Metformin Is a Pyridoxal-5'-phosphate (PLP)-Competitive Inhibitor of SHMT2.

ABSTRACT: The anticancer actions of the biguanide metformin involve the functioning of the serine/glycine one-carbon metabolic network. We report that metformin directly and specifically targets the enzymatic activity of mitochondrial serine hydroxymethyltransferase (SHMT2). In vitro competitive binding assays with human recombinant SHMT1 and SHMT2 isoforms revealed that metformin preferentially inhibits SHMT2 activity by a non-catalytic mechanism. Computational docking coupled with molecular dynamics simulation predicted that metformin could occupy the cofactor pyridoxal-5'-phosphate (PLP) cavity and destabilize the formation of catalytically active SHMT2 oligomers. Differential scanning fluorimetry-based biophysical screening confirmed that metformin diminishes the capacity of PLP to promote the c

SUBMITTER: Tramonti A 

PROVIDER: S-EPMC8393646 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature