Nucleotide Degradation
Nucleotide Degradation The Digestion Pathway • Ingestion of food always includes nucleic acids. • As you know from BI 421, the low pH of the stomach does not affect the polymer. • In the duodenum, zymogens are converted to nucleases and the nucleotides are converted to nucleosides by non-specific phosphatases or nucleotidases.
nucleases • Only the non-ionic nucleosides are taken & phospho- diesterases up in the villi of the small intestine. Duodenum Non-specific phosphatases • In the cell, the first step is the release of nucleosides) the ribose sugar, most effectively done by a non-specific nucleoside phosphorylase to give ribose 1-phosphate (Rib1P) and the free bases. • Most ingested nucleic acids are degraded to Rib1P, purines, and pyrimidines.
1 Nucleotide Degradation: Overview Fate of Nucleic Acids: Once broken down to the nitrogenous bases they are either: Nucleotides 1. Salvaged for recycling into new nucleic acids (most cells; from internal, Pi not ingested, nucleic Nucleosides acids). Purine Nucleoside Pi aD-Rib 1-P (or Rib) 2. Oxidized (primarily in the Phosphorylase & intestine and liver) by first aD-dRib 1-P (or dRib) converting to nucleosides, Bases then to –Uric Acid (purines) –Acetyl-CoA & Purine & Pyrimidine Oxidation succinyl-CoA Salvage Pathway (pyrimidines) The Salvage Pathways are in competition with the de novo biosynthetic pathways, and are both ANABOLISM
Nucleotide Degradation Catabolism of Purines
Nucleotides:
Nucleosides:
Bases:
1. Dephosphorylation (via 5’-nucleotidase) 2. Deamination and hydrolysis of ribose lead to production of xanthine. 3. Hypoxanthine and xanthine are then oxidized into uric acid by xanthine oxidase. Spiders and other arachnids lack xanthine oxidase.
2 Nucleotide Degradation Catabolism of Purines
Nucleotides:
Nucleosides:
Bases:
1. Dephosphorylation (via 5’-nucleotidase) 2. Deamination and hydrolysis of ribose lead to production of xanthine. 3. Hypoxanthine and xanthine are then oxidized into uric acid by xanthine oxidase. Spiders and other arachnids lack xanthine oxidase.
Nucleotide Degradation Xanthine Oxidase
Hypoxanthine
H2O2 Hydride abstraction FAD Mo complex 2-FeS clusters
O2
Mechanism H+
3 Nucleotide Degradation Xanthine Oxidase
Hypoxanthine
H2O2 Hydride abstraction FAD Mo complex 2-FeS clusters
O2
Mechanism H+
Nucleotide Degradation Excess Uric Acid causes Gout • Painful joints (often in toes) due to deposits of sodium urate crystals • Primarily affects males • May involve genetic under- excretion of urate and/or may involve overconsumption of fructose • Treated with avoidance of purine- rich foods (seafood, liver) or avoidance of fructose
• Also treated with xanthine oxidase Allopurinol Inhibits inhibitor allopurinol Xanthine Oxidase
Oxypurinol binds tightly as a competitive inhibitor, locking XO in the reduced form.
4 Nucleotide Degradation
• Degree of further oxidation of uric acid is organism dependent.
O 2 + 2H2O • Birds and insects don’t excrete “urate dioxygenase” Cu + H2O 2 amino-acid nitrogen as urea, but as uric acid to conserve water.
Conversion of Uric Acid to Allantoin, Allantoate, and Urea
Nucleotide Degradation In muscle Purine Nucleotide Cycle …a way to get energy back when ATP low (AMP high)
Net:
Myoadenylate deaminase deficiency
5 Nucleotide Degradation Hyperuricemia: how sugar becomes fat • The interesting connection between sugar metabolism and nitrogen metabolism • What is even more interesting is that this metabolism is connected to fat metabolism as well • The production of Uric Acid converts liver mitochondria to fatty acid synthesis by unknown mechanisms.
Nucleotide Degradation Hyperuricemia: how sugar becomes fat • The interesting connection between sugar metabolism and nitrogen metabolism • What is even more interesting is that this metabolism is connected to fat metabolism as well • The production of Uric Acid converts liver mitochondria to fatty acid synthesis by unknown mechanisms.
6 Nucleotide Degradation Catabolism of Pyrimidines •Leads to NH + and urea nucleotidase 4 cytidine deaminase
Uridine/deoxythymidine •T is degraded to phosphorylase succinyl-CoA. •U & C are degraded to acetyl-CoA
Like reaction converting Orn to glutamate semialdehyde CoASH Val Like reaction putting CoA b-Alanine on isobutryl-semialdehyde aminotransferase CoASH in Val degradation methylmalonyl-CoA || || NAD+ NADH malonic semialdehyde methylmalonate-semialdehyde oxidative decarboxylase dehydrogenase (acylating)
Catabolism Nitrogen Metabolism Anabolism Nucleic Acids
Nucleotides Nucleosides Bases a- Uric acid 2° products CO2
+ NH4 a-Keto acids [N,Q,H(2),S,T,G,M,W(I)] a-Ketoglutarate Glutamate Urea cycle Sugars Aspartate Oxaloacetate Fatty acids
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