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8885d_c18_656-689 2/3/04 11:39 AM Page 662 mac76 mac76:385_reb: AMİNO ASİT BİYOSENTEZİ Nükleotid ve Amino Asit Biyosentezinde Önemli Reaksiyon Sınıfları 662 Chapter 18 Amino Acid Oxidation and th...

8885d_c18_656-689 2/3/04 11:39 AM Page 662 mac76 mac76:385_reb: AMİNO ASİT BİYOSENTEZİ Nükleotid ve Amino Asit Biyosentezinde Önemli Reaksiyon Sınıfları 662 Chapter 18 Amino Acid Oxidation and the Production of Urea R B R C COO" H C COO" : R # -Keto 1. Transaminasyon O ! NH3 L-Amino H C COO" acid R C COO" R C COO" ! acid H2O ! ! NH NH H! NH rxnları ve diğer ! ! A ! H CH CH CH2 NH3 N! HO C HO HO CH2 yeniden düzenlenme Lys CH P P P HO HO ! ! P : P CH3 N CH3 N CH3 N reaksiyonları Enz H H H ! ! CH3 N CH3 N H H Schiff base Quinonoid intermediate intermediate Pyridoxamine pirodoklsal fosfat (vit Pyridoxal phosphate (aldimine form, (aldimine) phosphate on enzyme) B)içeren enzimler B Lys ! NH 3 tarafından R H H! R C COO" C COO" H Enz gerçekleştirilirler. NH ! NH ! R C COO" CH CH ! NH3 D-Amino HO HO acid ! P P ! Pyridoxal : CH3 N CH3 N phosphate H H (aldimine form, Quinonoid intermediate on regenerated enzyme) R R R R R O ! Lys NH 3 H C " H C H C C H C H C H R H! ! NH ! NH O" NH ! H C H ! NH NH ! Enz CH CH CH CO2 C CH ! NH3 Amine HO HO HO HO HO ! P P P P P ! ! C ! Pyridoxal : CH3 N CH3 N CH3 N CH3 N CH3 N phosphate H H H H H (aldimine form, Carbanion Quinonoid Schiff base Quinonoid on regenerated intermediate intermediate intermediate enzyme) (aldimine) Resonance structures for stabili- zation of a carbanion by PLP MECHANISM FIGURE 18–6 Some amino acid transformations at the of an unstable carbanion on the ! carbon (inset). A quinonoid inter- ! carbon that are facilitated by pyridoxal phosphate. Pyridoxal phos- mediate is involved in all three types of reactions. The transamination phate is generally bonded to the enzyme through a Schiff base (see route ( A ) is especially important in the pathways described in this Fig. 18–5b, d). Reactions begin (top left) with formation of a new Schiff chapter. The pathway highlighted here (shown left to right) represents base (aldimine) between the !-amino group of the amino acid and only part of the overall reaction catalyzed by aminotransferases. To PLP, which substitutes for the enzyme-PLP linkage. Three alternative complete the process, a second !-keto acid replaces the one that is fates for this Schiff base are shown: A transamination, B racemiza- released, and this is converted to an amino acid in a reversal of the  18.3 Pathways of Amino Acid Degradation 673 FIGURE 18–17 Conversions of one-carbon units on tetrahydrofolate. The different molecular species are grouped according to oxidation state, with the most reduced at the top and most oxidized at the bot- tom. All species within a single shaded box are at the same oxidation state. The conversion of N5,N10-methylenetetrahydrofolate to N5- methyltetrahydrofolate is effectively irreversible. The enzymatic trans- 1.Kofaktör olarak fer of formyl groups, as in purine synthesis (see Fig. 22–33) and in the formation of formylmethionine in prokaryotes (Chapter 27), generally Oxidation state (group transferred) Tetrahidrofolat ya da uses N10-formyltetrahydrofolate rather than N5-formyltetrahydrofolate. The latter species is significantly more stable and therefore a weaker H N CH2 S-adenosilmetiyonin donor of formyl groups. N5-formyltetrahydrofolate is a minor byprod- uct of the cyclohydrolase reaction, and can also form spontancously. 