Mechanism-based Inhibition of Gut Microbial Tryptophanases Reduces Serum Indoxyl Sulfate

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2023 Aug 26

PMID 37633277

Authors

Amanda L Graboski

Mark E Kowalewski

Joshua B Simpson

Xufeng Cao

Mary Ha

Jianan Zhang

William G Walton

Daniel P Flaherty

Matthew R Redinbo

Affiliations

Soon will be listed here.

Abstract

Indoxyl sulfate is a microbially derived uremic toxin that accumulates in late-stage chronic kidney disease and contributes to both renal and cardiovascular toxicity. Indoxyl sulfate is generated by the metabolism of indole, a compound created solely by gut microbial tryptophanases. Here, we characterize the landscape of tryptophanase enzymes in the human gut microbiome and find remarkable structural and functional similarities across diverse taxa. We leverage this homology through a medicinal chemistry campaign to create a potent pan-inhibitor, (3S) ALG-05, and validate its action as a transition-state analog. (3S) ALG-05 successfully reduces indole production in microbial culture and displays minimal toxicity against microbial and mammalian cells. Mice treated with (3S) ALG-05 show reduced cecal indole and serum indoxyl sulfate levels with minimal changes in other tryptophan-metabolizing pathways. These studies present a non-bactericidal pan-inhibitor of gut microbial tryptophanases with potential promise for reducing indoxyl sulfate in chronic kidney disease.

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