridge s. The s e bonds pre fe re ntia lly s ta bilize the de oxy form of he moglobin, producing a de cre a s e in oxyge n a ffinity. Bis phos phoglyce ra te 2,3-BP G is a n importa nt re gula tor of the binding of oxyge n to he moglobin.

It is the mos t a bunda nt orga nic phos pha te in the RBC, whe re its conce ntra tion is a pproxima te ly tha t of he moglobin. This pre fe re ntia l binding s ta bilize s the T conforma tion of de oxyhe moglobin. This pocke t contains several positive ly cha rge d amino acids that form ionic bonds with the ne ga tive ly cha rge d phos pha te groups of 2,3-BP G. S hift o f the o xyg e n-dis s o c iatio n c urve : He moglobin from. Howe ve r, a s s e e n in the RBC, the pre s e nce of 2,3-BP G s ignifica ntly re duce s the a ffinity of he moglobin for oxyge n, s hifting the oxyge n-dis s ocia tion curve to the right Figure 3.

This re duce d a ffinity e na ble s he moglobin to re le a s e oxyge n e fficie ntly a t the pa rtia l pre s s ure s found in the tis s ue s. Globula r P rote ins d. Intra ce llula r le ve ls of 2,3BP G a re a ls o e le va te d in chronic a ne mia , in which fe we r tha n norma l RBCs a re a va ila ble to s upply the bodys oxyge n ne e ds.

Ele va te d 2,3-BP G le ve ls lowe r the oxyge n a ffinity of he moglobin, pe rmitting gre a te r unloa ding of oxyge n in the ca pilla rie s of the tis s ue s s e e Figure 3. Howe ve r, s toring blood in the curre ntly a va ila ble me dia re s ults in a de cre a s e in 2,3-BP G. S tore d blood dis pla ys a n a bnorma lly high oxyge n a ffinity a nd fa ils to unloa d its bound oxyge n prope rly in the tis s ue s. He moglobin de ficie nt in 2,3-BP G thus a cts a s a n oxyge n tra p ra the r tha n a s a n oxyge n tra ns port s ys te m. Howe ve r, s e ve re ly ill pa tie nts ma y be compromis e d if tra ns fus e d with la rge qua ntitie s of s uch 2,3-BP Gs trippe d blood.

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Although the conte nt of 2,3-BP G wa s not gre a tly improve d in the longte rm by the s e cha nge s , a de nos ine triphos pha te production wa s incre a s e d a nd improve d RBC s urviva l. Howe ve r, s ome CO 2 is ca rrie d a s ca rba ma te bound to the N-te rmina l a mino groups of he moglobin forming ca rba minohe moglobin a s s hown in Figure 3. The binding of CO 2 s ta bilize s the T or de oxy form of he moglobin, re s ulting in a de cre a s e in its a ffinity for oxyge n s e e p.

In the lungs , CO 2 dis s ocia te s from the he moglobin a nd is re le a s e d in the bre a th. Whe n CO binds to one or more of the four he me s ite s , he moglobin s hifts to the R conforma tion, ca us ing the re ma ining he me s ite s to bind oxyge n with high a ffinity. This s hifts the oxyge n-dis s ocia tion curve to the le ft a nd cha nge s the norma l s igmoida l s ha pe towa rd a hype rbola. As a re s ult, the a ffe cte d he moglobin is una ble to re le a s e oxyge n to the tis s ue s Figure 3. Cons e que ntly, e ve n minute conce ntra tions of CO in the e nvironme nt ca n produce toxic conce ntra tions of ca rboxyhe moglobin in the blood.

For exa mple , incre a s e d le ve ls of CO a re found in the blood of toba cco s moke rs. CO toxicity a ppe a rs to re s ult from a. Globula r He me prote ins combina tion of tis s ue hypoxia a nd dire ct CO-me dia te d da ma ge a t the ce llula r le ve l. Mino r he mo g lo bins It is importa nt to re me mbe r tha t huma n he moglobin A HbA is jus t one me mbe r of a functiona lly a nd s tructura lly re la te d fa mily of prote ins , the he moglobins Figure 3. Ea ch of the s e oxyge n-ca rrying prote ins is a te tra me r, compos e d of two -globin or -like polype ptide s a nd two -globin or -like polype ptide s.

Ce rta in he moglobins , s uch a s HbF, a re norma lly s ynthe s ize d only during fe ta l de ve lopme nt, whe re a s othe rs , s uch a s HbA2 , a re s ynthe s ize d in the a dult, a lthough a t low le ve ls compa re d with HbA. The cha ins a re me mbe rs of the -globin ge ne fa mily s e e p. In the fifth we e k of ge s ta tion, the s ite of globin s ynthe s is s hifts , firs t to the live r a nd the n to the ma rrow, a nd the prima ry product is HbF.

HbA s ynthe s is s ta rts in the bone ma rrow a t a bout the e ighth month of pre gna ncy a nd gra dua lly re pla ce s HbF.

