Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Drug Metab Pharmacokinet. 2019 Jun;34(3):187-193. doi: 10.1016/j.dmpk.2019.02.003. Epub 2019 Feb 21.
Mandelic acid (MA) is generally used as a biomarker of the exposure of styrene, which is classified as a class of hazardous environmental pollutants, and also used as an important chiral intermediate in pharmaceutical industry. The previous studies have found the excretion of phenylglyoxylic acid (PGA) in human and rat, a metabolite of MA, was mainly from S-MA rather than R-MA. The metabolic mechanism, however, is not clear. In order to explore the possible metabolic mechanism, the enzyme types involved in the stereoselectivity metabolism of MA were firstly studied, and then human and rat long-chain 2-hydroxy-acid oxidase 2 (HAO2) were recombinantly expressed to study the metabolic profiles of S-MA and its analogues. The results indicated that HAO2 might catalyze the stereoselectivity metabolism of S-MA in rats. Human HAO2 (hHAO2) and rat HAO2 (rHAO2) isozymes β and β were successfully cloned and expressed with high purity and good enzyme activities. The enzyme kinetic profiles of these enzymes were different for S-MA and analogues. The order of catalytic efficiency for hHAO2 and rHAO2, however, was reverse. It might be relevance to the difference in active amino acid residues and loop 4 in human and rat L-2-hydroxy acid oxidase isozyme B crystal structures.
扁桃酸（MA）通常用作苯乙烯暴露的生物标志物，苯乙烯被归类为危险环境污染物，也可用作制药行业的重要手性中间体。先前的研究发现，人类和大鼠中 MA 的代谢产物苯乙醇酸（PGA）的排泄主要来自 S-MA，而不是 R-MA。然而，其代谢机制尚不清楚。为了探讨可能的代谢机制，首先研究了 MA 立体选择性代谢涉及的酶类型，然后重组表达了人源和大鼠长链 2-羟基酸氧化酶 2（HAO2），以研究 S-MA 及其类似物的代谢谱。结果表明，HAO2 可能在大鼠中催化 S-MA 的立体选择性代谢。成功克隆并表达了高纯度和良好酶活性的人源 HAO2（hHAO2）和大鼠 HAO2（rHAO2）同工酶β和β。这些酶对 S-MA 和类似物的酶动力学谱不同。然而，hHAO2 和 rHAO2 的催化效率顺序相反。这可能与人源和大鼠源 L-2-羟基酸氧化酶同工酶 B 晶体结构中活性氨基酸残基和环 4 的差异有关。
