7ta0 | pdb_00007ta0

Human Ornithine Aminotransferase (hOAT) soaked with 5-aminovaleric acid

spinqualitylabelsall models 7ta0, resolution 2.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ta0 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.33Å Ligands: I3B, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease OAT_HUMAN Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:258870. HOGA is a slowly progressive blinding autosomal recessive disorder. Function OAT_HUMAN Publication Abstract from PubMed Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and occurs predominantly in patients with underlying chronic liver diseases. Over the past decade, human ornithine aminotransferase (hOAT), which is an enzyme that catalyzes the metabolic conversion of ornithine into an intermediate for proline or glutamate synthesis, has been found to be overexpressed in HCC cells. hOAT has since emerged as a promising target for novel anticancer therapies, especially for the ongoing rational design effort to discover mechanism-based inactivators (MBIs). Despite the significance of hOAT in human metabolism and its clinical potential as a drug target against HCC, there are significant knowledge deficits with regard to its catalytic mechanism and structural characteristics. Ongoing MBI design efforts require in-depth knowledge of the enzyme active site, in particular, pKa values of potential nucleophiles and residues necessary for the molecular recognition of ligands. Here, we conducted a study detailing the fundamental active site properties of hOAT using stopped-flow spectrophotometry and X-ray crystallography. Our results quantitatively revealed the pH-dependence of the multi-step reaction mechanism and illuminated the roles of ornithine alpha- and delta-amino groups in substrate recognition and in facilitating catalytic turnover. These findings provided insights of the catalytic mechanism that could benefit the rational design of MBIs against hOAT. In addition, hOAT's substrate recognition and turnover of several fragment-sized alternative substrates, which could serve as structural templates for MBI design, were also elucidated. Determination of the pH-Dependence, Substrate Specificity and Turnovers of Alternative Substrates for Human Ornithine Aminotransferase.,Butrin A, Butrin A, Wawrzak Z, Moran G, Liu D J Biol Chem. 2022 Apr 20:101969. doi: 10.1016/j.jbc.2022.101969. PMID:35460691 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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