Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1647, Issue 1-2, Pages 70-75Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S1570-9639(03)00055-4
Keywords
alanine : glyoxylate aminotransferase; primary hyperoxaluria type 1; peroxisomal protein targeting; mitochondrial protein targeting; kidney stone; human genetic disease
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The pyridoxal-phosphate (PLP)-dependent enzyme alanine:glyoxylate aminotransferase (AGT) is mistargeted from peroxisomes to mitochondria in patients with the hereditary kidney stone disease primary hyperoxaluria type I (PHI) due to the synergistic interaction between a common Pro(11) Leu polymorphism and a PH1-specific Gly(170) Arg mutation. The kinetic partitioning of newly synthesised AGT between peroxisomes and mitochondria is determined by the combined effects of (1) the generation of cryptic mitochondrial targeting information, and (2) the inhibition of AGT dimerization. The crystal structure of AGT has recently been solved, allowing the effects of the various polymorphisms and mutations to be rationalised in terms of AGT's three-dimensional conformation. Procedures that increase dimer stability and/or increase the rate of dimer formation have potential in the formulation of novel strategies to treat this otherwise intractable life-threatening disease. (C) 2003 Elsevier Science B.V. All rights reserved.
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