Lippincotts Illustrated Reviews Biochemistry: 6th Edition

Figure 3. The highe r oxyge n a ffinity of HbF fa cilita te s the tra ns fe r of oxyge n from the ma te rna l circula tion a cros s the pla ce nta to the RBC of the fe tus. Globula r P rote ins 2. He mo g lo bin A2 : HbA2 is a minor compone nt of norma l a dult. It is compos e d of two -globin cha ins a nd two -globin cha ins 2 2 ; s e e Figure 3. The mos t a bunda nt form of glycos yla te d he moglobin is HbA1c. It ha s glucos e re s idue s a tta che d pre domina ntly to the NH2 groups of the N-te rmina l va line s of the -globin cha ins Figure 3.

Incre a s e d a mounts of HbA1c a re found in RBC of pa tie nts with dia be te s me llitus , be ca us e the ir HbA ha s conta ct with highe r glucos e conce ntra tions during the da y life time of the s e ce lls. The none nzymic a ddition of a s uga r to a prote in is re fe rre d to a s glyca tion. The -ge ne clus te r on chromos ome 16 conta ins two ge ne s for the -globin cha ins. It a ls o conta ins the ge ne tha t is e xpre s s e d e a rly in de ve lopme nt a s a n -globin-like compone nt of e mbryonic he moblobin. Eac h c an pro vide -g lo bin c hains that c o mbine with -g lo bin c hains.

HbA 2 2. The re a re a n a dditiona l four -globin-like ge ne s : the ge ne which, like the ge ne , is e xpre s s e d e a rly in e mbryonic de ve lopme nt , two ge ne s G a nd A tha t a re e xpre s s e d in HbF , a nd the ge ne tha t code s for the globin cha in found in the minor a dult he moglobin HbA2. S te ps in g lo bin c hain s ynthe s is Expre s s ion of a globin ge ne be gins in the nucle us of RBC pre curs ors , whe re the DNA s e que nce e ncoding the ge ne is tra ns cribe d. The RNA produce d by tra ns cription is a ctua lly a pre curs or of the me s s e nge r RNA mRNA tha t is us e d a s a te mpla te for the s ynthe s is of a globin cha in.

Be fore it ca n s e rve this function, two noncoding s tre tche s of RNA introns mus t be re move d from the mRNA pre curs or s e que nce a nd the re ma ining thre e fra gme nts e xons joine d in a line a r ma nne r. The re s ulting ma ture mRNA e nte rs the cytos ol, whe re its ge ne tic informa tion is tra ns la te d, producing a globin cha in. A s umma ry of this proce s s is s hown in Figure 3. A more de ta ile d de s cription of ge ne e xpre s ion is pre s e nte d in Unit VI, p. The firs t thre e conditions re s ult from production of he moglobin with a n a lte re d a mino a cid s e que nce qua lita tive he moglobinopa thy , whe re a s the tha la s s e mia s a re ca us e d by de cre a s e d production of norma l he moglobin qua ntita tive he moglobinopa thy.

Description:

S ic kle c e ll ane mia he mo g lo bin S dis e as e S ickle ce ll a ne mia , the mos t common of the RBC s ickling dis e a s e s , is a ge ne tic dis orde r of the blood ca us e d by a s ingle nucle otide s ubs titution a point muta tion, s e e p. It is the mos t common inhe rite d blood dis orde r in the Unite d S ta te s , a ffe cting 50, Ame rica ns. It occurs prima rily in the Africa n Ame rica n popula tion, a ffe cting one of ne wborn Africa n Ame rica n infa nts in the Unite d S ta te s.

It occurs in individua ls who ha ve inhe rite d two muta nt ge ne s one from e a ch pa re nt tha t code for synthe s is of the cha ins of the globin mole cule s. S ickle ce ll a ne mia is cha ra cte rize d by life long e pis ode s of pa in cris e s ; chronic he molytic a ne mia with a s s ocia te d hype rbilirubine mia s e e p. Glo bin g e ne 5'. The re fore , during e le ctrophores is a t a lka line pH, HbS migra te s more s lowly towa rd the a node pos itive e le ctrode tha n doe s HbA Figure 3.

This a lte re d mobility of HbS is a re s ult of the a bs e nce of the ne ga tive ly cha rge d gluta ma te re s idues in the two cha ins , the re by re nde ring HbS le s s ne ga tive tha n HbA. S ic kling and tis s ue ano xia: The re pla ce me nt of the cha rge d glu-. HbC Fig ure 3. He te rozygote s , re pre s e nting 1 in 12 Africa n Ame rica ns , ha ve one norma l a nd one s ickle ce ll ge ne. The blood ce lls of s uch he te rozygote s conta in both HbS a nd HbA. The s e individua ls ha ve s ickle ce ll tra it.

The y us ua lly do not s how clinica l s ymptoms but ma y unde r conditions of e xtre me phys ica l e xe rtion with de hydra tion a nd ca n ha ve a norma l life s pa n. HbC Pos itions ns at the Ge l s tart of electro- He mo g lo bins are ne g ative ly phores iss c harg e d and mig rate to ward the ano de. At low oxygen te ns ion, de oxyhe moglobin S polyme rize s ins ide the RBC, forming a ne twork of ins oluble fibrous polyme rs tha t s tiffe n a nd dis tort the ce ll, producing rigid, mis s ha pe n RBC.

