LIPPINCOTT BIOCHEMISTRY 6TH EDITION PDF

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Library of Congress Cataloging-in-Publication Data Ferrier, Denise R . Biochemistry / Denise R. Ferrier. -- 6th ed. p. ; cm. -- (Lippincott's illustrated. KD TRIPATHI MD. Ex-Director-Professor and Head of Pharmacology. Maulana Azad Medical College Essentials of Medical Phar. Rev. ed. of: Biochemistry / Pamela C. Champe, Richard A. Harvey, Denise R. Ferrier. 4th ed. Visit Lippincott Williams & Wilkins on the Internet: http://www. bestthing.info Lippincott .. glutamate by nonpolar valine at the sixth position in the β .


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Lippincott's Illustrated Reviews Biochemistry 6th Edition for decades has served as a very important study guide for the medical students for. Lippincott's Illustrated Reviews: Biochemistry – 6th edition - Book Reviews. Download the Medical Book: API Textbook of Medicine 9th Edition PDF For Free. Denise R. Ferrier PhD Biochemistry Lippincott Illustrated Reviews Series, 6th bestthing.info - Ebook download as PDF File .pdf), Text File .txt) or read book online.

The he lix-loop-he lix motif is a n e xa mple found in a numbe r of prote ins tha t function a s tra ns cription fa ctors s e e p. S upe rs e conda ry s tructure s a re us ua lly produce d by the clos e pa cking of s ide cha ins from a dja ce nt s e conda ry s tructura l e le me nts.

Some of the more common motifs a re illus tra te d in Figure 2.

The s tructure of globula r prote ins in a que ous s olution is compa ct. The s e nonre pe titive s e conda ry s tructure s a re not ra ndom. The s e form prima rily the core inte rior re gion of the mole cule. Motifs ma y be a s s ocia te d with pa rticula r functions. Inte ra ctions be twe e n the a mino a cid s ide cha ins guide the folding of the polype ptide to form a compa ct s tructure.

Te rtia ry S tructure of Globula r P rote ins 19 A. The folding of the polype ptide cha in s brings the cys te ine re s idue s into proximity a nd pe rmits cova le nt bonding of the ir s ide cha ins.

The two cys te ine s ma y be s e pa ra te d from e a ch othe r by ma ny a mino a cids in the prima ry s e que nce of a polype ptide or ma y e ve n be loca te d on two diffe re nt polype ptide cha ins. Folding of the pe ptide cha in within a doma in us ua lly occurs inde pe nde ntly of folding in othe r doma ins.

Io nic inte rac tio ns: Ne ga tive ly cha rge d groups. Re ca ll tha t prote ins loca te d in nonpola r lipid e nvironme nts. Dis ulfide bo nds: A dis ulfide bond is a cova le nt linka ge forme d from the s ulfhydryl group —S H of e a ch of two cys te ine re s idue s to produce a cys tine re s idue Figure 2.

Hydro pho bic inte rac tio ns Fig ure 2. Hydro pho bic inte rac tio ns: Amino a cids with nonpola r s ide cha ins te nd to be loca te d in the inte rior of the polype ptide mole cule. CH3 B. A dis ulfide bond contribute s to the s ta bility of the thre e -dime ns iona l s ha pe of the prote in mole cule a nd pre ve nts it from be coming de na ture d in the e xtra ce llula r e nvironme nt.

P olype ptide cha ins tha t a re gre a te r tha n a mino a cids in le ngth ge ne ra lly cons is t of two or more doma ins. The following four type s of inte ra ctions coope ra te in s ta bilizing the te rtia ry s tructure s of globula r prote ins.

Inte rac tio ns s tabilizing te rtiary s truc ture The unique thre e -dime ns iona l s tructure of e a ch polype ptide is de te rmine d by its a mino a cid s e que nce. The core of a doma in is built from combina tions of s upe rs e conda ry s tructura l e le me nts motifs. Forma tion of hydroge n bonds betwe e n pola r groups on the s urfa ce of prote ins a nd the a que ous s olve nt e nha nce s the s olubility of the prote in. Amino a cid s ide cha ins conta ining oxyge n.

In contra s t. As a pe ptide folds. De na ture d prote ins a re ofte n ins oluble a nd pre cipita te from s olution. 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. The pa rtia lly folde d prote in e nte rs the ca ge.

