Pathways of one-carbon metabolism

Pathways of one-carbon metabolism. Folate cofactors are used in the distribution of one-carbon units across two distinct metabolic cycles, one relating to the de novo synthesis of DNA and the other involved in providing methyl groups for at least 40 different methyltransferase reactions. In the DNA synthesis cycle, formyl derivatives of tetrahydrofolate (THF) are used in de novo purine biosynthesis. In de novo pyrimidine biosynthesis, 5,10-methyleneTHF is required in the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thus folate cofactors play an essential role in cellular proliferation. The THF cofactor pool also provides a continuous supply of methyl groups for biologic methylation reactions via the conversion of homocysteine to methionine, using 5-methylTHF as the methyl donor, with vitamin B12-dependent methionine synthase (MS) transferring the methyl group to homocysteine. (In liver and kidney homocysteine is also remethylated to methionine through an alternative folate-independent pathway involving betaine homocysteine methyltransferase.) Methionine is then converted to S-adenosylmethionine (SAM), the cosubstrate of all methyltransferase enzymes. This cycle is completed by the regeneration of homocysteine from S-adenosylhomocysteine (SAH), the coproduct of the methylation process. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5,10-methyleneTHF to 5-methylTHF, thereby committing one-carbon units to methylation reactions and away from DNA synthesis. Mitochondrial and cytosolic folate-linked metabolism of serine and formate generate the majority of one-carbon groups for all of these processes. In addition to all of the enzymes involved in folate pathways, the reduced folate carrier (RFC), folate receptors (FRs), proton coupled folate transporter (PCFT), and mitochondrial folate transporter (MFT) play key roles in maintaining folate concentrations within the cell.

Publication

The Search for Genetic Polymorphisms in the Homocysteine/Folate Pathway That Contribute to the Etiology of Human Neural Tube Defects. (2009) Anne M. Molloy, et al. Birth Defects Res A Clin Mol Teratol. 2009 Apr;85(4):285-294. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions