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上海交大 生物化学 课件 chapter 29


CHAPTER 29 BIOSYNTHESIS OF NUCLEOTIDES

? Nucleotides play key roles in the following biochemical processes:
1. As activated precursors of DNA and RNA核酸前体 2. Their derivatives are activated intermediates in many biosyntheses, e.g. UDP-Glc and CDP-DAG and S-A Met 活性中间物 3. ATP is a universal currency of energy in biological systems, GTP powers many movements of macromolecules能量通用形式 4. Adenine nucleotides are components of 3 major coenzymes: NAD+, FAD, and CoA辅酶 5. As metabolic regulators, e.g. cAMP and ATP 代谢调 节物

? Nucleotides are synthesized from simple building blocks (de novo synthesis从头合成) or by the recycling of preformed bases (salvage synthesis节约利用途经)
– Purines (Pur.) and pyrimidines (Pyr.) are built de novo from AA, FH4 derivatives, NH4+ and CO2 – The PR moiety of ribonucleotides comes from PRPP, an activated donor

? Deoxyribonucleotides are synthesized by reduction of ribonucleotides(dNDP from NDP) ? Finally, dTMP is formed by methylation甲基化 of dUMP (UMP→ dUMP → dTMP) ? Nucleotide analogs are valuable drugs in the treatment of cancers(P753), viral infections, autoimmune diseases, and genetic disorders such as gout痛风症(P757)

The purine ring is synthesized from AA, FH4 derivatives, and CO2
? The Pur Ring is assembled de novo from several simple precursors
– 1. Gly (C-4, C-5, N-7) 2. Asp (N-1) 3. Gln (N-3, N-9)两次 – FH4 (C-2, C-8)两次 – CO2 (C-6)

PRPP is the donor of the PR unit of nucleotides (Nt)
? PRPP provides PR portion for the synthesis of Pur and Pyr Nt, just as for that of Trp

? PRPP is synthesized from ATP and R-5-P, which is primarily formed by PPP
– PRPP synthetase catalyzes the transfer of the β- γ pyrophosphoryl group of ATP to C-1 of R-5-P – PRPP has an α-configuration at C-1, the activated carbon atom α构型

The Pur ring is assembled on PR
? The committed step in the de novo synthesis of Pur Nt is the formation of 5-phosphoribosylamine (5-磷酸核糖胺) from PRPP and Gln
– catalyzed by amido-phosphoribosyl transferase 酰胺磷酸核糖转移酶 – The amide group (酰胺基) from Gln displaces the PPi group attached to C-1 of PRPP – The configuration at C-1 is inverted from α to βin this reaction – The resulting C-N glycosidic bond has βconfiguration that is characteristic of naturally occurring Nt β-构型是天然存在的核苷酸中的糖苷键的构型 – This reaction is driven forward by the hydrolysis of PPi

? PRPP→phosphoribosylamine 磷酸核糖胺 → glycinamide ribonucleotide 甘氨酰胺核苷酸 → formylglycinamide ribonucleotide 甲酰甘氨酰胺核苷酸 → formylglycinamidine ribonucleotide 甲酰甘氨脒核苷 酸→ 5-aminoimidazole ribonucleotide 5-氨基咪唑核苷酸
1N→ 2C2N → 3C2N → 3C3N→成环(3C2N+侧链1N) 胺基1N + Gly 2C1N+甲酰基1C+胺基1N → 咪唑环3C2N +侧1N

→ 5-aminoimidazole-4-carboxylate ribonucleotide 5-氨 基咪 唑 4-羧酸核苷酸→5-aminoimidazole-4-Nsuccinocarboxamide ribonucleotide 5-氨基咪唑4- N-琥珀 酸氨甲酰核苷酸→ 5-aminoimidazole-4- carboxamide ribonucleotide 5-氨基咪唑 4-氨甲酰核苷酸 → 5-formamidoimidazole-4-carboxamide ribonucleotide 5- 甲酰胺咪唑-4-氨甲酰核苷酸→ IMP 次黄苷酸
(3C2N +) 1N → 1C1N → 5C2N→ 1C2N→ 2C2N→成环(5C4N) 侧链氨基1N + CO2 1C +Asp 4C1N -延胡索酸4C+甲酰基1C→ 次 黄嘌呤5C4N