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. De na turing a ge nts include he a t. Hs p 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. Othe rs form ca ge -like ma cromole cula r s tructure s compos e d of two s ta cke d rings.

The cha pe rone s. The s e s ma ll s tructure s combine to form la rge r s tructure s. Additiona l e ve nts s ta bilize s e conda ry s tructure a nd initia te forma tion of te rtia ry s tructure. S ome biologica lly a ctive prote ins or s e gme nts the re of la ck a s ta ble te rtia ry s tructure. Pro te in fo lding 1 Fo rmatio n o f s e c o ndary s truc ture s Inte ra ctions be twe e n the s ide cha ins of a mino a cids de te rmine how a long polype ptide cha in folds into the intrica te thre e -dime ns iona l s ha pe of the functiona l prote in.

P rote in folding. S tructure of P rote ins C. S ubunits a re he ld toge the r prima rily by non-. De na tura tion ma y. This is be ca us e. In a ddition. If the prote ins function a s e nzyme 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.

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.

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. Muta tions to pre s e nilin. This pe ptide. P rote in Mis folding cova le nt inte ra ctions for e xa mple. Accumula tion of the s e ins oluble. 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.

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. 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.

Denaturation may be reversible or. Interactions between the amino acid side chains guide the folding of the polypeptide chain to form s econdary. S tructure of P rote ins B. The infe ctive a ge nt is. Ce ntra l to unde rs ta nding prote in s tructure is the conce pt of the native co nformation Figure 2. In Alzhe ime r dis eas e. The TSEs a re inva ria bly fata l. 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.

Afte r a n e xte ns ive s e rie s of purifica tion proce dure s. Disease can occur when an apparently normal protein assumes a conformation that is cytotoxic.

In addition. 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. 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.

In TSEs. The unique three-dimensional structure of the native conformation is determined by its primary s tructure. Irre ve rs ible de naturatio n. Ure a Extre me s of pH. The pe ptide bonds tha t link a mino a cids in a prote in mos t commonly occur in the cis configura tion. 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 mos t like ly cha nge in the prima ry s tructure of the muta nt prote in is: 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.

Qua te rna ry s tructure re quire s more tha n one polype ptide. The pe ptide bond is a lmos t a lwa ys tra ns. P roline. It is s ta bilize d by inte rcha in hydroge n bonds. The re is no fa mily his tory of de me ntia. 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. The hydrophobic e ffe ct. The pa tie nt wa s te ntative ly dia gnos e d with 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.

De na tura tion ma y be re ve rs ible or irre ve rs ible. It is a s s ocia te d with the a ccumula tion of a myloid pre curs or prote in. It ma y be found in typica l globula r prote ins. Which one of the following be s t de s cribe s Alzhe ime r dis e a s e?

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. It ma y be found in s upe rs e conda ry s tructure s. The prima ry driving force for prote in folding is the hydrophobic e ffe ct. 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.

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. Fibrous s tructura l prote ins a re dis cus s e d in Cha pte r 4. In myoglobin a nd he moglobin.

He me prote in cytochrome c. In he moglobin a nd myoglobin. S tructure of he me. By a rra nging the s e funda me nta l s tructura l e le me nts in diffe re nt combina tions. 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.

S truc ture and func tio n o f myo g lo bin Myoglobin. Lo c atio n o f po lar and no npo lar amino ac id re s idue s: The inte rior of the myoglobin mole cule is compos e d a lmos t e ntire ly of nonpola r a mino a cids. Myoglobin is a compa ct mole cule. The prote in. S che ma tic dia gra m of the oxyge n-binding s ite of myoglobin. Ionic bonds a re a ls o te rme d e le ctros ta tic inte ra ctions or s a lt bridge s. 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.

Nota ble e xce ptions a re two his tidine re s idue s Figure 3. 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.

The y a re pa cke d clos e ly toge the r. Binding o f the he me g ro up: The he me group of the myoglobin mole cule s its in a cre vice. Mous e myoglobin double knockouts s e e p. The s e cond. Mode l of myoglobin s howing he lice s A to H.

Circula tory s ys te ms ove rcome this. Furthe rmore. He moglobin A. 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. S tructure of he moglobin s howing the polype ptide ba ckbone. Quate rnary s truc ture o f he mo g lo bin: The he moglobin te tra me r ca n be e nvis ione d a s be ing compos e d of two ide ntica l dime rs.

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. 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.

