Active site and loop 4 movements within human glycolate oxidase: implications for substrate specificity and drug design.

[primary hyperoxaluria type 1]

Human glycolate oxidase (GO ) catalyzes the FMN-dependent oxidation of glycolate to glyoxylate and glyoxylate to oxalate , a key metabolite in kidney stone formation . We report herein the structures of recombinant GO complexed with sulfate , glyoxylate , and an inhibitor , 4 -carboxy-5 -dodecylsulfanyl-1 ,2 ,3 -triazole (CDST ), determined by X-ray crystallography . In contrast to most alpha-hydroxy acid oxidases including spinach glycolate oxidase , a loop region , known as loop 4 , is completely visible when the GO active site contains a small ligand . The lack of electron density for this loop in the GO-CDST complex , which mimics a large substrate , suggests that a disordered to ordered transition may occur with the binding of substrates . The conformational flexibility of Trp 110 appears to be responsible for enabling GO to react with alpha-hydroxy acids of various chain lengths . Moreover , the movement of Trp 110 disrupts a hydrogen-bonding network between Trp 110 , Leu 191 , Tyr 134 , and Tyr 208 . This loss of interactions is the first indication that active site movements are directly linked to changes in the conformation of loop 4 . The kinetic parameters for the oxidation of glycolate , glyoxylate , and 2 -hydroxy octanoate indicate that the oxidation of glycolate to glyoxylate is the primary reaction catalyzed by GO , while the oxidation of glyoxylate to oxalate is most likely not relevant under normal conditions . However , drugs that exploit the unique structural features of GO may ultimately prove to be useful for decreasing glycolate and glyoxylate levels in primary hyperoxaluria type 1 patients who have the inability to convert peroxisomal glyoxylate to glycine .

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Diseases presenting "small ligand" symptom

primary hyperoxaluria type 1

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