(+)-Sesamin, a sesame lignan, is a potent inhibitor of gut bacterial tryptophan indole-lyase that is a key enzyme in chronic kidney disease pathogenesis

Daiki Oikawa, Satoshi Yamashita, Seiji Takahashi, Toshiyuki Waki, Koichi Kikuchi, Takaaki Abe, Takane Katayama, Toru Nakayama

Research output: Contribution to journalArticlepeer-review

Abstract

The progression of chronic kidney disease (CKD) increases the risks of cardiovascular morbidity and end-stage kidney disease. Indoxyl sulfate (IS), which is derived from dietary L-tryptophan by the action of bacterial L-tryptophan indole-lyase (TIL) in the gut, serves as a uremic toxin that exacerbates CKD-related kidney disorder. A mouse model previously showed that inhibition of TIL by 2-aza-L-tyrosine effectively reduced the plasma IS level, causing the recovery of renal damage. In this study, we found that (+)-sesamin and related lignans, which occur abundantly in sesame seeds, inhibit intestinal bacteria TILs. Kinetic studies revealed that (+)-sesamin and sesamol competitively inhibited Escherichia coli TIL (EcTIL) with Ki values of 7 μM and 14 μM, respectively. These Ki values were smaller than that of 2-aza-L-tyrosine (143 μM). Molecular docking simulation of (+)-sesamin- (or sesamol-)binding to EcTIL predicted that these inhibitors potentially bind near the active site of EcTIL, where the cofactor pyridoxal 5′-phosphate is bound, consistent with the kinetic results. (+)-Sesamin is a phytochemical with a long history of consumption and is generally regarded as safe. Hence, dietary supplementation of (+)-sesamin encapsulated in enteric capsules could be a promising mechanism-based strategy to prevent CKD progression. Moreover, the present findings would provide a new structural basis for designing more potent TIL inhibitors for the development of mechanism-based therapeutic drugs to treat CKD.

Original languageEnglish
Pages (from-to)158-162
Number of pages5
JournalBiochemical and biophysical research communications
Volume590
DOIs
Publication statusPublished - 2022 Jan 29

Keywords

  • Chronic kidney disease
  • Enzyme inhibition
  • Sesamin
  • Sesamol
  • Sesamum indicum L.
  • Tryptophan indole-lyase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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