Serine Racemase is a Cysteine Racemase and Physiologic Down Regulator of Insulin Promoter Methylation

Endogenous D-stereoisomers are being recognized as functionally important molecules in mammals. Here we report the first identification of endogenous D-cysteine in mammalian pancreas. Serine Racemase (SR) is the biosynthetic enzyme for D- cysteine. D-cysteine is present in substantial amounts in the eyes, brain and pancreas of mice. To characterize endogenous D-cysteine, we used SR deficient mice lacking racemizing ability and show 3.5 fold reduction in pancreatic D-cysteine. SR-/- mice produce 6-10 fold higher levels of insulin in the pancreas and plasma and are stored as amyloid aggregates in secretory vesicles and exosomes respectively. Lack of SR and endogenous D-cysteine globally decreased levels of nucleotides and cAMP, followed by reduced phosphorylation of CREB (S133) including lower expression of DNA methyltransferase (DNMT) 1, 3A and 3B, and reduced DNMT enzymatic and promoter activities in the pancreas. This results in decreased DNA methylation globally and specifically of the Ins1 promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1 transporters in cells. Dietary supplementation with methyl donors rescues the high insulin levels and low DNMT activity in SR-/- mice. Our data show that SR racemizes cysteine in the pancreas and is a physiologic down regulator of insulin promoter methylation.