5 N H CH2 CH3 kullanılması ile karbon Conversion of N5-formyltetrahydrofolate to N5, N10-methenyltetrahy- drofolate, requires ATP, because of an otherwise unfavorable equilib- CH3 N H 10 (most reduced) gruplarının transferi rium. Note that N5-formiminotetrahydrofolate is derived from histidine in a pathway shown in Figure 18–26. 5 N -Methyl- tetrahydrofolate Serine Glycine NAD" N 5,N 10-methylene- COO # COO # 2.Glutaminin amid tetrahydrofolate " " reductase NADH " H" H3N C H H3N C H nitrojeninden H N CH2OH H H2O H N CH2 CH2 türevlenen amino PLP 5 H serine hydroxymethyl transferase 5 H N CH2 N CH2 CH2OH grupların transferi (fig H 10 N H H2C 10 N N5,N10-Methylene- 18-6, 17, 18 Tetrahydrofolate tetrahydrofolate Formate NADP" N 5 ,N 10-methylene- tetrahydrofolate ATP dehydrogenase NADPH " H" N 10-formyl- tetrahydrofolate ADP " Pi H H H N H2O N NH" 4 N synthetase CH2 CH2 CH2 5 H 5 H 5 H cyclohydrolase cyclodeaminase N CH2 N CH2 N CH2 H 10 " 10 10 N HC N HC N N 5,N10-Methenyl- H C HN tetrahydrofolate O H N5-Formimino- ADP " Pi N10-Formyl- tetrahydrofolate O cyclohydrolase N 5 ,N 10-methenyl- tetrahydrofolate (minor); tetrahydrofolate C H spontaneous synthetase (most oxidized) ATP H N CH2 5 H N CH2 10 N5-Formyl- N H tetrahydrofolate O H adenosyl transferase (Fig. 18–18, step 1 ). This re- high-energy phosphate groups, are broken in this reac- 2. Kofaktör olarak Tetrahidrofolat ya da S-adenosilmetiyonin kullanılması ile karbon gruplarının transferi 8885d_c18_656-689 2/3/04 11:39 AM Page 674 mac76 mac76:385_reb: 3. Glutaminin amid nitrojeninden türevlenen amino grupların transferi 674 Chapter 18 Amino Acid Oxidation and the Production of Urea COO! " H3N C H NH2 N COO! CH2 N " H3N C H NH2 CH2 N O O O N CH2 N CH3 S N " PPi " Pi ! O P O P O P O CH2 CH2 Methionine O N H N O! O! O! " S CH2 N H H methionine O CH2 ATP H H adenosyl CH3 H transferase H H N CH2 OH OH 1 S-Adenosyl- H H H methionine N OH OH H Tetrahydrofolate 4 methionine coenzyme B12 synthase R H N 2 a variety of methyl CH2 transferases COO! COO! 5 H " " N CH2 H3N C H H3N C H R CH3 CH3 N CH2 CH2 H hydrolase CH2 CH2 N 5-Methyltetrahydrofolate 3 SH Adenosine H 2O S Adenosine Homocysteine S-Adenosyl- homocysteine FIGURE 18–18 Synthesis of methionine and S-adenosylmethionine methyl donor in the formation of methionine. S-Adenosylmethionine, in an activated-methyl cycle. The steps are described in the text. In which has a positively charged sulfur (and is thus a sulfonium ion), is the methionine synthase reaction (step 4 ), the methyl group is trans- a powerful methylating agent in a number of biosynthetic reactions. ferred to cobalamin to form methylcobalamin, which in turn is the The methyl group acceptor (step 2 ) is designated R. AMİNO ASİT BİYOSENTEZİ Tüm amino asitler GLİKOLİSİS, SİTRİK ASİT DÖNGÜSÜ ya da PENTOZ FOSFAT YOLundaki aramoleküllerden türevlenirler. Nitrojen bu pathwaylere glutamat ve glutamin yoluyla girmektedir. Amino asitlerin çoğu bir ya da birkaç adımda belli metabolitlerden türevlenebilirken Aromatik amino asitler gibi bazı aa’lerin biyosentezi daha karmaşıktır. Organizmalar amino asit sentezleyebilme yetekneleri açısından çeşitlilik gösterirler. Pembe : glikolisis Mavi:sitrik asit döngüsü Mor: pentoz fosfat yolu  AMİNO ASİT BİYOSENTEZİ Organizmalar amino asit sentezleyebilme yetekneleri açısından çeşitlilik gösterirler. Bakteri ve bitkiler 20 amino asidin hepsini sentezleyebilirken, memeliler yaklaşık yarısını sentezleyebilmektedir. Sentezlenebilen amino asitlere “nonesential amino asitler “ esas olmayan amino asitler denir, bunların diyetle alınmasına gerek yoktur. Diğer amino asitler temel aminoasitler “essential” amino asitler olarak adlandırılır ki bunları yiyeceklerle almamız gereklidir. (insanlar için; Histidin, izolösin, lösin, lizin, metionin, sistein, fenilalanin, tirozin, treonin, triptofan ve valin) Amino asit biyosentezi yollarını anlaşılır hale getirmenin en pratik yolu metabolik prekürsörlerine göre sınıflandırmaktır.