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Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors.

ABSTRACT: Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid substrates as reactive acyl adenylate (acyl-AMP) intermediates and subsequent coupling to various nucleophiles to generate ester, thioester, and amide products. Inspired by natural products, acyl sulfonyladenosines (acyl-AMS) that mimic the tightly bound acyl-AMP reaction intermediates have been developed as potent inhibitors of adenylate-forming enzymes. This simple yet powerful inhibitor design platform has provided a wide range of biological probes as well as several therapeutic lead compounds. Herein, we provide an overview of the nine structural classes of adenylate-forming enzymes and examples of acyl-AMS inhibitors that have been developed for each.

SUBMITTER: Lux MC

PROVIDER: S-EPMC6594144 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors.

Lux Michaelyn C MC Standke Lisa C LC Tan Derek S DS

The Journal of antibiotics 20190415 6

Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid substrates as reactive acyl adenylate (acyl-AMP) intermediates and subsequent coupling to various nucleophiles to generate ester, thioester, and amide products. Inspired by natural products, acyl sulfonyladenosines (acyl-AMS) that mimic the tightly bound acyl-AMP reaction intermediates have been developed as potent inhibitors of aden ...[more]

PMID: 30982830

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