The structure of a ternary complex of porcine sarcosine dehydrogenase with glycine and folic acid

Abstract

We have determined the crystal structure of porcine sarcosine dehydrogenase (SDH) complexed with glycine and folic acid. SDH is a mitochondrial bifunctional flavoenzyme that catalyzes the oxidative demethylation of sarcosine to produce glycine, and the formation of 5,10‐methylene tetrahydrofolate by transferring the oxidized methyl group to tetrahydrofolate. Electron transfer flavoprotein is the physiological electron acceptor, linking sarcosine oxidation to the mitochondrial electron tansport system. Similar to the structure of dimethylglycine oxidase from Arthrobacter globiformis, the SDH molecule is comprised of two distinct, approximately equal sized domains. The N‐terminal domain contains a covalently‐bound FAD (C8α of FAD to N3 of His108), and the C‐terminal domain binds folate. The structure also shows that a glycine molecule (product) is bound at the re‐face of the flavin ring and its nitrogen atom makes hydrogen bonds with His293 and Tyr318, suggesting that these two residues play a role in catalysis. The pterin ring of folic acid is found ~40 Å away from the glycine binding site, and the two binding sites are connected by a large irregular shaped channel. This work was supported by National Institutes of Health Grant GM29076.