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: Bu 6 öncül moleküle ilaveten amino asit ve nükleik asit biyosentezinde önemli bir aramolekül 5-fosforibozil-1-pirofosfat (PRPP) tır.  HCOH A HCOH 2 GSH A O thione HOCH A Glucose tase HCOH 6-phosphate GSSG A HC tty acids, A erols, etc. CH2OPO2" 3 ctive NADP! nthesis glucose 6-phosphate 2! PRPP pentoz fosfat yolundan türevlenen riboz-5- Mg dehydrogenase NADPH ! H! ecursors CPO A fosfat’dan sentezlenir. HCOH A O HOCH A 6-Phospho- HCOH glucono-# -lactone A HC A CH2OPO23" pathway. utathione, H 2O lactonase The other Mg 2! serves as cells that O O" M D oxidative C A les of the HCOH uction of A HOCH 6-Phospho- ) to CO2. A gluconate HCOH A HCOH ratio of A CH2OPO23" to oxi- NADP! xidative 2! lecules. 6-phosphogluconate Mg dehydrogenase NADPH ! H! pentose g oxida- CO2 osphate CH2OH ay, can A CP O. A HCOH D-Ribulose A ates HCOH 5-phosphate A CH2OPO23" pathway phosphopentose isomerase osphate 6PD) to CHO A olecular HCOH A overall HCOH D-Ribose forma- A 5-phosphate 6-phos- HCOH A hospho- CH2OPO23" Pentoz Fosfat Yolu Oksidatif Reaksiyonları ation by the ke- FIGURE 14–21 Oxidative reactions of the pentose phosphate path- nerates way. The end products are ribose 5-phosphate, CO2, and NADPH.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: Alfa-ketoglutarat Glutamat,Glutamin, Prolin ve Argininin biyosentezinde rol alır.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: GLUTAMAT ve GLUTAMİN İndirgenmiş nitrojen formu NH4+ (Amonyum) amino asitlerin ve diğer nitrojen içeren biyomoleküllerin yapısında özümsenmiştir. 2 amino asit glutamat ve glutamin kritik öneme sahiptir. Bu amino asitler, Amino gruplarının katabolizmasında ve Amonyak katabolizmasında önemli rol oynarlar Glutamat diğer amino asitlerin çoğu için amino grubu kaynağıdır. (transaminasyon rxn) Glutaminin amid nitrojeni birçok biyosentetik işlemde amino grup kaynaıdır. Yüksek organizmalarda birçok hücre tipinde ve hücre dışı sıvıda bu aminoasitlerin her ikisi birden ya da biri diğer amino asitlerden daha yüksek konsantrasyonda bulunur.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: E. coli’deki glutamat sitosoldeki başlıca maddedir. Glutamat konsantrasyonu sadece hücrenin nitrojen gereksinimine göre değil aynı zamanda sitosol ve dış çevre arasındaki osmotik dengeye göre ayarlanır. Glutamat ve glutaminin biyosentetik yolu oldukça basittir ve Çoğu organizma için tüm basamaklar ya da basamakların en azından bazıları ortaktır.  AMİNO ASİT BİYOSENTEZİ 838 prekürsörlerine Metabolik Chapter 22 Biosynthesis göre amino of Amino asit Acids, Nucleotides, biyosentezi and Related Molecules 6 sınıfa ayrılmaktadır: Glutamattaki NH4+ asimilasyonu için en önemli pathway 2 rxn gerektirir. assimilation of NH ! 4 into 1. Glutamin Sentaz enzimi ileglutamate katalizlenenrequires two bir rxn ile reactions. Glutamat Glutamine Syntheta ve NH4+’den First, glutamine Glutamin oluşması synthetase catalyzes the reaction of in Nitrogen Metabo ! glutamate and NH4 to yield glutamine. This reaction takes Bu rxn 2 adımda place in twogerçekleşir. steps, with enzyme-bound !-glutamyl The activity of gluta phosphate Enzime bağlı glutamil as an fosfat ara (see intermediate üründür. Fig. 18–8): tually all organisms metabolic role as an (1) Glutamate ! ATP 88n "-glutamyl phosphate ! ADP In enteric bacteria s usually complex. Th (2) !