Fig. 1

Model for the role of RIPS-1 methyltransferase in the mitochondrial and cytosolic vitamin B12-dependent pathways. Adenosyl cobalamin (B12) is required in the conversion of TCA cycle-dependent propionyl-CoA to succinyl-CoA. This process includes the isomerisation of d-methylmalonyl-CoA to l-methylmalonyl-CoA and is catalysed by the enzyme methylmalonyl-CoA epimerase (MCE-1), followed by the B12-dependent methyl malonyl-CoA mutase (MMCM-1) conversion to succinyl-CoA that feeds directly into the TCA cycle. In conditions where B12 is depleted or MCE-1 or MMCM-1 are disrupted, this pathway is interrupted and propionyl-CoA is converted into toxic propionate (and the acdh-1^prom::GFP marker is induced). Methyl cobalamin (vitamin B12) is also required for the folate and methionine cycles in the cytosol by acting as an essential co-factor for the methyltetrahydrofolate-homocysteine methyltransferase (methionine synthetase) enzyme (METR-1). This enzyme demethylates methyl tetrahydrofolate (methyl THF) to tetrahydrofolate (THF) in the folate cycle and methylates homocysteine to methionine in the methionine cycle. Methionine can be further converted to S-adenosyl methionine (SAM) then gets demethylated to S-adenosyl homocysteine (SAH). This demethylation reaction is a major source of methyl groups that is catalysed by S-adenosyl methionine methyltransferases including RIPS-1. The final step of the methionine cycle involves the conversion of SAH to homocysteine, which can ultimately feed into the TCA cycle via cystathionine, alpha-ketobutyrate, and propionyl-CoA. Thiol-reducing agents, including DTT, induce the S-adenosyl methionine methyltransferase RIPS-1. The vitamin B12-dependent reactions including methionine synthetase become rate-limiting, and in the absence of B12 supplementation, thiol-reducing agents cause developmental defects and lethality in C. elegans