AMP and GMP are formed from IMP
? IMP, the product of the de novo pathway, is the precursor of AMP and GMP ? IMP→adenylosuccinate 腺苷琥珀酸→AMP
The difference between AMP and IMP is the substitution of an –NH2 for the =O at C-6

? IMP→XMP 黄苷酸→GMP

? In the conversions of IMP into AMP and GMP, a carbonyl (羰基) oxygen atom is replaced by an amino group
– similarly, in the synthesis of IMP—step 4; in the formation of CTP from UTP(P748); and in the conversion of Cit into Arg in the urea cycle(P635) – The common mechanistic theme of these reactions is the conversion of the carbonyl oxygen into a derivative that can be readily displaced by an amino group 羰基氧→(含有磷酸基的衍生物)→氨基

? The reaction mechanism for replacement of a carbonyl oxygen by an amino group is shown by Fig 29-8 ? The attacking nitrogen can be from NH3, Gln or Asp(三者 都有氨基), The leaving group in this class of reactions can be Pi, PPi or the AMP(三者都有磷酸基) moiety

Pur bases can be recycled by salvage 补救 reactions that utilize PRPP
? Pur Nt (嘌呤核苷酸) can be synthesized from the preformed bases (formed from the hydrolytic degradation of NA and Nt) by a salvage reaction 节约利用途经(反应)

? which is simpler and much less costly than the reactions of the de novo pathway ? In the salvage reactions补救途经(节约利用途经), the PR moiety of PRPP is transferred to a Pur to form the corresponding Nt ? Two salvage enzymes with different specificities recover Pur bases
– Adenine phosphoribosyl transferase 腺嘌呤磷酸核糖 转移酶(APRT): Adenine+ PRPP→AMP+ PPi – Hypoxanthine-guanine phosphoribosyl transferase 次黄 嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT): Hypoxanthine (or guanine)+ PRPP→IMP (or GMP)+ PPi.

AMP, GMP, and IMP are feedback inhibitors of Pur Nt biosynthesis
? The synthesis of Pur Nt is controlled by feedback inhibition and other regulatory mechanisms at several sites

? 5-phosphoribosyl-1-pyrophosphate synthetase 5磷酸核糖-1-焦磷酸合成酶, the enzyme that synthesizes PRPP, is partially inhibited by Pur Nt
– The enzyme is not totally switched off when Pur are abundant for PRPP is also a precursor of Pyr and of His

? The committed step in Pur Nt biosynthesis is the conversion of PRPP into phosphoribosylamine 磷 酸核糖胺 by Gln-PRPP amidotransferase 谷酰胺 PRPP酰胺基转移酶
– This key enzyme is feedback-inhibited by many Pur Nt – It is noteworthy that AMP and GMP, the final products of the pathway, are synergistic 协同的in inhibiting the amidotransferase

? Inosinate (IMP) (次黄苷酸) is the branch point in the synthesis of AMP and GMP
– The reactions leading away from IMP are sites of feedback inhibition – AMP and GMP inhibit the conversion of IMP into adenylosuccinate 腺苷琥珀酸 and IMP into XMP黄苷酸

? GTP and ATP are the substrates in the synthesis of AMP and GMP reciprocally 交互
– This reciprocal substrate relation tends to balance the synthesis of adenine and guanine Nt 使两种嘌呤核苷酸的合成平衡

? In E.coli, most of the gene encoding enzymes of the de novo pathway are coordinately regulated
– Specifically, their transcription is blocked by the purine repressor (Pur R) 嘌呤阻抑蛋白, a DNA-binding protein, when hypoxanthine (次黄嘌呤) and guanine are abundant. 嘌呤↑→嘌 呤阻抑蛋白与DNA结合→ 阻断转录→编码从头合成嘌呤核苷 酸的酶↓

The Pyr ring is synthesized from carbamoyl phosphate 氨甲酰磷酸and Asp
? the Pyr ring is assembled first and then linked to PR to form a Pyr Nt, in contrast with the reaction sequence in the de novo synthesis of Pur Nt 嘌呤核苷酸的合成是在磷酸核糖 (PR)的基础上合成嘌呤环(碱基);而嘧啶核苷酸的合成则 是先合成嘧啶环(碱基),再加入磷酸核糖(PR). ? The precursors of the Pyr ring are carbamoyl phosphate and Asp ? There are two major differences in the synthesis of carbamoyl phosphate used to synthesize Pyr and to make urea
– compartmentation: (in eukaryotes) in the cytosol (for Pyr) and in mito (for urea), respectively, and by different carbamoyl phosphate synthetase 区域不同(合成酶不同)

