《生物化学—代谢篇》第二十三章 核苷酸代谢

第23章 核苷酸代謝

第23章 核苷酸代谢

、核苷酸降解代谢 1. Uric acid is the excreted end product of purine catabolism in humans and many other animals For adenosine, the amino group is hydrolyzed before the ribose group is removed For guanosine, the amino group is hydrolyzed after the ribose group is removed Xanthine oxidase, having multiple cofactors (including an FAD, a Mo complex, four different Fe-s clusters), catalyzes the o2-dependent conversion of hypoxanthine to xanthine and xanthine to uric acid

一、核苷酸降解代谢 1. Uric acid is the excreted end product of purine catabolism in humans and many other animals • For adenosine, the amino group is hydrolyzed before the ribose group is removed. • For guanosine, the amino group is hydrolyzed after the ribose group is removed. • Xanthine oxidase, having multiple cofactors (including an FAD, a Mo complex, four different Fe-S clusters), catalyzes the O2 -dependent conversion of hypoxanthine to xanthine and xanthine to uric acid

Uric acid can be further converted to allantoin allantoate urea or Nh4+ in various animals. The deficiency of adenosine deaminase causes the severe immunodeficiency disease in humans (it is likely the accumulated adenosine is converted to datP which inhibits the formation of all dNdps by ribonucleotide reductase) Overproduction of uric acid was revealed to cause gout(痛风) Allopurinol, an inhibitor of xanthine oxidase is used to treat gout

• Uric acid can be further converted to allantoin, allantoate, urea or NH4+ in various animals. • The deficiency of adenosine deaminase causes the severe immunodeficiency disease in humans (it is likely the accumulated adenosine is converted to dATP, which inhibits the formation of all dNDPs by ribonucleotide reductase). • Overproduction of uric acid was revealed to cause gout (痛风). • Allopurinol, an inhibitor of xanthine oxidase, is used to treat gout

Dephosphorylation.O Excreted by Pi GMP nosine HNO Dephosphorylation HoO HgO -OH Uric acid Primates, birds reptiles, insects Deamination HO Guanosine Inosine 402+HO te oxdase Deribosylation h,o Hao Deribosylatio cO Ribose Ribe NHg C c-o Allantoin Most mammals HN HN Hy ypoxanthin °°首首(尿囊素) (keto form) H2N N H2 H2O xanthinekH20+O% oxidase,Hyo NH2CO0 NH2 NH: Oxidatio Allanton Bony fishes Deamination guanine 、黄嘌呤) HO (尿囊酸) HO N COO CHO xanthine H,0 +O2 oxidase →H2O2 Oxidatio Amphibians, Urea cartilaginous 2 H2N-C-NHg HN 2H20 -OH →2 HO N Mar ANHA invertebrates Uric acid 尿

(黄嘌呤) (尿酸) (尿囊素） (尿囊酸) Dephosphorylation Dephosphorylation Deamination Deamination Deribosylation Deribosylation Oxidation Oxidation

OH OH C、已 C N C N C N CH HC C HC C N且 N且 Allopurinol Hypoxanthine (enol form) Allopurinol was designed to be a competitive inhibitor of xanthine oxidase to treat gout by Elion and Hitchings who shared the nobel prize in 19 88 for their discoveries of important principles for drug treatment

Allopurinol was designed to be a competitive inhibitor of xanthine oxidase to treat gout by Elion and Hitchings, who shared the Nobel Prize in 1988 for their discoveries of important principles for drug treatment

2. Pyrimidines are broken down via reduction The degradation of thymine produces mathylmalonyl-CoA, which can be converted to succinyl-CoA (a citric acid cycle intermediate) by the catalysis of of uracil and cytidine produces malonyl-CoA, which is one precursor for fatty acid biosynthesis To a limited extent, catabolism of pyrimidine nucleotides contributes to the energy metabolism of the cell

2. Pyrimidines are broken down via reduction • The degradation of thymine produces mathylmalonyl-CoA, which can be converted to succinyl-CoA (a citric acid cycle intermediate) by the catalysis of of uracil and cytidine produces malonyl-CoA, which is one precursor for fatty acid biosynthesis. • To a limited extent, catabolism of pyrimidine nucleotides contributes to the energy metabolism of the cell

C-CHs Degradation products of NADPH.H NADP pyrimidines can enter the citric acid cycle Ce CH. Dihydrothymine dahrydropyn ate/H, o I2N-C-NH-CH-CH-c B Ureidoisobutyrate CHs , O NHI+ HCO H N-CH -CH-C a-Ketoglutarate → Glutamate Propionyl-COA SuccinyI-CoA Methylmalonyl- semialdehyde

Propionyl-CoA Succinyl-CoA Degradation products of pyrimdines can enter the citric acid cycle

核苷酸的生物合成 1. Nucleotides are synthesized via either the de novo pathways or the salvage pathways In the de novo pathway simple precursors, including amino acids, PRPP, NH+ CO2r and one-carbon units(carried on Ha folate) are used In the salvage pathway the free bases and nucleosides released from nucleic acid breakdown are used

二、核苷酸的生物合成 1. Nucleotides are synthesized via either the de novo pathways or the salvage pathways • In the de novo pathway simple precursors, including amino acids, PRPP, NH4 +, CO2 , and one-carbon units (carried on H4 folate) are used. • In the salvage pathway the free bases and nucleosides released from nucleic acid breakdown are used

The free bases(a, G, C U, tare not intermediates during the de novo synthesis: the purine ring is assembled on ribose phosphate to make amp and gmp, the pyrimidine ring is first synthesized as orotate(乳清酸), Which is then attached to ribose phosphate before being converted to UTP and ctP(dTmp is made from dUMP) The deoxyribonucleotides(dNDPs)are synthesized by reduction of ribonucleotides (NDPS)

• The free bases (A, G, C, U, T) are not intermediates during the de novo synthesis: the purine ring is assembled on ribose phosphate to make AMP and GMP; the pyrimidine ring is first synthesized as orotate（乳清酸）, which is then attached to ribose phosphate before being converted to UTP and CTP (dTMP is made from dUMP). • The deoxyribonucleotides (dNDPs) are synthesized by reduction of ribonucleotides (NDPs)

2. Radioisotope tracer(放射同位素示踪 experiments revealed the origins of the atoms in the purine and pyrimidine rings Buchanan and Greenberg revealed this by feeding a variety of isotopically labeled compounds to pigeons(1940s) The atoms of the purine rings were found to be derived from formate, co2, Gly, Asp, and gIn The atoms of the pyrimidine rings were found to be derived from Asp, gIn and HCO3-

2. Radioisotope tracer(放射同位素示踪) experiments revealed the origins of the atoms in the purine and pyrimidine rings • Buchanan and Greenberg revealed this by feeding a variety of isotopically labeled compounds to pigeons (1940s). • The atoms of the purine rings were found to be derived from formate, CO2 , Gly, Asp, and Gln. • The atoms of the pyrimidine rings were found to be derived from Asp, Gln and HCO3 -