Abstract
One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.
Highlights
One-carbon metabolism (OCM) refers to the complex network of biochemical reactions that mediate delivery of one-carbon units to various anabolic pathways [1]
The directionality of each pathway relies on the differential abundance of NAD(P)H and NAD(P)+ in the different compartments: Reduced NAD(P)H:NAD(P)+ ratio in mitochondria favors the activity of methylene-THF dehydrogenase 2 (MTHFD2)/ methylene-THF dehydrogenase 2 like (MTHFD2L) enzymes towards 10-formyl THF formation and formate synthesis, while augmented nicotinamide adenine dinucleotide phosphate (NADPH):NADP+ ratio favors the activity of methylene-THF dehydrogenase 1 (MTHFD1) towards formate catabolism and 5-10-methylene THF synthesis, which is required for the subsequent serine production [1]
Low dietary folate and cobalamin intake leads to increased Hcy levels since they are required for methionine regeneration from Hcy
Summary
One-carbon metabolism (OCM) refers to the complex network of biochemical reactions that mediate delivery of one-carbon units to various anabolic pathways [1]. PCFT is expressed mainly in the upper gastrointestinal tract and in tumors, supporting transport of folates under acidic conditions [8,9]. RFC is an organic anion antiporter expressed ubiquitously and is the major tissue folate transporter [10,11]. All natural folates differ in the oxidation state of the pteridine ring and are present in their reduced form, compared to the fully oxidized and monoglutamated folic acid, which is commonly used as a synthetic food supplement. All natural folates differ in the oxidation state of the pteridine ring and are prese2notfi2n6 their reduced form, compared to the fully oxidized and monoglutamated folic acid, which is commonly used as a synthetic food supplement. OOnnee--CCaarrbboonn MMeettaabboolliicc PPaatthhwwaayyss OOCCMM iisshhiigghhllyy ccoommppaarrttmmeennttaalliizzeedd,, ssiinnccee ppaarraalllleell,, iinntteerrccoonnnneecctteedd ppaatthhwwaayysseexxiissttiinn tthheeccyyttoossooll,,mmiittoocchhoonnddrriiaa,, aanndd nnuucclleeuuss [[1166]]. Tsr.heedT.hinevionlvvoedlvfeodlaftoelfaotermfosramresdaer-e depicted in green boxes, while the respective enzymes are written in red
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