– Gln rather than NH4+ is the N donor in the cytosolic synthesis of carbamoyl phosphate 氮供体不同
? Also, N-acetylglutamate does not serve as an allosteric activator in the cytosolic synthesis. (变构激活剂需否) ? Gln+ 2ATP+ HCO3- → carbamoyl phosphate+ 2ADP+ Pi+ Glu

? The committed step in the biosynthesis of Pyr is the formation of Ncarbamoylaspartate N-氨甲酰天冬氨酸 from Asp and carbamoyl phosphate 4C1N + 1C1N = 5C2N = 4C2N(嘧啶环) +1C(侧链羧基, 后脱去) – This carbamoylation 氨甲酰化 is catalyzed by Asp transcarbamoylase 天冬氨酸转氨甲酰酶

? The Pyr ring is formed in the carbamoylaspartate cyclization环 化 with loss of water to yield dihydroorotate (DHO, 二氢乳清 酸,由二氢乳清酸酶催化). ? Orotate (乳清酸) is then formed by dehydrogenation of DHO(由 二氢乳清酸脱氢酶催化).

Orotate acquires a PR moiety from PRPP to form a Pyr Nt
? Orotate→orotidylate (OMP) (乳清苷酸)→UMP
– acquisition of a PR group from PRPP to form a Pyr Nt, this reaction is driven by the hydrolysis of PPi – OMP is decarboxylated to yield UMP, a major Pyr Nt

Pyr biosynthesis in higher organisms is catalyzed by multifunctional enzymes
? In E .coli 6 enzymes that synthesize UMP from simple precursors appear to be unassociated ? In eukaryotes, by contrast, 5 of them are clustered in two complexes
– One of these multifunctional enzymes was discovered when cultured mammalian cells were treated with N-(phosphonacetyl)-L-Asp (PALA, N-磷 酸乙酰-L-天冬氨酸) 用抑制剂处理培养的哺乳细胞,发现(在克服抑制作 用而继续存活的细胞中)三种酶(Carbamoyl phosphate synthetase, Asp transcarbamoylase, and DHOase )的浓度都(同时)提高了100倍 – Carbamoyl phosphate synthetase, Asp transcarbamoylase, and DHOase are covalently joined in a single 240-kd polypeptide chain – This multifunctional enzyme is called CAD – Orotate乳清酸PR transferase and OMP decarboxylase are also associated in eukaryotes

? Multifunctional enzymes also mediate the synthesis of Pur in vertebrates (step2+3+5; 6+7; 9+10)

? Indeed, the covalent linkage of functionally related enzymes occurs often in eukaryotes 真核生物中功能相关 的酶经常共价连接在一起(在同一条多肽链上)
– The mammalian FA synthase, which contains 7 enzymatic activities in each of two chains, is another striking example

? The clustering of enzymes catalyzing a reaction sequence has several potential advantages
– their synthesis is coordinated and their assembly into a coherent complex is easily assured协调合成 – side reactions are minimized as substrates are channeled from one catalytic site to the next副作用少 – a covalently linked multifunctional complex is likely to be more stable than one formed by noncovalent interactions稳定

? Multifunctional enzymes probably evolved by exon shuffling外显子改组

Nucleoside (Ns) mono-, di-, and triphosphates are interconvertible
? The active forms of Nt in biosynthesis and energy conversions are NDP and NTP ? conversion of NMP to NDP is catalyzed by specific nucleoside monophosphate kinase 核苷 单磷酸激酶 (1→2)
– that utilize ATP as the phosphoryl donor e.g : – UMP+ ATP→UDP+ ADP; – AMP+ ATP→2ADP

? Ns diphosphates and triphosphates are interconverted by nucleoside diphosphate kinase 核苷二磷酸激酶, an enzyme that has broad specificity (2→3) ? XDP+ YTP → XTP + YDP X and Y can be any of several ribonucleosides or deoxyribonucleosides

CTP is formed by aminationan of UTP
? both CTP and UTP are the major Pyr ribonucleotides
– The only difference: carbonyl oxygen at C-4(UTP) is replaced by an amino group(CTP)

