Nucleotide Metabolism 2024 PDF

Nucleotide metabolism Learning objectives 1. Explain the significance of nucleotide catabolism and anabolism (i.e. biosynthesis) 2. Briefly understand the oxidation of purines and pyrimidines (note the flow of Cs and Ns), and recognize the degradation products 3. Briefly understan...

Nucleotide metabolism Learning objectives 1. Explain the significance of nucleotide catabolism and anabolism (i.e. biosynthesis) 2. Briefly understand the oxidation of purines and pyrimidines (note the flow of Cs and Ns), and recognize the degradation products 3. Briefly understand the salvage reactions for nucleotides 4. Briefly understand the biosynthesis of purines, pyrimidines, and deoxyribonucleotides (note the flow of Cs and Ns) 5. Briefly explain GOUT and anticancer drugs in relation to nucleotide metabolism  Nucleotide metabolism Nucleotides - Monomeric unit of nucleic acids (DNA and RNA) - 3 structural components: Ribose, Base, Phosphate 2 Purines: Pyrimidines: 3 Other nucleotide-containing biomolecules 1. Nucleotide triphosphates - ATP, GTP, CTP, UTP 5’ 1’ 4 2. Signaling molecules - cAMP, cGMP, ppGpp - Induce molecular changes inside cells Adenine Guanine Guanine 5 3. Enzyme cofactors - ADP is a structural component in many enzyme cofactors Examples: Co-enzyme A (for transfer of fatty acyl groups) NAD(P)+ and FAD (for electron transfer reactions) Co-enzyme A (CoA) 6 FAD 7  Degradation of nucleotides NTPs, Co-enzyme A, NAD(P)+, FAD, etc. Phosphate removal Sugar removal (purines and pyrimidines) 8 (Recycling of intact bases for inter-conversions)  Catabolism of purine nucleotides (AMP and GMP) AMP ↓ Phosphate removal Adenosine GMP Phosphate removal ↓ ↓ Deamination of adenine Inosine Guanosine ↓ Sugar removal Sugar removal ↓ [Excreted in urine in human] 9 GOUT - A disease characterized by elevated levels of uric acid - May be associated with high-nucleotide diets - Accumulation of sodium urate crystals (formed from uric acid) - Painful joint inflammation (usually the big toe joint) Allopurinol - A drug for treatment of GOUT - Structurally similar to hypoxanthine (substrate for xanthine dehydrogenase) - Conversion to oxypurinol which is an inhibitor of xanthine dehydrogenase/oxidase 10  Catabolism of purine nucleotides (AMP and GMP) AMP ↓ Phosphate removal Adenosine GMP Phosphate removal ↓ ↓ Deamination of purine Inosine Guanosine ↓ Sugar removal Sugar removal ↓ Inhibition by oxypurinol 11 Catabolism of pyrimidine nucleotides (CMP, UMP, dTMP) Phosphate Deamination Sugar Sugar removal of pyrimidine removal removal CMP Cytidine Uridine Thymidine Phosphate Phosphate removal removal UMP dTMP - Nitrogens in pyrimidines are released as + NH4 and then urea - Pyrimidine carbon skeletons are degraded to acetyl CoA or succinyl CoA which can be completely oxidized 12  Salvage of purines Inter-conversions of purine nucleotides occurs mainly at monophosphate level: (PRPP: 5-phosphoriboxyl 1-pyrophosphate) 13  Salvage of pyrimidines Inter-conversions of pyrimidine nucleotides at different levels: 14  Biosynthesis of new purines - 1st step: formation of 5-phosphoriboxyl 1-pyrophosphate (PRPP) - The purine ring is assembled around the N attached to the ribose phosphate Sources of different atoms in the purine ring: Ribose 5-phosphate (from pentose phosphate pathway) AMP Multiple steps 15  Azaserine, Acivicin (anti-cancer drugs) 16 Formation of AMP and GMP from IMP: 17  Biosynthesis of new pyrimidines The ring structure is assembled before attachment of ribose phosphate: First reaction: (Cytosolic) [Recall: Carbamoyl phosphate synthetase I, a mitochondrial matrix enzyme, catalyzes the formation of carbamoyl phosphate from HCO3- and NH4+] 18 Formation of UTP from carbamoyl phosphate: Aspartate provides most of Attachment of ribose 5-phosphate the skeleton in Pyrimidine PRPP: 5-phosphoriboxyl 1-pyrophosphate (the same activated sugar used for purine nucleotide biosynthesis, see p. 14) 19 Pyrimidine ring is formed before sugar attachment Formation of CTP from UTP: 20  Biosynthesis of Deoxyribonucleotides - Most dNDPs are synthesized from their corresponding NDPs - ADP → dADP; GDP → dGDP; CDP → dCDP; UDP → dUDP - Reduction of ribose in the NDP to deoxyribose - Involvement of a series of electron transfer reactions - NADPH is the final reducing agent (NDP) (dNDP) 21 Formation of dTMP from dUMP: - methyl group transfer reaction involving tetrahydrofolate as a cofactor - Serine is the source of carbon in the methyl group transfer UDP → dUDP → dUMP dTMP Fluorouracil (anticancer drug) Methotrexate, Amphopterin (anticancer drugs) 22