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==Overview== | ==Overview== | ||
A deficiency of the liver-specific enzyme alanine:glyoxylate, aminotransferase (AGT) is responsible for the potentially lethal, hereditary kidney stone disease primary hyperoxaluria type 1 (PH1). Many, of the mutations in the gene encoding AGT are associated with specific, enzymatic phenotypes such as accelerated proteolysis (Ser205Pro), intra-peroxisomal aggregation (Gly41Arg), inhibition of pyridoxal, phosphate binding and loss of catalytic activity (Gly82Glu), and, peroxisome-to-mitochondrion mistargeting (Gly170Arg). Several mutations, including that responsible for AGT mistargeting, co-segregate and interact, synergistically with a Pro11Leu polymorphism found at high frequency in, the normal population. In order to gain further insights into the, mechanistic link between genotype and enzymatic phenotype in PH1, we have, determined the crystal structure of normal human AGT complexed to the, competitive inhibitor amino-oxyacetic acid to 2.5A. Analysis of this, structure allows the effects of these mutations and polymorphism to be, rationalised in terms of AGT tertiary and quaternary conformation, and in, particular it provides a possible explanation for the Pro11Leu-Gly170Arg, synergism that leads to AGT mistargeting. | A deficiency of the liver-specific enzyme alanine:glyoxylate, aminotransferase (AGT) is responsible for the potentially lethal, hereditary kidney stone disease primary hyperoxaluria type 1 (PH1). Many, of the mutations in the gene encoding AGT are associated with specific, enzymatic phenotypes such as accelerated proteolysis (Ser205Pro), intra-peroxisomal aggregation (Gly41Arg), inhibition of pyridoxal, phosphate binding and loss of catalytic activity (Gly82Glu), and, peroxisome-to-mitochondrion mistargeting (Gly170Arg). Several mutations, including that responsible for AGT mistargeting, co-segregate and interact, synergistically with a Pro11Leu polymorphism found at high frequency in, the normal population. In order to gain further insights into the, mechanistic link between genotype and enzymatic phenotype in PH1, we have, determined the crystal structure of normal human AGT complexed to the, competitive inhibitor amino-oxyacetic acid to 2.5A. Analysis of this, structure allows the effects of these mutations and polymorphism to be, rationalised in terms of AGT tertiary and quaternary conformation, and in, particular it provides a possible explanation for the Pro11Leu-Gly170Arg, synergism that leads to AGT mistargeting. | ||
==Disease== | |||
Known diseases associated with this structure: Hyperoxaluria, primary, type 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604285 604285]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:11:08 2007'' | ||