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A chemical catalyst enabling histone acylation with endogenous acyl-CoA.


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.

SUBMITTER: Habazaki M 

PROVIDER: S-EPMC10517024 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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A chemical catalyst enabling histone acylation with endogenous acyl-CoA.

Habazaki Misuzu M   Mizumoto Shinsuke S   Kajino Hidetoshi H   Kujirai Tomoya T   Kurumizaka Hitoshi H   Kawashima Shigehiro A SA   Yamatsugu Kenzo K   Kanai Motomu M  

Nature communications 20230922 1


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 acti  ...[more]

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