Structural basis for selective inhibition of human serine hydroxymethyltransferase by secondary bile acid conjugate

• Published in: iScience 2021-02, Vol.24 (2), p.102036-102036, Article 102036
• Main Authors: Ota, Tomoki, Senoo, Akinobu, Shirakawa, Masumi, Nonaka, Hiroshi, Saito, Yutaro, Ito, Sho, Ueno, Go, Nagatoishi, Satoru, Tsumoto, Kouhei, Sando, Shinsuke
• Format: Article
• Language: English
• Subjects: Metabolic Engineering; Molecular Interaction; Structural Biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102036

Bile acids are metabolites of cholesterol that facilitate lipid digestion and absorption in the small bowel. Bile acids work as agonists of receptors to regulate their own metabolism. Bile acids also regulate other biological systems such as sugar metabolism, intestinal multidrug resistance, and adaptive immunity. However, numerous physiological roles of bile acids remain undetermined. In this study, we solved the crystal structure of human serine hydroxymethyltransferase (hSHMT) in complex with an endogenous secondary bile acid glycine conjugate. The specific interaction between hSHMT and the ligand was demonstrated using mutational analyses, biophysical measurements, and structure-activity relationship studies, suggesting that secondary bile acid conjugates may act as modulators of SHMT activity. [Display omitted] •The crystal structures of hSHMT in complex with secondary bile acid glycine conjugate•Specific interactions between hSHMT and secondary bile acid conjugate were validated•Biological role of bile acids as modulators for one-carbon metabolism is suggested Molecular Interaction; Structural Biology; Metabolic Engineering