S implifie d dra wing s howing the he lice s. In this ins ta nce. S tro ng inte rac tio ns. Be ca use the iron is a ls o linke d to the proxima l his tidine F8. The R conforma tion is the high-oxyge na ffinity form of he moglobin.

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 he ld toge the r prima rily by pola r bonds. In the T form. 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.

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. R fo rm: The T conforma tion is the low-oxyge n-a ffinity form of he moglobin. The binding of O 2 to the he me iron pulls the iron into the pla ne of the he me. 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. O2 "R.

Lippincott's Illustrated Reviews Biochemistry, 6 E

P uls e oxime try is a noninva s ive. T fo rm: 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 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. This re fle cts the fa ct tha t myoglobin re ve rs ibly binds a s ingle mole cule of oxyge n.

Myoglobin is de s igne d to bind oxyge n re le a s e d by he moglobin a t the low pO 2 found in mus cle. Myo g lo bin: The oxyge n-dis s ocia tion curve for myoglobin ha s a hype rbolic s ha pe s e e Figure 3. Although it is more difficult for the firs t oxyge n mole cule to bind to he moglobin. Fig ure 3. 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 highe r the oxyge n a ffinity tha t is. This pe rmits o xyg e n de live ry to re s po nd to s mall c hange s in pO2. 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.

He me —he me inte rac tio ns: The s igmoida l oxyge n-dis s ocia tion curve re fle cts s pe cific s tructura l cha nge s tha t a re initia te d a t one he me group a nd tra ns mitte d to othe r he me groups in the he moglobin te tra me r. The binding of oxyge n to monome ric myoglobin is not influe nce d by a llos te ric e ffe ctors.

Oxyg e n-dis s o c iatio n c urve: 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. Globula r He me prote ins 29 pa rtia l pre s s ure s of oxyge n pO 2 is ca lle d the oxyge n-dis s ocia tion curve.

He mo g lo bin: The oxyge n-dis s ocia tion curve for he moglobin is s igmoida l in s ha pe s e e Figure 3. O2 binds to he mo g lo bin. Protons a re a llos te ric e ffe ctors of he moglobin. Globula r P rote ins a. Lo ading and unlo ading o xyg e n: The re le a s e of oxyge n from he moglobin is e nha nce d 2 CO2 binds to he mo g lo bin. This diffe re ntia l pH gra die nt tha t is. CO2 oxyge n a llows he moglobin to de live r more oxyge n to the tis s ue s in re s pons e to re la tive ly s ma ll cha nge s in the pa rtia l pre s s ure of oxyge n.

In the tis s ue s. Both re s ult in a de cre a s e d oxyge n a ffinity of he moglobin a nd. This cha nge in oxyge n binding is ca lle d the Bohr e ffe ct. Conve rs e ly. CO 2 is conve rte d by ca rbonic a nhydra s e to ca rbonic a cid: A mole cule with a hype rbolic oxyge n-dis s ocia tion curve.

Re pla ce me nt of one of the se a mino a cids ca n re sult in he moglobin varia nts with abnormally high oxyge n affinity that may be compensated for by increased RBC production erythrocytosis. The Bohr e ffe ct re fle cts the fa ct tha t the de oxy form of he moglobin ha s a gre a te r a ffinity for protons tha n doe s 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. Globula r He me prote ins 31 b.

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Binding o f 2. He moglobin from which 2. 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.

P is a phos phoryl group. The s e bonds pre fe re ntia lly s ta bilize the de oxy form of he moglobin. The e ffe ct of binding 2. One molecule of 2. It is the mos t a bunda nt orga nic phos pha te in the RBC.

This pre fe re ntia l binding s ta bilize s the T conforma tion of de oxyhe moglobin. Binding s ite o f 2. He moglobin. 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. The a ffinity of he moglobin for CO is time s gre a te r tha n for oxyge n.

Binding o f CO2: Mos t of the CO 2 produce d in me ta bolis m is hydra te d a nd tra ns porte d a s bica rbona te ion s e e p. Intra ce llula r le ve ls of 2.

Globula r P rote ins d. The ma ximum s tora ge time for RBC ha s be e n double d 21 to 42 da ys. For exa mple. Cons e que ntly. Although the conte nt of 2. CO toxicity a ppe a rs to re s ult from a. The conce ntra tion of 2. Binding o f CO: Whe n CO binds to one or more of the four he me s ite s. 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.

