A chemical catalyst enabling histone acylation with endogenous acyl-CoA

Misuzu Habazaki, Shinsuke Mizumoto, Hidetoshi Kajino, Tomoya Kujirai, Hitoshi Kurumizaka, Shigehiro A. Kawashima (), Kenzo Yamatsugu () and Motomu Kanai ()
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Misuzu Habazaki: The University of Tokyo, 7-3-1 Hongo
Shinsuke Mizumoto: The University of Tokyo, 7-3-1 Hongo
Hidetoshi Kajino: The University of Tokyo, 7-3-1 Hongo
Tomoya Kujirai: The University of Tokyo
Hitoshi Kurumizaka: The University of Tokyo
Shigehiro A. Kawashima: The University of Tokyo, 7-3-1 Hongo
Kenzo Yamatsugu: The University of Tokyo, 7-3-1 Hongo
Motomu Kanai: The University of Tokyo, 7-3-1 Hongo

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41426-z

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