? In mammals, amide group of Gln is amino donor, whereas in E.coli NH4+ is used in this reaction ? Mammals avoids having a high level of NH4+ in plasma by generating it in situ 原位from a donor such as Gln – ATP is consumed in both amination reactions – As in the conversions of IMP to AMP and GMP, an acyl phosphate intermediate酰基磷酸中间物 is nucleophilically亲核 attacked by a nitrogen atom

Pyr Nt biosynthesis in bacteria is regulated by feedback inhibition
? The committed step in Pyr Nt biosynthesis in E.coli is the formation of N-carbamoylaspartate from Asp and carbamoyl phosphate ? Aspartate transcarbamoylase (ATCase), the enzyme that catalyzes this reaction is feedbackinhibited by CTP, the final product in the pathway ? A second control site is carbamoyl phosphate synthetase, which is feedback-inhibited by UMP

Ribonucleotide reductase 核苷酸还原酶, a radical自由基 enzyme, catalyzes the synthesis of deoxyribonucleotides脱氧核苷酸
? dNt are the precursors of DNA, that are formed by the reduction of ribonucleotides
– The 2’-hydroxyl group on the ribose moiety is replaced by a hydrogen atom

? substrates are ribonucleoside diphosphates or triphosphates (NDP or NTP), and ultimate reductant is NADPH: NDP→dNDP ? The electrons from NADPH are transferred to the substrate through a series of carriers:
– – – – a flavin黄素 the sulfhydryls巯基 of a small protein a pair of irons that generate a tyrosyl radical and then another pair of sulfhydryls

? Ribonucleotide reductase catalyzes the final stage:

The substrate specificity and catalytic activity of ribonucleotide reductase are precisely controlled
? There are two allosteric sites in ribonucleotide reductase: one for overall activity(1), another for substrate specificity(2,3,4) 1. NDP → dNDP ATP+, dATP- (overall catalytic activity) 核糖 核苷酸促进,脱氧核糖核苷酸抑制(脱氧核糖核苷酸的形成), 以保 持核糖核苷酸和脱氧核糖核苷酸之间的平衡 2. UDP (CDP) → dUDP (dCDP) dATP or ATP+ (the balance between Py and Pu)嘌呤核苷酸(或脱氧嘌呤核糖核苷 酸)促进脱氧嘧啶核糖核苷酸合成 3. GDP→dGDP dTTP+ (the balance between Py and Pu) 脱氧嘧啶核糖核苷酸促进脱氧嘌呤核糖核苷酸合成 4. ADP→dADP dGTP+ (the balance between two different Pu Nt) 鸟嘌呤脱氧核糖核苷酸促进腺嘌呤脱氧核糖核苷酸合成

Thioredoxin 硫氧还蛋白 and glutaredoxin 谷氧还蛋白 carry electrons to ribonucleotide reductase(RR)
? Two carriers of reducing power to ribonucleotide reductase were found—thioredoxin and glutaredoxin ? The process of the transfer of the reducing power (NADPH还原力 →RR核糖核苷酸还原酶→ribose unit底物) is shown:
– NADPH→TR (FAD+TR) 硫氧还蛋白还原酶→T硫氧还蛋白 →RR→ribose unit – NADPH→GR (GR+ FAD) 谷氧还蛋白还原酶→G 谷胱甘肽→GX 谷氧还蛋白→RR→ribose unit

Deoxythymidylate (dTMP) is formed by methylation甲基化 of deoxyuridylate (dUMP)
? uracil is not a component of DNA
– Rather, DNA contains thymine, the methylated analog of uracil

? thymidylate synthase胸苷酸合酶catalyzes this finishing touch: dUMP is methylated to dTMP

? The methyl donor in this reaction is a FH4 derivative (N5,N10-methylene FH4) rather than S-A Met ? What is the source of electrons for this reduction?

– The methyl group inserted into dTMP is more reduced than the methylene group in the donor – The two electrons come in the form of a hydride ion (H-) from the FH4 moiety itself – This hydrogen becomes part of the methyl group of dTMP

? In this reaction, FH4 is oxidized to FH2. Thus N5, N10methylene FH4 serves both as an electron donor and as a one-carbon donor in the methylation reaction 既作为电 子供体,又作为一碳单位供体
– We see here, as in the synthesis of Pu, the key role of FH4 derivatives. – Indeed, Nt metabolism and AA metabolism are closely tied by one-carbon transfer 核苷酸代谢和AA代谢通过一碳单位转 移而密切连接

Three-dimensional structure of E.coli dihydrofolate reductase with a bound methotrexate.

