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Human glycolate oxidase 1: a structural and biochemical examination of a possible target for hyperoxaluria treatment
Author(s) -
Murray Michael,
Holmes Ross P.,
Lowther W. Todd
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb23-a
Subject(s) - glyoxylate cycle , oxalate , biochemistry , photorespiration , enzyme , oxidase test , biology , stereochemistry , chemistry , inorganic chemistry
Human glycolate oxidase 1 (GO1) catalyzes the FMN‐dependent oxidation of glycolate to glyoxylate. In a second reaction, GO1 is also able to further oxidize glyoxylate to oxalate. The calcium salt of oxalate is highly insoluble and readily precipitates from solution. Here, we report the crystal structures of GO1 complexed with sulfate, glyoxylate, and an inhibitor, DSTC. The protein shows the same α8/β8 fold of other α‐hydroxy acid oxidases, most notably spinach glycolate oxidase. A loop region disordered in crystal structures from other enzymes in this family is visible for the first time. The GO1/DSTC complex indicates that this loop may be involved in a disordered to ordered transition that occurs upon substrate binding. Differences in the active site residues between the three structures indicate that the conformational flexibility of Trp110 may allow GO1 to react with α‐hydroxy acids of various chain lengths. Additionally, the kinetic parameters of GO1 for glycolate and glyoxylate have been determined. This analysis indicates that the oxidation of glycolate to glyoxylate is the primary reaction catalyzed by the enzyme while the oxidation of glyoxylate to oxalate is most likely not biologically relevant. However, the role of GO1 in glyoxylate production may prove important in disease etiology, especially in cases such as primary hyperoxaluria type I. Funding provided by NIH grant #R21 DK 74945