In the lungs. He moglobin de ficie nt in 2. 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. 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. CO inhibits Comple x IV of the e le ctron tra ns port cha in s e e p. 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.

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. 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.

Figure 3. Unde r phys iologic conditions , HbF. 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.

The mos t a bunda nt form of glycos yla te d he moglobin is HbA1c. 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.

Globin ge ne fa millie s a ls o conta in globin-like ge ne s tha t a re not e xpre s s e d, tha t is , the ir ge ne tic informa tion is not us e d to produce globin cha ins. 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. 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. The life time of a RBC in s ickle ce ll a ne mia is le s s tha n 20 da ys , compa red with da ys.

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. Ele ctrophore s is of he moglobin obta ine d from lys e d RBC is routine ly us e d in the dia gnos is of s ickle ce ll tra it a nd s ickle ce ll dis e a s e. 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.

The morbidity a nd morta lity a s s ocia te d with s ickle ce ll a ne mia ha s le d to its inclus ion in ne wborn s cre e ning pa ne ls to a llow prophyla ctic a ntibiotic the ra py to be gin s oon a fte r the birth of a n a ffe cte d child. 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.

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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.

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. P a tie nts with HbS C dis e a s e a re doubly he te rozygous.

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. 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 RBC of ne wborns ha ve a pproxima te ly ha lf the ca pa city of thos e of a dults to re duce 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. A tha la ss emia can be ca us ed by a varie ty of muta tions, including entire ge ne de letions , or substitutions or de le tions of one to many nucle otide s in the DNA.

Incre a s e in. The s e pa tie nts re quire re gular tra ns fus ions of blood. Although this tre a tme nt is life s a ving, the cumula tive e ffe ct of the tra ns fus ions is iron ove rloa d a s yndrome known a s he mos ide ros is.

Us e of iron che la tion the ra py ha s improve d morbidity a nd morta lity. The s ubunits occupy diffe re nt re la tive pos itions in de oxyhe moglobin compa re d with oxyhe moglobin. It ha s a cons tra ine d s tructure tha t limits the move me nt of the polype ptide cha ins.

The T form is the lo w-o xyg e n-affinity fo rm of Hb. The binding of O 2 to Hb ca us e s rupture of s ome of the ionic a nd hydroge n bonds , a nd move me nt of the dime rs. The R form is the hig h-o xyg e naffinity fo rm of Hb. The o xyg e n-dis s o c iatio n c urve for Hb is s ig mo idal in s ha pe in contra s t to tha t of myo g lo bin , which is hype rbo lic , indica ting tha t the s ubunits coope ra te in binding O 2.

Co o pe rative binding of O 2 by the four s ubunits of Hb me a ns tha t the binding of a n O 2 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 Hb mole cule.

He mo g lo bin Bart dis e as e with hydro ps fe talis us ually fatal at birth. To cope long-te rm with the e ffe cts of c hro nic hypo xia or ane mia , the conce ntra tion of 2,3-BPG in re d blo o d c e lls incre a s e s. It the re fore a ls o s hifts the oxyge n-dis s ocia tion curve to the right. Carbo n mo no xide CO binds tightly but re ve rs ibly to the Hb iron, forming c arbo xyhe mo g lo bin. He mo g lo bino pathie s a re dis orde rs ca us e d e ithe r by production of a s truc turally abno rmal Hb mole cule ; s ynthe s is of ins uffic ie nt quantitie s of norma l Hb s ubunits , or, ra re ly, both Figure 3.

HbA is the mos t a bunda nt he moglobin in norma l adults. Fetal blood has a lower affinity for oxygen than does adult blood because HbF has an increased affinity for 2,3-bisphosphoglycerate. HbA1c differs from HbA by a single, genetically determined amino acid substitution.

HbA2 appears early in fetal life. Acidos is de cre a s e s the s olubility of HbS. Acidos is incre a s e s the a ffinity of he moglobin for O 2.

Acidos is fa vors the conve rs ion of he moglobin from the ta ut to the re la xe d conforma tion.

Acidos is s hifts the oxyge n-dis s ocia tion curve to the le ft. Acidos is de cre a s e s the a bility of 2,3-bis phos phoglyce ra te to bind to he moglobin.

The Bohr effect results in a lower affinity for oxygen at higher pH values. Carbon dioxide increases the oxygen affinity of hemoglobin by binding to the C-terminal groups of the polypeptide chains. The oxyge n a ffinity of he moglobin incre a se s a s the percentage saturation increases.