? It is noteworthy that the deoxyribose and thymine units of DNA are formed by modification of ribonucleotides DNA中的脱氧核糖和胸腺嘧啶 由RNA中的核糖核苷酸修饰后形成
– In contrast, no known ribonucleotide is formed from a deoxyribonucleotide – These precursor-product relations strongly imply that ribonucleotides came first in evolution – The reactions catalyzed by ribonucleotide reductase and thymidylate synthase are recapitulations (重述) of the transition from a RNA world to one in which DNA became the store of genetic information

Potent competitive inhibitors of dihydrofolate reductase

(A)The anticancer drugs aminopterin 氨基蝶呤(4-氨基 叶酸) and methotrexate氨甲 蝶呤 contain an – NH2 group in place of the –OH group of dihydrofolate. Methotrexate also differs in having a –CH3 group instead of –H at N10. (B)Trimethoprim 三甲氧苄二氨嘧啶, an antibacterial folate analog.

FH2 reductase catalyzes the regeneration of FH4, a one-carbon carrier
? For carrying OCU, FH4 must be regenerated from FH2 that is produced in the synthesis of dTMP
– This is accomplished by FH2 reductase using NADPH as the reductant: FH2+NADPH+ H+ →FH4+ NADP+ – A hydride ion is directly transferred from nicotinamide ring of NADPH to pteridine ring of FH2

Several valuable anticancer drugs block the synthesis of dTMP
? Rapidly dividing cells require an abundant supply of dTMP for the synthesis of DNA ? The vulnerability易受性 of these cells to the inhibition of dTMP synthesis has been exploited in cancer chemotherapy ? dTMP synthase胸苷酸合酶 and FH2 reductase 二氢叶酸还原酶 are choice target enzymes
– Fluorouracil 氟尿嘧啶 or fluorodeoxyuridine 氟脱氧尿苷, a chemically useful anticancer drug, is converted in vivo into fluorodeoxyuridylate (F-dUMP) – This analog of dUMP irreversibly inhibits thymidylate synthase after acting as a normal substrate through part of the catalytic cycle – First, a sulfhydryl group of the enzyme adds to C-6 of the bound FdUMP

? -CH2-FH4 then adds to C-5 of this intermediate
– In the case of dUMP, a hydride ion of the folate is subsequently shifted to the –CH2-, and a proton is taken away from C-5 of the bound Nt – However, F+ cannot be abstracted from F-dUMP by the enzyme, and so catalysis is blocked at the stage of the covalent complex formed by (1) F-dUMP, (2) –CH2-FH4, and (3)-SH of the enzyme – This is an example of suicide inhibition自杀抑制, in which an enzyme converts a substrate into a reactive inhibitor that immediately inactivates its catalytic activity

? The synthesis of dTMP can also be blocked by inhibiting the regeneration of FH4 ? Analogs of FH2, such as aminopterin氨基蝶呤 and methotrexate 氨甲蝶呤, are potent competitive inhibitors (Ki <1nmol/L) of FH2 reductase

? Methotrexate is a valuable drug in the treatment of many rapidly growing tumors, such as acute leukemia and choriocarcinoma 绒毛膜癌 ? However, it is quite toxic because it kills rapidly replicating cells whether they are malignant恶性 or not
– Stem cells in bone marrow 骨髓, epithelial cells上皮细胞of the intestinal tract, and hair follicles毛囊 are vulnerable to the action of this folate antagonist拮抗剂, accounting for many of its toxic side effects

? Folate analogs such as trimethoprim 三甲氧苄二氨嘧啶 binds 105-fold less tightly to mammalian FH2 reductase than it does to reductases of susceptible microorganisms

NAD+, FAD, and CoA are formed from ATP

? NAD+: nicotinate 烟酸, 或尼克酸→nicotinate Nt烟酸核 苷酸 – Nicotinate is derived from Trp. Humans can synthesize the required amount of it if the supply of Trp in the diet is adequate – However, an exogenous supply of it is required if the dietary intake of Trp is low

