Chemistry Department, Binghamton University, Binghamton, NY 13902, United States.
Chemistry Department, Binghamton University, Binghamton, NY 13902, United States.
Bioorg Med Chem. 2023 Mar 15;82:117231. doi: 10.1016/j.bmc.2023.117231. Epub 2023 Mar 5.
A native enzyme's usual assurance in recognizing their physiological substrate(s) at the ground state and on going to the transition state can be undermined by interactions with selected small molecule antagonists, leading to the generation of abnormal products. We classify this mode of enzyme antagonism resulting in the gain-of-nonnative-function as paracatalytic induction. Enzymes bound by paracatalytic inducers exhibit new or enhanced activity toward transformations that appear aberrant or erroneous. The enzyme/ paracatalytic inducer complex may take up native substrate but then bring about a transformation that is chemically distinct from the normal reaction. Alternatively, the enzyme / paracatalytic inducer complex may exhibit abnormal ground state selectivity, preferentially interacting with and transforming a molecule outside the physiological substrate scope. Paracatalytic inducers can be cytotoxic, while in other cases they divert enzyme activity toward transformations that appear adaptive and even therapeutically useful. In this perspective, we highlight two noteworthy examples from recent literature.
天然酶通常能在基态和过渡态识别其生理底物，但与选定的小分子拮抗剂相互作用会破坏这种识别，导致产生异常产物。我们将这种导致获得非天然功能的酶拮抗作用模式归类为副催化诱导。被副催化诱导剂结合的酶对异常或错误的转化表现出新的或增强的活性。酶/副催化诱导剂复合物可能结合天然底物，但随后发生的转化在化学上与正常反应不同。或者，酶/副催化诱导剂复合物可能表现出异常的基态选择性，优先与生理底物范围之外的分子相互作用并将其转化。副催化诱导剂可能具有细胞毒性，而在其他情况下，它们会使酶活性转向看起来适应性强甚至具有治疗作用的转化。在这篇观点文章中，我们重点介绍了最近文献中的两个值得注意的例子。