-Glutamyl phosphate ! NH! 4 88n glutamine ! Pi ! H ! of Mr 50,000 (Fig. 22 Sum: Glutamate ! NH4 ! ATP 88n ! ically and by covalen ! glutamine ! ADP ! Pi ! H (22–1) at least six end pro Glutamin Sentaz tüm organizmalarda bulunur. allosteric inhibitors o Glutamine synthetase is found in all organisms. In ad- dition toNH4+ its importance asimilasyonufor içinNH ! hibitor alone produc Bakterilerde 4 assimilation önemli olduğu kadarinmemelilerde bacte- amino asit ria, it has a central metabolizmasında role merkezi bir in amino acid metabolism in roldedir. fects of multiple inh Toksik converting mammals, serbest NH4+’ün toxic kan freeileNH taşınabilmesi ! için glutamineall eight together vir 4 to glutamine for dönüştürülmesini transport in the bloodsağlar (Chapter 18). control mechanism In bacteria and plants, glutamate is produced from glutamine levels to quirements.  4 dition to its NH! hibito fects ria, it has a importance central rolefor in amino 4 assimilation acid metabolism in bacte- in ria, it has converting a central role in free amino acid ! metabolism in fects all eio mammals, toxic AMİNO ASİT BİYOSENTEZİ NH 4 to glutamine for mammals, converting toxic free NH ! all eig contr transport in the blood (Chapter 18). 4 to glutamine for Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: transport in theand blood (Chapter 18). is produced from contro gluta In bacteria plants, glutamate glutam In bacteria and plants, glutamate is produced from quire glutamine in a Glutamat, 2. Bakteri ve bitkilerde reactionGlutamat catalyzed Sentazby glutamate ile katalizlenen bir rxnsyn- ile quirem glutamine in a reaction catalyzed by glutamate syn- thase. ve"-Ketoglutarate, Glutamin an intermediate of the citric alfa-ketoglutarattan üretilir. thase. "-Ketoglutarate, an intermediate of the citric acid cycle, sitrik Alfa-ketoglutarat undergoes reductive asit döngüsünde amination bir ara moleküldür with gluta- ve nitrojen acid cycle, undergoes reductive amination with donorü gluta- mine olarak as nitrogen glutamin donor: ile indirgeyici mine as nitrogen donor: aminasyon rxnuna girer glutamine NADPH H! 88n ! "-Ketoglutarate ! ! ! "-Ketoglutarate ! glutamine ! NADPH ! H 88n 2 glutamate ! NADP 2 glutamate ! NADP ! ! (22–2) (22–2) The Thenetnetreaction reaction of of glutamine synthetase and glutamine synthetase and glutamate glutamate Glutamin Sentaz ve Glutamat Sentazın net reaksiyonu aşağıdaki şekilde özetlenebilir. synthase synthase (Eqns (Eqns 22–1 22–1 and 22–2) is NH! ! NH "-Ketoglutarate ! "-Ketoglutarate 44 ! NADPH ! ATP ! ATP 88n 88n L L -glutamate NADP! !ADP ! NADP! ! ! !PPi i ADP! Glutamate synthase Glutamate synthase is is not not present present in in animals, animals, which, which,in- in- stead, maintain stead, maintain high high levels levels of of glutamate glutamate by by processes processes such as such as the the transamination transamination of "-ketoglutarate during of "-ketoglutarate during  The net reaction of glutamine synthetase and glutamate synthase (Eqns 22–1 and 22–2) is "-KetoglutarateAMİNO ! NH! ASİT BİYOSENTEZİ 4 ! NADPH ! ATP 88n L-glutamate ! NADP ! ADP ! Pi ! Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: Glutamate synthase is not present in animals, which, in- Glutamat stead,Sentaz hayvanlarda maintain high levels yoktur. of glutamate by processes Glutamat,such as the transamination alfa-ketoglutarat’ın of "-ketoglutarate amino asit metabolizması during boyunca transaminasyonu amino acid catabolism. ile elde edilir (a) Glutamate can also be formed in yet another, albeit Minör miktarda minor, olmakla beraberthe pathway: glutamat, alfa-ketoglutarat reaction ve NH4+’ün bir of "-ketoglutarate and adımda Glutamata dönüştürülmesi ile de elde edilebilir NH! 4 to form glutamate in one step. This is catalyzed by L-glutamate dehydrogenase, an enzyme present in all or- bu rxn L-Glutamat Dehidrogenaz ile gerçekleştirilir. ganisms. Reducing power is furnished by NADPH: 4 ! NADPH 88n "-Ketoglutarate ! NH! L-glutamate ! NADP ! H2O ! We encountered this reaction in the catabolism of amino acids (see Fig. 18–7). In eukaryotic cells, L-glutamate dehydrogenase is located in the mitochondrial matrix. The reaction equilibrium favors reactants, and the Km for NH!4 (~1 mM) is so high that the reaction probably makes only a modest contribution to NH! 4 assimilation  of Mr 50,000 (Fig. 22–5) and is regulated both alloster- 4 ! ATP 88n Sum: Glutamate ! NH! ically and by covalent modification. Alanine, glycine, and glutamine ! ADP ! Pi ! H! (22–1) at least six end products of glutamine metabolism are Glutamine synthetase is found in all organisms. In ad- allosteric inhibitors of the enzyme (Fig. 22–6). Each in- dition to its importance for NH! hibitor alone produces only partial inhibition, but the ef- 4 assimilation in bacte- ria, sis of Amino Acids, Nucleotides, andit Related has a central Molecules AMİNO ASİT BİYOSENTEZİ role in amino acid metabolism in fects of multiple inhibitors are more than additive, and all eight together virtually shut down the enzyme. This mammals, converting toxic free NH! 4 to glutamine for transport in the blood (Chapter 18). control mechanism provides a constant adjustment of Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: mate requires two reactions. In bacteria Synthetase Glutamine and plants, glutamate Is a Primary is produced Regulatoryfrom Point glutamine levels to match immediate metabolic re- glutamate syn- quirements. e catalyzes the reaction of glutamine in a reaction in Nitrogen Metabolism catalyzed by glutamine. This reaction thase. "-Ketoglutarate, an intermediate of the citric enzyme-bound !-glutamyl acidThe activity cycle, of glutamine undergoes synthetase reductive amination is regulated in vir- with gluta- e (see Fig. 18–8): Glutamin Setaz Nitrojen metabolizmasının primer minetually all organisms—not as nitrogen donor: surprising, given its central metabolic role as an entry point for !reduced nitrogen. utamyl phosphate ! ADP H!4 88n glutamine ! Pi ! düzenleyicisidir. H ! "-Ketoglutarate ! glutamine In enteric bacteria such!asNADPH E. coli, glutamate ! !H the88n usually complex. The enzyme has 12 identical(22–2) 2 NADP regulation ! is un- subunits The of r 50,000 of netMreaction (Fig. 22–5) and glutamine is regulated synthetase both alloster- and glutamate 8n ically (Eqns synthase and by22–1 covalent and modification. 22–2) is Alanine, glycine, and e ! ADP ! Pi ! H! E. coli’de bu enzim 12 alt üniteden oluşan 50.000 D büyüklüğünde kompleks bir (22–1) at least six end !products of glutamine metabolism are "-Ketoglutarate ! NH4 ! of allosteric inhibitors NADPH 88n 22–6). Each in- ! ATP (Fig. the enzyme nd in all organisms. In ad- NH! yapıdır. 