The he moglobin te tra me r binds four mole cule s of 2,3-bisphosphoglycerate. Oxyhemoglobin and deoxyhemoglobin have the same affinity for protons. HbA1c is a glycosylate d form of HbA, forme d none nzymica lly in re d ce lls. HbS is s ignifica ntly le s s s oluble in the de oxyge na te d form, compa re d with oxyhemoglobin S.

A decrease in pH acidosis causes the oxygen-dissociation curve to shift to the right, indicating a decreased affinity for oxyge n. This fa vors the forma tion of the de oxy, or ta ut, form of he moglobin, a nd ca n pre cipita te a s ickle ce ll cris is. The binding of 2,3-bisphosphoglycerate is increased, because it binds only to the deoxy form of hemoglobins.

The binding of oxygen at one he me group incre a s e s the oxyge n a ffinity of the remaining heme groups in the same mole cule.

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A ris e in pH re s ults in incre a s e d a ffinity for oxyge n. Ca rbon dioxide de cre a se s oxygen affinity because it lowers the pH; moreover, binding of carbon dioxide to the N-termini s ta bilize s the ta ut, de oxy form. He moglobin binds one molecule of 2,3-bisphosphoglycerate.

Deoxyhemoglobin has a greater affinity for protons and, therefore, is a weaker acid.

He me —he me inte rac tio n le a ds to Firs t O2 binding with lo w affinity. Hig h affinity fo r CO le a ds to S tabilizatio n o f the re laxe d s tate le a ds to Inc re as e d affinity fo r bo und O2 le a ds to. Study Ques tions continued 3. In Hb He ls inki, this a mino a cid ha s be e n re pla ce d by me thionine.

Which of the following s hould be true conce rning Hb He ls inki? It s hould be s ta bilize d in the ta ut, ra the r tha n the re la xe d, form. Its O 2 -dis s ocia tion curve s hould be s hifte d to the right re la tive to HbA.

It re s ults in a ne mia. The re la xe d form is the high-oxyge n-a ffinity form of he moglobin. De cre a s e d O 2 de live ry is compe ns a te d for by incre a s e d RBC production. In HbC, the polar glutamate is replaced by polar lysine rather than by nonpolar valine as in HbS.

S ynthe s is o f ins uffic ie nt quantitie s o f no rmal he mo g lo bin for e xa mple. Blood obtaine d for analysis was brown colored. Which one of the following is the most likely diagnosis?

This ma y be caused by the action of certain drugs such as nitrates. The methemoglobinemias are characterized by chocolate cyanosis a brownish blue coloration of the skin and mucous membranes and chocolate-colored blood as a result of the da rk-colore d me the moglobin.

S ymptoms a re re la te d to tiss ue hypoxia a nd include a nxie ty, hea da che , a nd dyspne a. Be nzoca ine , a n aromatic amine used as a topical anesthetic, is a cause of acquired methemoglobinemia. HbF reduces HbS concentration. It also inhibits polymerization of deoxy HbS. Fibro us Pro te ins I. OVERVIEW Colla ge n a nd e la s tin a re e xa mple s of common, we ll-cha ra cte rize d fibrous prote ins of the e xtra ce llula r ma trix tha t s e rve s tructura l functions in the body.

Ea ch fibrous prote in e xhibits s pe cia l me cha nica l prope rtie s , re s ulting from its unique s tructure , which a re obta ine d by combining s pe cific a mino a cids into re gula r, s e conda ry s tructura l e le me nts. This is in contra s t to globula r prote ins , whos e s ha pe s a re the re s ult of comple x inte ra ctions be twe e n s e conda ry, te rtia ry, a nd, s ome time s , qua te rna ry s tructura l e le me nts.

Although the s e mole cule s a re found throughout the body, the ir type s a nd orga niza tion a re dicta te d by the s tructura l role colla ge n pla ys in a pa rticula r orga n. In othe r tis s ue s , colla ge n ma y be bundle d in tight, pa ra lle l fibe rs tha t provide gre a t s tre ngth, a s in te ndons. In the corne a of the e ye , colla ge n is s ta cke d s o a s to tra ns mit light with a minimum of s ca tte ring.

