Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for primary hyperoxaluria type 1.

CYCLOSERINE ENANTIOMERS ARE REVERSIBLE INHIBITORS OF HUMAN ALANINE:GLYOXYLATE AMINOTRANSFERASE: IMPLICATIONS FOR PRIMARY HYPEROXALURIA TYPE 1. Biochem J. 2019 Dec 03;: Authors: Dindo M, Grottelli S, Annunziato G, Giardina G, Pieroni M, Pampalone G, Faccini A, Cutruzzolà F, Laurino P, Costantino G, Cellini B Abstract Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate stones deposition in the urinary tract as a consequence of glyoxylate accumulation. Most missense mutations cause AGT misfolding, as in the case of the G41R, which induces aggregation and proteolytic degradation. We have investigated the interaction of wild-type AGT and the pathogenic G41R variant with D-cycloserine (DCS, commercialized as Seromycin), a natural product used as a second-line treatment of multidrug-resistant tuberculosis, and its synthetic enantiomer L-cycloserine (LCS). In contrast with evidences previously reported on other PLP-enzymes, both ligands are AGT reversible inhibitors showing inhibition constants in the micromolar range. While LCS undergoes half-transamination generating a ketimine intermediate and behaves as a classical competitive inhibitor, DCS displays a time-dependent binding mainly generating an oxime intermedia...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research