Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis.
Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis.
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DOI：
10.1016/j.bmc.2014.06.034
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发表时间：
2014-10
影响因子：
3.5
通讯作者：
V. Polić;K. Auclair
中科院分区：
文献类型：
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作者：
V. Polić;K. Auclair
P450酶（P450s）以其高区域和立体选择性氧化未活化的C单键H键的能力而众所周知。因此，人们对利用P450作为潜在的生物催化剂产生了兴趣。虽然细菌P450通常表现出比它们的哺乳动物对应物更高的活性，但它们往往更具底物选择性。另一方面，大多数药物代谢P450显示出显着的底物混杂，但产物预测仍然具有挑战性。蛋白质工程是克服这些问题的一种既定策略。一个较少探索，但有前途的替代方案涉及基板工程。本文综述了利用小分子控制P450的底物特异性和产物选择性。重点是两种方法，一种利用非共价诱饵分子，另一种涉及共价底物修饰。
P450 enzymes (P450s) are well known for their ability to oxidize unactivated Csingle bondH bonds with high regio- and stereoselectivity. Hence, there is emerging interest in exploiting P450s as potential biocatalysts. Although bacterial P450s typically show higher activity than their mammalian counterparts, they tend to be more substrate selective. Most drug-metabolizing P450s on the other hand, display remarkable substrate promiscuity, yet product prediction remains challenging. Protein engineering is one established strategy to overcome these issues. A less explored, yet promising alternative involves substrate engineering. This review discusses the use of small molecules for controlling the substrate specificity and product selectivity of P450s. The focus is on two approaches, one taking advantage of non-covalent decoy molecules, and the other involving covalent substrate modifications.