2gcg
Ternary Crystal Structure of Human Glyoxylate Reductase/Hydroxypyruvate Reductase
Structural highlights
DiseaseGRHPR_HUMAN Defects in GRHPR are the cause of hyperoxaluria primary type 2 (HP2) [MIM:260000; also known as primary hyperoxaluria type II (PH2). HP2 is a disorder where the main clinical manifestation is calcium oxalate nephrolithiasis though chronic as well as terminal renal insufficiency has been described. It is characterized by an elevated urinary excretion of oxalate and L-glycerate.[1] FunctionGRHPR_HUMAN Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate oxidizes D-glycerate to hydroxypyruvate. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHuman glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is a D-2-hydroxy-acid dehydrogenase that plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver. Deficiency of this enzyme is the underlying cause of primary hyperoxaluria type 2 (PH2) and leads to increased urinary oxalate levels, formation of kidney stones and renal failure. Here we describe the crystal structure of human GRHPR at 2.2 A resolution. There are four copies of GRHPR in the crystallographic asymmetric unit: in each homodimer, one subunit forms a ternary (enzyme+NADPH+reduced substrate) complex, and the other a binary (enzyme+NADPH) form. The spatial arrangement of the two enzyme domains is the same in binary and ternary forms. This first crystal structure of a true ternary complex of an enzyme from this family demonstrates the relationship of substrate and catalytic residues within the active site, confirming earlier proposals of the mode of substrate binding, stereospecificity and likely catalytic mechanism for these enzymes. GRHPR has an unusual substrate specificity, preferring glyoxylate and hydroxypyruvate, but not pyruvate. A tryptophan residue (Trp141) from the neighbouring subunit of the dimer is projected into the active site region and appears to contribute to the selectivity for hydroxypyruvate. This first crystal structure of a human GRHPR enzyme also explains the deleterious effects of naturally occurring missense mutations of this enzyme that lead to PH2. Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate reductase.,Booth MP, Conners R, Rumsby G, Brady RL J Mol Biol. 2006 Jun 30;360(1):178-89. Epub 2006 May 22. PMID:16756993[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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