Type s The colla ge n s upe rfa mily of prote ins include s more tha n 25 colla ge n type s a s we ll a s a dditiona l prote ins tha t ha ve collage n-like doma ins. The colla -. He avy s taining in re g io ns with g aps Fig ure 4. Ne two rk-fo rming c o llag e ns: The fibe rs de rive d from type III colla ge n a re pre va le nt in more dis te ns ible tis s ue s s uch a s blood ve s s e ls. Fibril-as s o c iate d c o llag e ns: Type I colla ge n fibe rs compos e d of colla ge n fibrils a re found in s upporting e le me nts of high te ns ile s tre ngth for e xa mple.

Fibril-fo rming c o llag e ns: Type s I. In the e le ctron micros cope. Triple -he lic al s truc ture: Unlike mos t globula r prote ins tha t a re folde d into compa ct s tructure s. Amino ac id s e que nc e: Colla ge n is rich in proline a nd glycine. Afte r a dditiona l e nzymic modifica tion. S truc ture 1. The s e re s idue s re s ult from the hydroxyla tion of s ome of the proline a nd lys ine re s idue s a fte r the ir incorpora tion into polype ptide cha ins Figure 4.

The glycine re s idue s a re pa rt of a re pe a ting s e que nce. Mos t commonly. Colla ge n is one of ma ny prote ins tha t norma lly function outs ide of ce lls. Glyc o s ylatio n: Bio s ynthe s is The polype ptide pre curs ors of the colla ge n mole cule a re s ynthe s ize d in fibrobla s ts or in the re la te d os te obla s ts of bone a nd chondrobla s ts of ca rtila ge. The y a re e nzymica lly modifie d a nd form the triple he lix.

Ge ne ra tion of hydroxyproline ma ximize s forma tion of inte rcha in hydroge n bonds tha t s ta bilize the triple -he lica l s tructure. The s igna l s e que nce fa cilita te s the binding of ribos ome s to the rough e ndopla s mic re ticulum RER. Like mos t prote ins produce d for e xport. Hyp is hydroxyproline. Figure 4. Colla ge n 45 B. It fits into the re s tricte d s pa ce s whe re the thre e cha ins of the he lix come toge the r.

Hydro xypro line and hydro xylys ine: Colla ge n conta ins hydroxy- proline a nd hydroxylys ine. The hydroxyla tion is. Fibrous P rote ins 3 S e le c te d pro line and lys ine re s idue s are hydro xylate d.

Fig ure 4. S ome hydroxylys ine re s idue s a re modifie d by gly- cos yla tion with glucos e or glucos yl-ga la ctos e s e e Figure 4.

Hydro xylatio n: In the case of ascorbic a cid de ficie ncy a nd. Afte r hydroxyla tion a nd glycos yla tion. P roline a nd lys ine re s idue s found in the Y-pos ition of the —Gly—X—Y— s e que nce ca n be hydroxyla te d to form hydroxyproline a nd hydroxylys ine re s idue s. The procolla ge n mole cule s move through the Golgi a ppa ra tus. The se hydroxylation reactions require molecular oxygen.

Pa tie nts with a s corbic a cid de ficie ncy a ls o ofte n s how bruis e s on the limbs a s a re s ult of s ubcuta ne ous e xtra va s a tion le a ka ge of blood due to ca pilla ry fra gility Figure 4. The re s ulting de ficie ncy dis e a s e is known a s s curvy.

The ve s icle s fus e with the ce ll me mbra ne. The following a re e xa mple s of dis e a s e s tha t a re the re s ult of de fe ctive colla ge n s ynthe s is. De g radatio n Fig ure 4. The va s cula r form. The y form a n orde re d. Ehle rs -Danlo s s yndro me: Bre a kdown of colla ge n fibe rs is de pe nde nt on the prote olytic a ction of colla ge na s e s. EDS ca n be ca us e d by a de ficie ncy of colla ge n-proce s s ing e nzyme s for e xa mple.

Co llag e no pathie s De fe cts in a ny one of the ma ny s te ps in colla ge n fibe r s ynthe s is ca n re s ult in a ge ne tic dis e a s e involving a n ina bility of colla ge n to form fibe rs prope rly a nd. Cro s s -link fo rmatio n: The re a ctive a lde hyde s tha t re s ult a llys ine a nd hydroxya llys ine ca n conde ns e with lys ine or hydroxylys ine re s idue s in ne ighboring colla ge n mole cule s to form cova le nt cros s -links a nd.

For type I colla ge n. Fibrous P rote ins 6. The s e fra gme nts a re furthe r de gra de d by othe r ma trix prote ina s e s.