? A dietary deficiency of Trp and nicotinate can lead to pellagra 糙皮病, a disease charecterized by dermatitis 皮 炎, diarrhea 腹泻, and dementia 痴呆 ? Nicotinate Nt → desamido-NAD+ 脱酰胺NAD+ →NAD+ ? NADP+ is derived from NAD+ by phosphorylation of the 2’-hydroxyl group of the adenine ribose moiety – This transfer of a phosphoryl group from ATP is catalyzed by NAD+ kinase

? FAD: riboflavin 核黄素 (VB2)→riboflavin 5’phosphate (or flavin mononucleotide)→ flavin adenine dinucleotide 黄素 腺嘌呤二核苷酸 ? Both 5’-phosphate and AMP unit come from ATP, so 2 ATP consumed here

? CoA: the AMP moiety of CoA also comes from ATP
– pantothenate泛酸(+ATP) →4’-phosphopantothenate 4’-磷酸泛酸 (+Cys+ATP) →4’-phosphopantothenyl cystein 4’-磷酸泛酰半胱 氨酸(-CO2)→4’-phosphopantotheine 4’-磷酸泛酰巯基乙胺 (+ATP) →dephospho-CoA 脱磷酸CoA(+ATP)→CoA

? A common feature of the biosyntheses of NAD+, FAD, and CoA is the transfer of the AMP moiety of ATP to the phosphate group of a phosphorylated intermediate ATP将 AMP(单位)转移到磷酸化中间物的磷酸基上 ? The PPi formed in these condensations is then hydrolyzed to Pi
– As in many other biosyntheses, much of the thermodynamic driving force comes from the hydrolysis of the released PPi

Pu in humans are degraded to urate 尿酸
? The Nt of a cell undergo continuous turnover
– Nt are hydrolytically degraded to Ns by nucleotidase 核苷酸酶 – Phosphorylytic cleavage of Ns to free bases and R-1-P (or deoxyribose 1-P) is catalyzed by Ns phosphorylases 核苷磷酸 化酶 – R-1-P is isomerized by phosphoribomutase磷酸核糖变位酶to R-5-P, a substrate in the synthesis of PRPP

? Some of the bases are reused to form Nt by salvage pathways

? AMP→IMP(脱氨,腺苷酸脱氨酶)→hypoxanthine 次黄嘌呤 (水解除去磷酸,磷酸解切出核糖)→xanthine黄嘌呤→uric acid尿酸(以上两步都由黄嘌呤氧化酶催化) ? In humans, urate is the final product of Pu degradation and is excreted in the urine

Gout 痛风 is induced by high serum levels of urate尿酸
? Hyperuricemia 高尿酸血can induce gout, a disease that affects the joints and kidneys
– Inflammation of the joints is triggered by the precipitation of sodium urate尿酸钠crystals

Micrograph of sodium urate crystals.

Gout is thought to be an inherited metabolic disease
– A small proportion of patients with gout have a partial deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT), the enzyme catalyzing the salvage synthesis of IMP and GMP – A deficiency of HGPRT leads to reduced synthesis of GMP and IMP by the salvage pathway – The consequent increase in the level of PRPP markedly accelerates Pu biosynthesis by the de novo pathway ? The formation of 5-phosphoribosyl-1-amine, the first committed intermediate, is normally limited by the availability of PRPP ? Excessive PRPP also interferes with feedback inhibition of the amidotransferase 转酰胺酶 that catalyzes this step
HGPRT部分缺陷→节约利用途径受阻→PRPP增加(变构调控受损的高活 性PRPP合成酶也导致PRPP增加) → 嘌呤从头合成加速 (限速酶活性升 高)→ 嘌呤分解产物(尿酸)增多 → 痛风症

– Gout can also result from excess PRPP produced by a hyperactive synthetase 高活性PRPP合成酶having impaired allosteric regulation

? Allopurinol 别嘌呤醇, an analog of hypoxanthine is extensively used to treat gout
– Its mechanism of action is that it acts first as a substrate and then as an inhibitor of xanthine oxidase先作为黄嘌呤氧化酶的底 物,(经催化改变)后作为此酶的“自杀”性抑制剂 – The oxidase hydroxylates it to alloxanthine 别黄嘌呤, which then remains tightly bound to the active site – The molybdenum钼 atom of xanthine oxidase is kept in the +4 oxidation state by the binding of alloxanthine instead of returning to the +6 oxidation state as in a normal catalytic cycle

