| RRC ID |
75209
|
| 著者 |
Oikawa D, Yamashita S, Takahashi S, Waki T, Kikuchi K, Abe T, Katayama T, Nakayama T.
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| タイトル |
(+)-Sesamin, a sesame lignan, is a potent inhibitor of gut bacterial tryptophan indole-lyase that is a key enzyme in chronic kidney disease pathogenesis.
|
| ジャーナル |
Biochem Biophys Res Commun
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| 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.
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| 巻・号 |
590
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| ページ |
158-162
|
| 公開日 |
2022-1-29
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| DOI |
10.1016/j.bbrc.2021.12.088
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| PII |
S0006-291X(21)01731-9
|
| PMID |
34974305
|
| MeSH |
Benzodioxoles / chemistry
Benzodioxoles / pharmacology
Dioxoles / chemistry
Dioxoles / pharmacology*
Enzyme Inhibitors / pharmacology*
Gastrointestinal Microbiome* / drug effects
Kinetics
Lignans / chemistry
Lignans / pharmacology*
Molecular Docking Simulation
Phenols / chemistry
Phenols / pharmacology
Renal Insufficiency, Chronic / enzymology*
Renal Insufficiency, Chronic / etiology*
Sesamum / chemistry*
Tryptophanase / antagonists & inhibitors*
Tryptophanase / metabolism
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| リソース情報 |
| 一般微生物 |
JCM 5827
JCM 1658
JCM 1238
JCM 1672
JCM 1673 |
