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

IF 3.1 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2026-03-15 DOI:10.1007/s00044-026-03538-1

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

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Abstract

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 (k_inact/K_I = 5.1 min⁻¹mM⁻¹) approximately 30-fold higher than that for GABA-AT (k_inact/K_I = 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.

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（1R,4S）-4-氨基-3-（三氟甲基）环戊烯-2-烯-1-羧酸通过稳定的醌类中间体灭活鸟氨酸转氨酶

鸟氨酸氨基转移酶（OAT）是一种吡哆醛5 ' -磷酸（PLP）依赖性酶，是癌细胞中谷氨酰胺供应的关键贡献者，表明其治疗肝细胞癌（HCC）的潜力，HCC是最常见的肝癌形式。为了确定一组初始的OAT失活因子，我们测试了γ-氨基丁酸转氨酶（GABA-AT）的失活因子，这是一种同源的plp依赖性酶，与人类OAT （hOAT）并鉴定了几种共失活因子。在活性分子中，(1R,4S)-4-氨基-3-（三氟甲基）环戊烷-2-烯-1-羧酸(2)的时间依赖性动力学和OAT机制途径尚未得到深入研究。在这项研究中，我们评估了2对hOAT的时间依赖性失活，并主要基于x射线晶体学研究了其潜在机制。结果表明，2作为一种时间依赖性的OAT失活剂，其失活效率（kinact/KI = 5.1 min−1mM−1）比GABA-AT （kinact/KI = 0.17 min−1mM−1）高约30倍，值得注意的是，通过稳定的醌类中间体进行失活途径，这一点得到了紫外可见光谱的证明。此图像的替代文本可能是使用AI生成的。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.