Dis ruption in coppe r home os ta s is ca us e s coppe r de ficie ncy X-linke d Me nke s dis e a s e or ove rloa d Wils on dis e a s e. More tha n 1. Fo rmatio n o f c o llag e n fibrils: Lys yl oxida s e is irre ve rs ibly inhibite d by a toxin from pla nts in the ge nus La thyrus. The cla s s ic form of EDS. Othe rs include cytochrome oxida s e s e e p.

Ela s tin 49 inhe rita nce. De ntinoge ne s is impe rfe cta. This is known a s a domina nt-ne ga tive e ffe ct. Tropoe la s tin is se creted by the cell into the extra ce llular spa ce. S truc ture Ela s tin is a n ins oluble prote in polyme r s ynthe s ize d from a pre curs or. Type II.

The re. Thre e of the a llys yl s ide cha ins plus one una lte re d lys yl s ide cha in from the s a me or ne ighboring polype ptide s form a de s mos ine cros s -link Figure 4.

Muta tions in the fibrillin-1 prote in a re re s pons ible for Ma rfa n s yndrome. This produce s e la stin. P a tie nts with Ma rfa n s yndrome. It fre que ntly is de gra de d. The mos t common muta tions ca us e the re pla ce me nt of glycine in —Gly—X—Y— by a mino a cids with bulky s ide cha ins. P he notypic s e ve rity ra nge s from mild to le tha l.

Some of the lysyl s ide cha ins of the tropoe la s tin polype ptide s a re oxida tive ly de a mina te d by lys yl oxida s e. This s yndrome. Incorpora tion of jus t one muta nt cha in ma y re s ult in de gra da tion of the triple he lix. Ela s tin is a ls o rich in proline a nd lys ine but conta ins sca nt hydroxyproline a nd hydroxylys ine. Type I OI. The y ca n be s tre tche d to s e ve ra l time s the ir norma l le ngth but re coil to the ir origina l s ha pe whe n the s tre tching force is re la xe d.

With this dis e a s e. It is cha ra cte rize d by multiple fra cture s a t birth. Ela s tic fibe rs compos e d of e la s tin a nd glycoprote in microfibrils a re found in the lungs. Fibrous P rote ins B. Extra he pa tic s ynthe s is occurs in monocyte s a nd a lve ola r ma cropha ge s.

In the Unite d S ta te s. S moke rs with AAT de ficie ncy. The prote olytic a ctivity of e la s ta s e ca n de s troy the e la s tin in a lve ola r wa lls if unoppos e d by the a ction of AAT.

In a he te rozygote. The muta tion ca us e s the norma lly monome ric AAT to polyme rize within the e ndopla s mic re ticulum of he pa tocyte s. S moking ca us e s the oxida tion a nd s ubs e que nt ina ctiva tion of the me thionine. The AAT diffus e s from the blood into the lung. Unite d S ta te s. 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. A numbe r of diffe re nt muta tions in the ge ne for AAT a re known to ca us e a de ficie ncy of the prote in.

In the norma l lung. An individua l mus t inhe rit two a bnorma l AAT a lle le s to be a t ris k for the de ve lopme nt of e mphys e ma. Be ca us e lung tis s ue ca nnot re ge ne ra te. Blood a nd othe r body fluids conta in a prote in.

Me thionine in AAT is re quire d for the binding of the inhibitor to its ta rge t prote a s e s. Cha pte r S umma ry 51 Co llag e n s truc ture Co llag e n s ynthe s is compos e d of involve s Dis o rde rs o f c o llag e n s ynthe s is e xa mple s include De pos ition of ins oluble fibe rs outs ide the ce ll.

S moking incre a s e s ris k. Ge ne tic de fe cts in AAT ca n le a d to e mphys e ma lung a nd cirrhos is live r. Mos t pa tie nts with s e ve re dis e a s e ha ve muta tions in the ge ne for type I colla ge n.

The s tructura lly a bnorma l cha ins pre ve nt folding of the prote in into a triple -he lica l conforma tion. The de ficie ncy of e la s ta s e inhibitor ca n be re ve rs e d by we e kly intra ve nous a dminis tra tion of AAT. P ote ntia lly le tha l va s cula r proble ms occur.