4 assimilation in bacte- L-glutamate ! NADP ! ADP ! Pi ! hibitor alone produces only partial inhibition, but the ef- amino acid metabolism in Glutamate fects ofsynthase multipleisinhibitors not presentareinmore thanwhich, animals, additive, in- and ree NH! to glutamine for all maintain stead, eight together high virtually levels of shut down the glutamate by enzyme. This processes 4 suchcontrol as themechanism provides a constant adjustment during of ter 18). Hem allosterik hem de kovalent modifikasyonlarla düzenlenir. utamate is produced from amino glutamine transamination of "-ketoglutarate levels to match immediate metabolic re- acid catabolism. quirements. (a) lyzed by glutamate syn- Glutamate can also be formed in yet another, albeit intermediate of the citric minor, pathway: the reaction of "-ketoglutarate and ! tive amination with gluta- NH4 to form glutamate in one step. This is catalyzed by L-glutamate dehydrogenase, an enzyme present in all or- ganisms. Reducing power is furnished by NADPH: NADPH ! H! 88n (22–2) "-Ketoglutarate ! NH4 ! NADPH 88n ! utamate ! NADP! L-glutamate ! NADP! ! H2O synthetase and glutamate –2) is We encountered this reaction in the catabolism of amino acids (see Fig. 18–7). In eukaryotic cells, L-glutamate PH ! ATP 88n dehydrogenase is located in the mitochondrial matrix. amate ! NADP! ! ADP ! Pi The reaction equilibrium favors reactants, and the K m ! esent in animals, which, in- for NH 4 (~1 m M ) is so high that the reaction probably ! of glutamate by processes makes only a modest contribution to NH4 assimilation of "-ketoglutarate during into amino acids and other metabolites. (Recall that the glutamate dehydrogenase reaction, in reverse (see Fig. (a) ! rmed in yet another, albeit 18–10), is one source of NH4 destined for the urea cy- ! n of "-ketoglutarate and cle.) Concentrations of NH4 high enough for the gluta- e step. This is catalyzed by mate dehydrogenase reaction to make a significant con- (b) an enzyme present in all or- tribution to glutamate levels generally occur only when furnished by NADPH: NH3 is added to the soil or when organisms are grown FIGURE 22–5 Subunit structure of glutamine synthetase as deter- in a laboratory in the presence of high NH3 concentra- mined by x-ray diffraction. (PDB ID 2GLS) (a) Side view. The 12 sub- PH 88n tions. In general, soil bacteria and plants rely on the two- units are identical; they are differently colored to illustrate packing -glutamate ! NADP! ! H2O enzyme pathway outlined above (Eqns 22–1, 22–2). and placement. (b) Top view, showing active sites (green).  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: E. coli Glutamin Sentaz 76 mac76:385_reb: Hem allosterik hem de kovalanet modifikasyonlarla düzenlenir. Alanin, glisin ve glutamin metabolizmasının 6 ürünü bu enzimi allosterik olarak22.1inhibe eder. Overview of Nitrogen Metabolism 839 Glutamate ulation is inhibi- NH3 P to) Tyr397, lo- 22–7). This co- glutamine synthetase ATP Her bir inhibitör tek başına kısmi inhibisyon to the allosteric sağlarken re subunits are deadenylylation ADP + Pi se (AT in Fig. ascade that re- Glycine Alanine 8 inhibitör birlikte enzimi durdurur. tarate, ATP, and s modulated by I, and the activ- nt modification Bu kontrol mekanizması Glutamin seviyesine, The adenylyl- PII (PII-UMP) e same complex acil metabolik gereksinimlerle uyumlu sürekli bir ayarlanma sağlar. AMP Glutamine CTP synthetase. The en- Tryptophan Histidine d products of gluta- erve as indicators of e cell. Carbamoyl phosphate Glucosamine 6-phosphate O Adenine ! FIGURE 22–7 Second level of regulation of glutamine synthetase:  inhibitors, and activity decreases as more subunits are adenylylated. Both adenylylation and deadenylylation ADP + Pi are promoted by adenylyltransferase (AT in Fig. Glycine 22–7), part of a complex enzymatic cascade that re- Alanine AMP Glutamine CTP sponds to levels of glutamine, !