? We see here another example of suicide inhibition. (another example: 5-Fu or F-dUMP) 自杀性抑制(原本不具抑制作用的底物经酶的催 化作用后与酶共价结合并使之立即失活,即酶‘自杀“. 别嘌呤 醇—黄嘌呤氧化酶; 5-Fu —胸苷酸合酶) ? The synthesis of urate from hypoxanthine and xanthine decreases soon after the administration of allopurinol. ? Hence, the serum concentration of hypoxanthine and xanthine rise, whereas that of urate drops 血清中次黄嘌呤(和黄嘌呤)浓度升高, 而 尿酸浓度降低

? The formation of uric acid stones is virtually abolished by allopurinol, and the arthritis becomes less severe. ? Also, the rate of Pu biosynthesis decreases because allopurinol sequesters 螯合 PRPP by forming the Nt ? Furthermore, allopurinol ribonucleotide inhibits the conversion of PRPP into phosphoribosylamine 别嘌呤醇抑制黄嘌呤氧化酶(减少尿酸的生成),螯合 PRPP(形成核 苷酸)从而减少嘌呤的从头合成,此别嘌呤醇核苷酸抑制由 PRPP(+Gln)生成5-磷酸核糖胺(限速步骤)

Urate plays a beneficial role as a potent antioxidant
? average serum level of urate in humans is close to solubility limit and is tenfold higher than prosimians 原猴类 ? A striking increase in urate level occurred in the evolution of primates 灵长目 ? What is selective advantage of a urate level so high that it teeters on the brink of 甘冒风险 gout in many people? 人类血清中尿酸的浓度是原猴类的十倍,已接近其溶解 度的极限(类似地,哺乳动物血红素降解的最终产物是 胆红素而不是胆绿素,它也存在溶解度低的问题)

– It turns out that urate has a markedly beneficial action . – Urate is a very efficient scavenger 清道夫 of highly reactive and harmful oxygen species 高度有害的活性氧类物质—
? namely, hydroxyl radicals 自由基 ? suproxide anion 超氧化物阴离子 ? singlet oxygen单线态氧 ? and oxygenated 氧合heme intermediates in high Fe valence states (+4 and +5)

– Indeed, urate is about as effective as ascorbate 抗坏血 酸as an antioxidant – The increased level of urate in humans compared with prosimians and other lower primates may contribute significantly to the longer life span of humans and to the lower incidence of human cancer

? We see in urate, as in bilirubin, an expression of the principle
– that some end products of degradative metabolic pathways play important roles as protective agents 降解 代谢途径的某些最终产物作为保护剂而发挥重要作 用

Lesch-Nyhan syndrome 莱-纳二氏综合症: selfmutilation 自毁容貌, mental retardation, and excessive production of urate
? A nearly total absence of HGPRT has devastating consequences HGPRT完全缺如(痛风症中此酶部分缺陷) ? The most striking expression of this inborn error of metabolism, called the Lesch-Nyhan syndrome, is compulsive self-destructive behavior
– They also tend to be aggressive toward others – Mental deficiency and spasticity 痉挛 are other characteristics of the syndrome

? The disease is inherited as a sex-linked recessive disorder. ? The biochemical consequences of the virtual absence of HGPRT are an elevated concentration of PRPP, a marked increase in the rate of Pu biosynthesis by de novo pathway, and an overproduction of urate

? The relation between the absence of the transferase(HGPRT) and the bizarre 古怪的 neurologic signs is an enigma
– The brain may be very dependent on the salvage pathway for the synthesis of IMP and GMP – In brain, HGPRT↑, amido-transferase (AT)↓ – Allopurinol cannot lower the PRPP level of this type of patients and so de novo Pu synthesis is not diminished. It fails to alleviate 缓解the neurologic symptoms别嘌呤醇 对此病症无效

? This syndrome demonstrates that the salvage pathway for the synthesis of IMP and GMP is not gratuitous无缘无故
– This pathway evidently serves a critical role that is not yet fully understood – Furthermore, the interplay between the de novo and salvage pathways of Pu synthesis remains to be elucidated – Moreover, this syndrome reveals that abnormal behavior or such as self mutilation and extreme hostility can be caused by the absence of a single enzyme


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