1 INTRODUCTION TO URIC ACID METABOLISM Uric acid is a purine base, amongst others (adenine, guanine, xanthine and hypoxanthine), that is derived from (i) de novo synthesis of purines or (ii) dietary purines. It is the end-product of purine metabolism Its metabolism (anabolism + catabolism) involves ONLY its anabolism becos once formed, it cannot be degraded by the human body; so, it’s eliminated via urine or feaces. Defect in this elimination results hyperuricemia and gout, and contribute to renal calculi PURINE BIOCHEMISTRY Purine base = pyrimidine ring (5C) + an Imidazole ring (6C) -We’ve mentioned the imp ortant purines bases: oAdenine, Guanine, Hypoxanthine, xanthine, Uric acid They ALL show lactam-lactim isomerism Purine nucleoside = purine base + a pentose (ribose) sugar joined by N-glycosyl bond btw carbon atom 1 (ofthe pentose) and Nitrogen atom 9 of the purine -There r 2 categories of purine Nucleoside ; oRibonucleoside –contain D-ribose oDeoxynucleoside –contains Deoxyribose -The names of the nucleoside will be Adenosine, Guanosine, xanthosine, …Purine nucleotide = purine nucleoside (i.e. Ribonucleoside or Deoxyribonucleosid) + phosphate in ester linkage with C-5 of the pentose -The phosphate are designated α, β, and γFUNCTIONS OF PURINE BASES i.Building blocks for RNA and DNA ii.Precursor of cyclic nucleotides like cAMP, cGMP, … that r involved in signal transduction iii. Source of chemical energy e.g. ATP, GTP iv.Precursor of purine cofactors and co-enzymes such as NAD (nicotinamide adenine dinucleotide) PURINE METABOLISM Purine anabolism/synthesis -Involves 2 ways oDe novo synthesis oSalvage pathway, an alternate pathways -Sources of purine for anabolism oENDOGENOUS: They may be synthesized denovofrom small molecules oEXOGENOUS (or dietary): derived from the breakdown of ingested nucleic acid, mostly from cell-rich meat. Plant diets are generally poor in purines. De novo Synthesis : First a preparatory phase takes place whereby a backbone of ribose 5-phosphate denoted by 5- phosphoribosyl phosphate (= ribose 5-phosphate + ATP) is formed, catalysed by Phosphoribosyl phosphate synthase (PRPP synthase) Next, is the synthesis of purine by sequential adding ofsmall molecule precursors (of uric acid) to this PRPP. The 1 st rxn is the committed step, catalyzed by Amido- phosphoribosyl transferase, and is the major site ofregulation of the pathway because this enz can be inhibited by the products of the rxn or by the PRPP, the substrate. The Salvage pathway : It involves 2 enzymes: -Adenine Phosphoribosyl transferase (APRT) and -Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) Purine catabolism : involves degradation of purine nucleotides (from DNA or from free Purines) to hypoxanthine, xanthine and then to uric acid. The most impt enz involved in this pathway is xanthine oxidase and the rxn it catalyzed is irreversible i.e. once hyoxanthine is formed, uric acid is sure to be formed
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