High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

Biochimie
Zhi-wei ChenF S Mathews

Abstract

Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent l-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b(2) (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC(50) in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 Å resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two ot...Continue Reading

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Citations

Dec 23, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Cristina Martin-HiguerasEduardo Salido
Jul 6, 2014·Journal of Medical Genetics·Yaacov FrishbergRuth Belostotsky
Jul 20, 2016·Journal of the American Society of Nephrology : JASN·Abigail LiebowJohn Knight
Nov 6, 2014·Biomolecular Concepts·Elvira Romero, Giovanni Gadda
Aug 3, 2019·Acta Crystallographica. Section D, Structural Biology·Hsien Wei YehTsung Lin Li
Jan 31, 2021·Journal of Personalized Medicine·Maria Dolores Moya-GarzonMonica Diaz-Gavilan
Jul 17, 2021·ACS Medicinal Chemistry Letters·Jinyue DingDavid A Powell
Jul 22, 2018·Journal of Medicinal Chemistry·María Dolores Moya-GarzónMónica Díaz-Gavilán

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