8v9m

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Human Ornithine Aminotransferase cocrystallized with its inhibitor, (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid.Human Ornithine Aminotransferase cocrystallized with its inhibitor, (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid.

Structural highlights

8v9m 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 1.61Å
Ligands:,
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.[1] [2] [3] [4] [5] [6]

Function

OAT_HUMAN

Publication Abstract from PubMed

Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, (19)F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored.

Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase.,Devitt AN, Vargas AL, Zhu W, Des Soye BJ, Butun FA, Alt T, Kaley N, Ferreira GM, Moran GR, Kelleher NL, Liu D, Silverman RB ACS Chem Biol. 2024 Apr 17. doi: 10.1021/acschembio.4c00022. PMID:38630468[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Ramesh V, McClatchey AI, Ramesh N, Benoit LA, Berson EL, Shih VE, Gusella JF. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3777-80. PMID:3375240
  2. ↑ Inana G, Chambers C, Hotta Y, Inouye L, Filpula D, Pulford S, Shiono T. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem. 1989 Oct 15;264(29):17432-6. PMID:2793865
  3. ↑ Michaud J, Brody LC, Steel G, Fontaine G, Martin LS, Valle D, Mitchell G. Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine delta-aminotransferase gene. Genomics. 1992 Jun;13(2):389-94. PMID:1612597
  4. ↑ Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302-7. PMID:1737786
  5. ↑ Michaud J, Thompson GN, Brody LC, Steel G, Obie C, Fontaine G, Schappert K, Keith CG, Valle D, Mitchell GA. Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V. Am J Hum Genet. 1995 Mar;56(3):616-22. PMID:7887415
  6. ↑ Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T. A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. Am J Hum Genet. 1995 Aug;57(2):284-91. PMID:7668253
  7. ↑ Devitt AN, Vargas AL, Zhu W, Des Soye BJ, Butun FA, Alt T, Kaley N, Ferreira GM, Moran GR, Kelleher NL, Liu D, Silverman RB. Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase. ACS Chem Biol. 2024 Apr 17. PMID:38630468 doi:10.1021/acschembio.4c00022

8v9m, resolution 1.61Å

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