IMP Dehydrogenase Mutants: Cell Culture Model for Hyperuricemia
Primary gout with associated hyperuricemia is a genetically heterogeneous disorder characterized by hyperuricemia due to increased rates of purine synthesis or enhanced cellular turnover. The genetic lesions which lead to enhanced rates of purine synthesis are mostly undefined. Several groups have reported that hyperuricemia can be associated with different types of kinetic alterations in the enzyme phosphoribosylpyrophosphate (PRPP) synthetase (1–3) or a deficiency in hypoxanthine-guanine phosphoribosyltransferase (4–5). The purine metabolic pathway is subject to a variety of control mechanisms including substrate availability, feedback inhibition of enzyme activity, compartmentalization of substrates and effectors, and regulation of enzyme levels. This biosynthetic pathway has two regulatory domains. The first occurs before the IMP branchpoint in which both PRPP synthetase and PRPP-glutamine amidotransferase are subject to allosteric inhibition by nucleotide effectors. The second regulatory domain occurs subsequent to IMP synthesis, where both adenylosuccinate synthetase and IMP dehydrogenase, the penultimate enzymes in AMP and GMP synthesis, respectively, are also regulated by ribonucleotide effectors. The genetic and metabolic heterogeneity of overproduction hyperuricemia suggests that defects in any one of these enzymes might lead to excessive rate of purine synthesis.
KeywordsMutant Cell Cell Culture Model Mycophenolic Acid Purine Synthesis Primary Gout
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