-ketoglutarate, ATP, and Pi. The activity of adenylyltransferase is modulated by binding to a regulatory protein called PII, and the activ- ity of PII, in turn, is regulated by covalent modification AMİNO ASİT BİYOSENTEZİ FIGURE 22–6 Allosteric regulation of glutamine synthetase. The en- zyme undergoes cumulative regulation by six end products of gluta- Tryptophan Histidine mine metabolism. Alanine and glycine probably serve as indicators of (uridylylation), again at a Tyr residue. The adenylyl- the general status of amino acid metabolism in the cell. Carbamoyl phosphate Glucosamine 6-phosphate Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: transferase complex with uridylylated PII (PII-UMP) stimulates deadenylylation, whereas the same complex (a) O Enzyme AMP O P O Glutamine CH 2 O CTP Adenine ! FIGURE 22–7 Second level of regulation of glutamine synthetase: Allosterik regülasyona ilaveten enzimin FIGURE 22–6 Allosteric regulation of glutamine synthetase. The en- Tryptophan aktif Obölgesinde H Histidine H yer alan Tyr covalent ! 997’nin modifications. (a) An adenylylated Tyr residue. (b) Cascade H H leading to adenylylation (inactivation) of glutamine synthetase. AT rep- adenilasyonu (AMP bağlanması) zyme undergoes cumulative regulation by six end products of gluta- mine metabolism. Alanine and glycine probably serve as indicators of da inhibisyon sağlamaktadır. resents adenylyltransferase; UT, uridylyltransferase. Details of this cas- OH OH cade are discussed in the text. the general status of amino acid metabolism in the cell. Carbamoyl phosphate Glucosamine 6-phosphate (b) (a) O " -Ketoglutarate Glutamate Enzyme O P O CH2 O Adenine ! FIGURE 22–7 Second level of regulation of glutamine synthetase: PII (a) An adenylylated Tyr residue. (b) Cascade AT O! covalent modifications. H H PII H H leading to adenylylation (inactivation) of glutamine synthetase. AT rep- resents adenylyltransferase; UT, uridylyltransferase. Details of this cas- OH OH cade are discussed in the text. ATP Bu(b) kovalent modifikasyon Pi AT PPi ATP enzimin allosterik inhibitörlere " -Ketoglutarate UTP UMPGlutamate AT adenylylation NH3 hassasiyetini P arttırır. II PII Glutamine Glutamine UT uridylylation ATP synthetase synthetase ATP (inactive) (active) Adenilasyon P ive deadenilasyon AT PP i ATP Gln AMP deadenylylation ADP Adenil transferaz UTP UMP enzimi ile adenylylation PPi H 2O NH3 + Pi kontrol edilir. Glutamine Glutamine AT ATP Pi ADP UT uridylylation synthetase synthetase (inactive) (active) AdenilGlnTransferaz, PP H O glutamin, AMP P UMP ADP +P P AT deadenylylation II i i 2 UMP II alfa-ketoglutarat, ATP AT ve Pi P ADP Glutamine i seviyelerine cevap olarak çalışan kompleks bir enzimatik kaskatın bir parçasıdır. AT PII UMP PII UMP Glutamine  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: PROLİN Glutamatın halkasal bir türevidir. 1. ATP glutamatın karboksil grubuyla bir açil fosfat oluşturmak üzere glutamat-gama- semialdehide indirgenir. NADH ya da NADPH kullanılır. 2. Bu aramolekül hızlı spontan bir halkalaşma yaşar 3. Proline indirgenir.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: ARGİNİN Ornitin yoluyla glutamattan ve hayvanlarda üre döngüsü yoluyla sentezlenir. Bakteriler ornitin biyosentezi için dolayısıyla arginin biyosentezi için de novo biyosentetik yoluna sahiptir. Bu yol prolin yoluyla bazı adımlarda paraleldir fakat glutamatsemialdehidin spontan halkalaşmasını önlemek adına 2 adım daha içermektedir.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: ARGİNİN 1. Glutamatın alfa-amino grubu asetilasyon rxnu ile bloklanır. bu rxn Asetil-CoA gerektirir. 2. Transaminasyonun ardından asetil grubu ornitin oluşturmak üzere (asetilornitaz enzimi ile )çıkarılır. 3. Ornitin sitrulin ve daha sonra Arginine çevrilir.  