S uch s ickle d ce lls fre que ntly block the flow of blood in the na rrow ca pilla rie s. This inte rruption in the s upply of oxyge n le a ds to loca lize d a noxia oxyge n de priva tion in the tis s ue , ca us ing pa in a nd e ve ntua lly de a th infa rction of ce lls in the vicinity of the blocka ge. Compa re d to norma l RBC, s ickle d ce lls ha ve a de cre as e d a bility to de form a nd a n incre a s e d te nde ncy to a dhe re to ve ss e l wa lls a nd s o ha ve difficulty moving through s ma ll ve s s e ls, the re by ca us ing microva s cula r occlus ion.

Variable s that inc re as e s ic kling : The e xte nt of s ickling a nd,. Tre atme nt: The ra py involve s a de qua te hydra tion, a na lge s ics ,. Inte rmitte nt tra ns fus ions with pa cke d RBC re duce the ris k of s troke , but the be ne fits mus t be we ighe d a ga ins t the complica tions of tra ns fus ion, which include iron ove rloa d he mos ide ros is , bloodborne infe ctions , a nd immunologic complica tions. Hydroxyure a hydroxyca rba mide , a n a ntitumor drug, is the ra pe utica lly us e ful be ca us e it incre a s e s circula ting le ve ls of HbF,.

In the de o xyg e nate d s tate , HbS po lyme rize s into lo ng , ro pe -like fibe rs. Intrac e llular fibe rs o f HbS dis to rt the e rythro c yte. This le a ds to de cre a se d fre que ncy of pa inful cris e s a nd re duce s morta lity. For e xa mple , he te rozygote s for the s ickle ce ll ge ne a re les s s us ce ptible to the s e ve re ma la ria ca us e d by the pa ra s ite P la s modium fa lcipa rum. This orga nis m s pe nds a n obliga tory pa rt of its life cycle in the RBC.

One the ory is tha t be ca us e the s e ce lls in individua ls he te rozygous for HbS , like thos e in homozygote s , ha ve a s horte r life s pa n tha n norma l, the pa ra s ite ca nnot comple te the intra ce llula r s ta ge of its de ve lopme nt.

This fa ct ma y provide a s e le ctive a dva nta ge to he te rozygote s living in re gions whe re ma la ria is a ma jor ca us e of de a th. He mo g lo bin C dis e as e Like HbS , HbC is a he moglobin va ria nt tha t ha s a s ingle a mino a cid s ubs titution in the s ixth pos ition of the -globin cha in s e e Figure 3. In HbC, howe ve r, a lys ine is s ubs titute d for the gluta ma te a s compa re d with a va line s ubs titution in HbS.

The s e pa tie nts do not s uffe r from infa rctive cris e s , a nd no s pe cific the ra py is re quire d.

In this dis e a s e , s ome -globin cha ins ha ve the s ickle ce ll muta tion, whe re a s othe r -globin cha ins ca rry the muta tion found in HbC dis e a s e. The y a re ca lle d compound he te rozygote s be ca us e both of the ir -globin ge ne s a re a bnorma l, a lthough diffe re nt from e a ch othe r. The clinica l cours e of a dults with HbS C a ne mia diffe rs from tha t of s ickle ce ll a ne mia in tha t s ymptoms s uch a s pa inful cris e s a re le s s fre que nt a nd le s s s e ve re. Howe ve r, the re is s ignifica nt clinica l va ria bility. Dis tribution of s ickle ce ll in Africa e xpre s s e d a s a pe rce nta ge of the popula tion with dis e a s e.

Dis tribution of ma la ria in Africa. He moglobin Hb te tra me rs forme d in -tha la s s e mia s. This oxida tion ma y be ca us e d by the a ction of ce rta in drugs , s uch a s nitra te s , or e ndoge nous products s uch a s re a ctive oxyge n s pecie s s e e p. The oxida tion ma y a ls o re s ult from inhe rite d de fe cts , for exa mple , ce rta in muta tions in the - or -globin cha in promote the forma tion of me the moglobin HbM. The y a re , the re fore , pa rticula rly s us ce ptible to the e ffe cts of HbM-producing compounds.

S ymptoms a re re la te d to the de gre e of tis s ue hypoxia and include a nxie ty, he a da che , a nd dys pne a. Thalas s e mias The tha la s s e mia s a re he re dita ry he molytic dis e a s e s in which a n imba la nce occurs in the synthes is of globin cha ins. As a group, they a re the mos t common s ingle ge ne dis orde rs in huma ns.

Norma lly, synthes is of the - a nd -globin cha ins is coordinate d, s o that e ach -globin cha in has a -globin chain pa rtner. This le a ds to the forma tion of 2 2 HbA. In the tha la ss emia s, the s ynthe sis of either the or the -globin chain is de fe ctive.