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

Tomoki Ota; Akinobu Senoo; Masumi Shirakawa; Hiroshi Nonaka; Yutaro Saito; Sho Ito; Go Ueno; Satoru Nagatoishi; Kouhei Tsumoto; Shinsuke Sando

doi:10.1016/j.isci.2021.102036

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

iScience. 2021 Jan 6;24(2):102036. doi: 10.1016/j.isci.2021.102036. eCollection 2021 Feb 19.

Authors

Tomoki Ota¹, Akinobu Senoo¹, Masumi Shirakawa¹, Hiroshi Nonaka¹, Yutaro Saito¹, Sho Ito^{2

3}, Go Ueno⁴, Satoru Nagatoishi⁵, Kouhei Tsumoto^{1

5

6}, Shinsuke Sando^{1

6}

Affiliations

¹ Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
² Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori-cho, Ako-gun, Hyogo, 678-1297, Japan.
³ ROD (Single Crystal Analysis) Group, Application Laboratories, Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo, 196-8666, Japan.
⁴ RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-5148, Japan.
⁵ Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
⁶ Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Abstract

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.

Keywords: Metabolic Engineering; Molecular Interaction; Structural Biology.