AMİNO ASİT BİYOSENTEZİ Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: Prolin ve Arginin yolu memelilerde farklıdır. P r o l i n g l u t a m a t t a n sentezlenebileceği gibi aynı zamanda diyetle alınan ya da doku proteinlerinden elde edilen argininden de yapılabilir.  666 Chapter 18 Amino Acid Oxidation and the Production of Urea " " NH3 NH3 AMİNO ASİT BİYOSENTEZİ " NH3 O ! R CH COO! CH3 CH COO C CH2 CH2 CH COO! Amino acids Alanine (from muscle) Metabolik prekürsörlerine göre H2N Glutamine (from -Ketoglutarate -Keto acid amino asit biyosentezi 6 sınıfa extrahepatic " tissues) NH3 ! ! OOC CH2 CH2 CH COO ayrılmaktadır: Glutamate Glutamine O ! glutaminase OOC CH2 C COO! Arginin Ornitin +üre Glutamate Oxaloacetate aspartate glutamate aminotransferase Arginaz dehydrogenase Aspartate -Keto- " glutarate NH3 " NH4 ! OOC CH2 CH COO! HCO! 3 2 ATP carbamoyl phosphate synthetase I Bir üre döngüsü enzimi olan 2ADP " Pi Carbamoyl ARGİNAZ arginini ornitin ve üreye H2N phosphate O C O O P O! dönüştürür. Mitochondrial O! 1 Pi matrix " O NH3 ! H2N C NH (CH2)3 CH COO Ornithine Citrulline Cytosol Citrulline ATP 2a PPi " NH3 " HN C NH (CH2)3 CH COO! NH3 " ! Urea O H3N (CH2)3 CH COO cycle O P O! NH2 Ornithine O N N Urea CH2 O N N O NH2 H H H2N C H H 4 Citrullyl-AMP OH OH intermediate H2O " " " Aspartate NH3 NH2 NH3 ! ! ! 2b OOC CH2 CH COO H2N C NH (CH2)3 CH COO Arginine AMP Argininosuccinate ! " " COO NH2 NH3 ! ! 3 OOC CH CH COO ! OOC CH2 CH NH C NH (CH2)3 CH COO ! Fumarate  AMİNO ASİT BİYOSENTEZİ 8885d_c22_833-880 2/6/04 8:35 AM Page 844 mac76 mac76:385_reb: Metabolik prekürsörlerine göre amino asit biyosentezi 6 sınıfa ayrılmaktadır: 844 Chapter 22 Biosynthesis of Amino Acids, Nucleotides, and Related Molecules COO# $ -Ketoglutarate COO# FIGURE 22–11 Ornithine #-aminotransferase ! ! reaction: a step in the mammalian pathway H 3N CH Glutamate H 3N CH to proline. This enzyme is found in the H2O H2C CH2 CH2 CH2 mitochondrial matrix of most tissues. H C ! CH COO# Although the equilibrium favors P5C CH2 ornithine CH2 "-aminotransferase H2O N formation, the reverse reaction is the only H mammalian pathway for synthesis of ornithine CH2 C O (and thus arginine) when arginine levels are ! NH3 H insufficient for protein synthesis. Ornithine Glutamate &1-Pyrroline-5- %-semialdehyde carboxylate (P5C) Ornitin, dehydrogenase (using NAD!) to yield 3-phosphohy- teine, which undergoes a reaction with serine, catalyzed droxypyruvate. Transamination from glutamate yields 3- by cystathionine !-synthase, to yield cystathionine phosphoserine, which is hydrolyzed to free serine by (Fig. 22–14). Finally, cystathionine "-lyase, a PLP- Ornitin aminotransferaz enzimi ile phosphoserine phosphatase. Serine (three carbons) is the precursor of glycine requiring enzyme, catalyzes removal of ammonia and cleavage of cystathionine to yield free cysteine. glutamat-semialdehide dönüştürülür. (two carbons) through removal of a carbon atom by serine hydroxymethyltransferase (Fig. 22–12). Tetrahydrofolate accepts the ! carbon (C-3) of serine, which forms a methylene bridge between N-5 and N-10 Semialdehit, to yield N 5,N10-methylenetetrahydrofolate (see Fig. COO# A pirolin-5-karboksilat halkasına 18–17). The overall reaction, which is reversible, also requires pyridoxal phosphate. In the liver of verte- HOCOOH A 3-Phosphoglycerate HOCO O O P brates, glycine can be made by another route: the re- A verse of the reaction shown in Figure 18–20c, cat- H daha sonra prolin halkasına dönüşür. alyzed by glycine synthase (also called glycine NAD! cleavage enzyme): phosphoglycerate