Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Nat Commun. 2023 Sep 22;14(1):5790. doi: 10.1038/s41467-023-41426-z.
Life emerges from a network of biomolecules and chemical reactions catalyzed by enzymes. As enzyme abnormalities are often connected to various diseases, a chemical catalyst promoting physiologically important intracellular reactions in place of malfunctional endogenous enzymes would have great utility in understanding and treating diseases. However, research into such small-molecule chemical enzyme surrogates remains limited, due to difficulties in developing a reactive catalyst capable of activating inert cellular metabolites present at low concentrations. Herein, we report a small-molecule catalyst, mBnA, as a surrogate for a histone acetyltransferase. A hydroxamic acid moiety of suitable electronic characteristics at the catalytic site, paired with a thiol-thioester exchange process, enables mBnA to activate endogenous acyl-CoAs present in low concentrations and promote histone lysine acylations in living cells without the addition of exogenous acyl donors. An enzyme surrogate utilizing cellular metabolites will be a unique tool for elucidation of and synthetic intervention in the chemistry of life and disease.
生命源自于由酶催化的生物分子和化学反应网络。由于酶的异常通常与各种疾病有关，因此用一种化学催化剂来替代功能失调的内源性酶，促进生理上重要的细胞内反应，对于理解和治疗疾病将具有重要的应用价值。然而，由于开发能够激活低浓度下存在的惰性细胞代谢物的反应性催化剂具有一定难度，因此针对此类小分子化学酶替代物的研究仍然有限。在此，我们报告了一种小分子催化剂 mBnA，可以作为组蛋白乙酰转移酶的替代物。催化部位具有合适电子特性的偕羟肟酸部分，与巯基-硫酯交换过程相结合，使 mBnA 能够激活低浓度存在的内源性酰基辅酶 A，并在无需添加外源酰基供体的情况下促进活细胞中的组蛋白赖氨酸酰化。利用细胞代谢物的酶替代物将成为阐明生命和疾病化学以及进行人工干预的独特工具。
