Precision Biotransformation of Emerging Pollutants by Human Cytochrome P450 Using Computational–Experimental Synergy: A Case Study of Tris(1,3-dichloro-2-propyl) Phosphate,Environmental Science & Technology

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Precision Biotransformation of Emerging Pollutants by Human Cytochrome P450 Using Computational–Experimental Synergy: A Case Study of Tris(1,3-dichloro-2-propyl) Phosphate
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2021-08-16 , DOI: 10.1021/acs.est.1c03036
Lihong Chai _{1,

2} , Huanni Zhang ₂ , Runqian Song ₂ , Haohan Yang ₁ , Haiying Yu ₃ , Piotr Paneth ₄ , Kasper P Kepp ₅ , Miki Akamatsu ₆ , Li Ji _{1,

2,

6}

Affiliation

Precision biotransformation is an envisioned strategy offering detailed insights into biotransformation pathways in real environmental settings using experimentally guided high-accuracy quantum chemistry. Emerging pollutants, whose metabolites are easily overlooked but may cause idiosyncratic toxicity, are important targets of such a strategy. We demonstrate here that complex metabolic reactions of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) catalyzed by human CYP450 enzymes can be mapped via a three-step synergy strategy: (i) screening the possible metabolites via high-throughout (moderate-accuracy) computations; (ii) analyzing the proposed metabolites in vitro by human liver microsomes and recombinant human CYP450 enzymes; and (iii) rationalizing the experimental data via precise mechanisms using high-level targeted computations. Through the bilateral dialogues from qualitative to semi-quantitative to quantitative levels, we show how TDCIPP metabolism especially by CYP3A4 generates bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) as an O-dealkylation metabolite and bis(1,3-dichloro-2-propyl) 3-chloro-1-hydroxy-2-propyl phosphate (alcohol_β-dehalogen) as a dehalogenation/reduction metabolite via the initial rate-determining H-abstraction from αC- and βC-positions. The relative yield ratio [dehalogenation/reduction]/[O-dealkylation] is derived from the relative barriers of H-abstraction at the βC- and αC-positions by CYP3A4, estimated as 0.002 to 0.23, viz., an in vitro measured ratio of 0.04. Importantly, alcohol_β-dehalogen formation points to a new mechanism involving successive oxidation and reduction functions of CYP450, with its precursor aldehyde_β-dehalogen being a key intermediate detected by trapping assays and rationalized by computations. We conclude that the proposed three-step synergy strategy may meet the increasing challenge of elucidating biotransformation mechanisms of substantial synthesized organic compounds in the future.

中文翻译：

使用计算-实验协同作用的人类细胞色素 P450 对新兴污染物的精确生物转化：以磷酸三（1,3-二氯-2-丙基）酯为例

精密生物转化是一种设想的策略，使用实验指导的高精度量子化学，提供对真实环境环境中生物转化途径的详细见解。新出现的污染物，其代谢物很容易被忽视，但可能导致异质毒性，是这种策略的重要目标。我们在此证明，由人类 CYP450 酶催化的三（1,3-二氯-2-丙基）磷酸盐 (TDCIPP) 的复杂代谢反应可以通过三步协同策略进行映射：（i）通过高-筛选可能的代谢物贯穿（中等精度）计算；(ii)在体外分析建议的代谢物通过人肝微粒体和重组人CYP450酶；(iii) 通过使用高级目标计算的精确机制来合理化实验数据。通过从定性到半定量再到定量水平的双边对话，我们展示了 TDCIPP 代谢，尤其是 CYP3A4 如何生成磷酸双 (1,3-二氯-2-丙基) 磷酸 (BDCIPP) 作为 O-脱烷基化代谢物和双 (1, 3-二氯-2-丙基）3-氯-1-羟基-2-丙基磷酸盐（醇_β-脱卤素）作为脱卤/还原代谢物，通过从 αC 和 βC 位置进行的初始定速 H-抽象。相对产率 [脱卤/还原]/[O-脱烷基化] 来自 CYP3A4 在 βC- 和 αC- 位置的 H-抽象相对势垒，估计为 0.002 至 0.23，即体外实测比值为0.04。重要的是，醇_{β-脱卤素的}形成指向了一种新的机制，涉及 CYP450 的连续氧化和还原功能，其前体醛_β-脱卤素是通过捕获测定检测并通过计算合理化的关键中间体。我们得出结论，所提出的三步协同策略可能会满足未来阐明大量合成有机化合物的生物转化机制的日益严峻的挑战。

更新日期：2021-10-19

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