Neuropharmacology & Neurotherapeutics
Dalfampridine
Mar. 06, 2021
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Folate and folate-mediated one-carbon metabolism
The one-carbon units carried by reduced folate are involved in cytosolic, mitochondrial, and nuclear folate pools and used for the biosynthesis of purines, thymidylate, amino acids, and S-adenosylmethionine (SAM). Over-expressed gamma-glutamylhydrolase (γGH) facilitates intracellular folate exportation by converting polyglutamylfolates (folate-Glun) to monoglutamylfolates (folate-Glu1), leading to intracellular folate deficiency (thickened circle and arrows in shadowed box).
Legend: AICAR: aminoimidazolecarboxamide ribonucleotide; AICART, aminoimidazolecarboxamide ribonucleotide transformylase; ADP: adenosine diphosphate; ATP: adenosine triphosphate; B2: riboflavin; B6: pyridoxal phosphate, the activated form of vitamin B6; B12: cobalamin (vitamin B12); 5,10-CH2-THF: 5,10-methylenetetrahydrofolate; DHF: dihydrofolate ; DHFR, dihydrofolate reductase; 5-CHO-THF: 5-formyltetrahydrofolate; 10-CHO-THF: 10-formyltetrahydrofolate; CO2: carbon dioxide; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate; FDH, 10-formyltetrahydrofolate dehydrogenase; γGH: γ-glutamylhydrolase; GAR: glycinamide ribonucleotide; GART, glycinamide ribonucleotide transformylase; Glu: glutamate: H+: proton; Hcy: homocysteine; H2O: water; MAT, methionine adenosyl transferase; Met: methionine; MT, methyltransferase; MTHF: methylenetetrahydrofolate ; MTHFD, methylenetetrahydrofolate dehydrogenase; MTHFR, methylenetetrahydrofolate reductase; MTHFS, 5,10-methenyltetrahydrofolate synthetase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; NADP+: nicotinamide adenine dinucleotide phosphate; NADPH: nicotinamide adenine dinucleotide phosphate (the reduced form of NADP⁺); Pi: inorganic phosphate; SAHH, S- adenosylhomocysteine hydrolase; SAH: S-adenosylhomocystein; SAM: S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF: tetrahydrofolate; TS, thymidylate synthase. (Source: Tu HC, Lee GH, Hsiao TH, et al. One crisis, diverse impacts: tissue-specificity of folate deficiency-induced circulation defects in zebrafish larvae. PLoS One 2017;12(11):e0188585.) (Creative Commons Attribution License.)