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<p>Ornithine aminotransferase (OAT), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is a key contributor to glutamine supply in cancer cells, suggesting its therapeutic potential for hepatocellular carcinoma (HCC), the most common form of liver cancer. To identify an initial set of OAT inactivators, we have tested inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), a homologous PLP-dependent enzyme, with human OAT (<i>h</i>OAT) and identified several co-inactivators. Among the active molecules, (1<i>R</i>,4<i>S</i>)-4-amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid (<b>2</b>) has not been thoroughly investigated for its time-dependent kinetics and mechanistic pathways with OAT. In this study, we evaluated the time-dependent inactivation of <i>h</i>OAT by <b>2</b> and investigated the underlying mechanism, primarily based on X-ray crystallography. The results demonstrated that <b>2</b> acts as a time-dependent OAT inactivator with an inactivation efficiency (<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> = 5.1 min<sup>−1</sup>mM<sup>−1</sup>) approximately 30-fold higher than that for GABA-AT (<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> = 0.17 min<sup>−1</sup>mM<sup>−1</sup>) and, notably, revealed an inactivation pathway that proceeds via a stable quinonoid intermediate, as evidenced by the UV-Vis spectroscopy.</p><p></p>

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Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月15日

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  • Koon Mook Kang,
  • Abigail L. Vargas,
  • Wei Zhu,
  • Inna Sokolenko,
  • Dali Liu,
  • Richard B. Silverman

摘要

Ornithine aminotransferase (OAT), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is a key contributor to glutamine supply in cancer cells, suggesting its therapeutic potential for hepatocellular carcinoma (HCC), the most common form of liver cancer. To identify an initial set of OAT inactivators, we have tested inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), a homologous PLP-dependent enzyme, with human OAT (hOAT) and identified several co-inactivators. Among the active molecules, (1R,4S)-4-amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid (2) has not been thoroughly investigated for its time-dependent kinetics and mechanistic pathways with OAT. In this study, we evaluated the time-dependent inactivation of hOAT by 2 and investigated the underlying mechanism, primarily based on X-ray crystallography. The results demonstrated that 2 acts as a time-dependent OAT inactivator with an inactivation efficiency (kinact/KI = 5.1 min−1mM−1) approximately 30-fold higher than that for GABA-AT (kinact/KI = 0.17 min−1mM−1) and, notably, revealed an inactivation pathway that proceeds via a stable quinonoid intermediate, as evidenced by the UV-Vis spectroscopy.