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Riboflavin is linked to the metabolism of B-vitamins involved in homocysteine remethylation and transsulfuration. Riboflavin is transformed to FMN and FAD by the action of riboflavin kinase (EC 2.7.1.26) and FAD synthase (EC 2.7.7.2.). FMN and FAD are cofactors for vitamin B6, cobalamin and folate metabolizing enzymes. Vitamin B6 and cobalamin serve as cofactors for enzymes involved in homocysteine metabolism, while folate serves as a one-carbon donor for the remethylation of homocysteine. Abbreviations: Cbl(I), cob(I)alamin; Cbl(II), cob(II)alamin; CBS, cystathionine β-synthase; CH2-THF, 5,10-methylenetetrahydrofolate; CH3-THF, 5-methyltetrahydrofolate; CL, cystathionine lyase; Cys, cysteine; FS, FAD synthase; Met, methionine; MS, methionine synthase; MSR, methionine synthase reductase; MTHFR, 5,10-methylenetetrahydrofolate reductase; PLP, pyridoxal-5'-phosphate; PMP, pyridoxamine-5'-phosphate; PNP, pyridoxine-5'-phosphate; PPO, pyridoxine-5'-phosphate oxidase; RK, riboflavin kinase; THF, tetrahydrofolate.

One-carbon metabolism. SAM is produced by one-carbon metabolism, which combines the folate cycle and the methionine cycle. Nutrients that fuel one-carbon metabolism are folate, serine, and glycine. DHFR reduces folate to THF, which enters into the folate cycle and serves as scaffold that carries 1-carbon groups in a variety of reactions, including the production of mTHF. The folate cycle is coupled to the methionine cycle through Vitamin B12 that serves as cofactor for the demethylation of mTHF and the production of methionine by methionine synthase. MAT enzyme converts methionine into SAM, which is then demethylated to form SAH. Deadenylation of SAH by SAHH generates hCYS, resulting in a full turn of the methionine cycle. Dihydrofolate reductase (DHFR); tetrahydrofolate (THF); methyl-THF (mTHF); homocysteine (hCYS); methionine adenyltransferase (MAT); S-adenosyl homocysteine hydrolase (SAHH)

Major pathway of the conversion of propionyl-CoA into succinyl-CoA. The biotin-dependent enzyme propionyl-CoA carboxylase converts propionyl-CoA into D-methylmalonyl-CoA, which is then racemized into L-methylmalonyl-CoA and isomerized into succinyl-CoA, a Krebs cycle intermediate. The L-methylmalonyl-CoA mutase reaction requires 5'-deoxyadenosylcobalamin, an activated form of vitamin B₁₂. The pathway of cellular processing of cobalamin (reduction from Cbl⁺³ to Cbl⁺²) and subsequently formation of adenosyl- (AdoCbl) and methylcobalamin (MeCbl) is depicted. Adenosyl-cobalamin is the cofactor of the methylmalonyl-CoA mutase reaction; methylcobalamin is the cofactor of the methionine synthase reaction.
The color-coded boxes around the cobalamin-processing enzymes indicate their role in causing: (1) methylmalonyl-CoA mutase or isolated AdoCbl deficiency and associated increase in serum methylmalonic acid [sMMA] (blue); (2) isolated MeCbl deficiency and hyperhomocysteinemia (green); (3) both cofactor deficiencies causing elevations in MMA and homocysteine (purple). Note: The light blue striped boxes indicate the enzymes (and the genes encoding them) that are deficient in different disorders in which methylmalonic acidemia occurs: epimerase deficiency (MCEE) and succinate-CoA ligase deficiency (SUCLA2/SUCLG1), combined malonic and methylmalonic acidemia (ACSF3, ZBTB11), and methylmalonyl-semialdehyde dehydrogenase deficiency (ALDH6A1). The light purple striped box indicates cblX deficiency (HCFC1), the only X-linked disorder in this pathway and rare transcription factors (ZNF143, THAP11) or neighboring genes (PRDX1) associated with cblC deficiency or epi-cblC. See Disorders of Intracellular Cobalamin Metabolism.
MMA = methylmalonic acid; Cbl = cobalamin; Cbl⁺³ = oxidized cobalamin, Cbl⁺² = reduced cobalamin; AdoCbl = 5'-deoxyadenosylcobalamin; MeCbl = methylcobalamin; TC = transcobalamin; TCblR = transcobalamin receptor.
The genes (and the enzymatic subtypes) associated with isolated methylmalonic acidemia included in this GeneReview are:
MMUT (mut⁰, mut^–)
MMAA (cblA)
MMAB (cblB)
MMADHC (cblD-MMA)
MCEE
Isolated methylmalonic acidemia caused by mutation of SUCLA2 and SUCLG1 is discussed in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria and SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria, respectively.