Muta tions in the ge ne for fibrillin a re re s pons ible for Ma rfa n s yndrome. Fibril-fo rming c o llag e n For e xa mple: S curvy re s ults in colla ge n with de cre a s e d te ns ile s tre ngth.

Individua ls with Ma rfa n s yndrome ha ve impa ire d s tructura l inte grity of the s ke le ton. Which pa iring of a de fe ctive or de ficie nt mole cule a nd the re s ulting pa thology be s t fits this clinica l de s cription? P roline is hydroxlya te d by prolyl hydroxyla s e. Colla ge n mole cule s conta in a n a bunda nce of pro line. Vita min C de ficie ncy impa irs hydroxyla tion. Vita min C de ficie ncy is cha ra cte rize d by ca pilla ry fra gility. At a ge 1 month. Colla ge n mole cule s typica lly form fibrils conta ining a long.

Elas tin is a conne ctive tis s ue prote in with rubbe r-like prope rtie s in tis s ue s s uch a s the lung. Colla ge n a ls o conta ins hydro xypro line. A ca re ful fa mily his tory ha s rule d out nona ccide nta l tra uma child a bus e a s a ca us e of the bone fra cture s. Bone s in a ffe cte d pa tie nts a re thin. The child mos t like ly ha s os te oge ne s is impe rfe cta. Hydroxyla tion incre a s e s inte rcha in hydroge n bond forma tion.

The a lve ola r da ma ge is due to the re te ntionba s e d de ficie ncy of AAT a prote a s e inhibitor in the lung s uch tha t e la s ta s e a prote a s e is unoppos e d. Choice s A. Vita min C a nd s curvy 4. De fe cts in type V colla ge n ca us e the cla s s ic form of EDS cha ra cte rize d by s kin e xte ns ibility a nd fra gility a nd joint hype rmobility. Fibrous P rote ins IV. Othe r type s of colla ge n form me s h-like ne tworks. AAT de ficie ncy s hould be s us pe cte d whe n chronic obs tructive pulmona ry dis e a s e de ve lops in a pa tie nt younge r tha n a ge 45 ye a rs who doe s not ha ve a his tory of chronic bronchitis or toba cco us e or whe n multiple fa mily me mbe rs de ve lop obs tructive lung dis e a s e a t a n e a rly a ge.

P ulmona ry proble ms a re not s e e n in this child. La cta te: Catalyze cle avag e o f bo nds by additio n o f wate r. Lac tate Pyruvate which a re prote in ca ta lys ts tha t incre a s e the ra te of re a ctions Catalyze trans fer o f C-.

Enzyme s thus dire ct a ll me ta bolic e ve nts. Among the ma ny 2. S ome e nzyme s re ta in the ir origina l trivia l na me s. The firs t is its s hort. Tra n s fe ra s e s c ontaining gro ups. For a give n e nzyme. The s e cond is the more comple te s ys te ma tic na me. Hyd ro la s es II. S ys te matic name 6. The a ctive s ite. Enzyme s a re prote in ca ta lys ts tha t incre a s e the ve locity of a che mica l re a ction a nd a re not cons ume d during the re a ction.

Full Name Comment goes here. Are you sure you want to Yes No. Be the first to like this. No Downloads. Views Total views. Actions Shares. Embeds 0 No embeds. No notes for slide. Lippincott biochemistry 6th edition 1. It'll discuss mainly concerning the above topic coupled with additional information associated with it. As per our directory, this particular PDF document shows up as --, formally introduced at 12 Jan, and take about We advise you to browse our broad line of digital book which spread from many various subject and resources obtainable.

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Now customize the name of a clipboard to store your clips. Visibility Others can see my Clipboard.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. RNAs with ca ta lytic a ctivity a re ca lle d ribozyme s s e e p. The s e drugs. Co o pe rative binding of O 2 by the four s ubunits of Hb me a ns tha t the binding of a n O 2 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 Hb mole cule.

The pe ptide ca nnot form a n inte rna l dis ulfide bond. Co llag e no pathie s De fe cts in a ny one of the ma ny s te ps in colla ge n fibe r s ynthe s is ca n re s ult in a ge ne tic dis e a s e involving a n ina bility of colla ge n to form fibe rs prope rly a nd. Gluta ma te. Othe r me c hanis ms: Coe nzyme s cos ubs tra te s a re s ma ll orga nic mole cule s tha t a s s ocia te tra n s ie ntly with a n e nzyme a nd le a ve the e nzyme in a cha nge d form.

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