Abstract
In folate-mediated one-carbon metabolism (FOCM), 5-formyltetrahydrofolate (5fTHF), a one-carbon substituted tetrahydrofolate (THF) vitamer, acts as an intracellular storage form of folate and as an inhibitor of the folate-dependent enzymes phosphoribosylaminoimidazolecarboxamide formyltransferase (AICARFT) and serine hydroxymethyltransferase (SHMT). Cellular levels of 5fTHF are regulated by a futile cycle comprising the enzymes SHMT and 5,10-methenyltetrahydrofolate synthetase (MTHFS). MTHFS is an essential gene in mice; however, the roles of both 5fTHF and MTHFS in mammalian FOCM remain to be fully elucidated. We present an extension of our previously published hybrid-stochastic model of FOCM by including the 5fTHF futile-cycle to explore its effect on the FOCM network. Model simulations indicate that MTHFS plays an essential role in preventing 5fTHF accumulation, which consequently averts inhibition of all other reactions in the metabolic network. Moreover, in silico experiments show that 10-formylTHF inhibition of MTHFS is critical for regulating purine synthesis. Model simulations also provide evidence that 5-methylTHF (and not 5fTHF) is the predominant physiological binder/inhibitor of SHMT. Finally, the model simulations indicate that the 5fTHF futile cycle dampens the stochastic noise in FOCM that results from both folate deficiency and a common variant in the methylenetetrahydrofolate reductase (MTHFR) gene.
Highlights
Folate-mediated one-carbon metabolism (FOCM, for a list of the abbreviations refer to Supplementary Table 1) is a tightly interconnected metabolic network in which tetrahydrofolates (THF) carry and chemically activate one-carbon moieties for biosynthetic reactions including de novo purine synthesis, de novo thymidylate synthesis, and remethylation of homocysteine to methionine[1]
Www.nature.com/scientificreports formyltransferase (PGT), is incorporated into the #2 and #8 carbons of the purine ring. 10fTHF is formed from THF and ATP by the synthetase activity of the trifunctional enzyme methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). 5fTHF is not used as a cofactor for folate-dependent biosynthetic reactions, rather it is thought to be an intracellular storage form of folate in dormant cells8. 5fTHF is regulated through a futile cycle catalyzed by serine hydroxymethyltransferase (SHMT) and methenyltetrahydrofolate synthetase (MTHFS). 5fTHF is generated from CHF in an irreversible reaction catalyzed by SHMT. 5fTHF is re-introduced to the folate cofactor pool by MTHFS, which converts 5fTHF to CHF in an irreversible, ATP-dependent reaction
The influence of the 5fTHF futile cycle, including the MTHFS-catalyzed synthesis of CHF from 5fTHF and the reverse reaction catalyzed by SHMT, on the folate-mediated one-carbon metabolism (FOCM) network was studied by comparing steady states and reaction velocities of this updated model, which is described by the parameters presented in Supplementary Table 2
Summary
Folate-mediated one-carbon metabolism (FOCM, for a list of the abbreviations refer to Supplementary Table 1) is a tightly interconnected metabolic network in which tetrahydrofolates (THF) carry and chemically activate one-carbon moieties for biosynthetic reactions including de novo purine synthesis, de novo thymidylate (dTMP) synthesis, and remethylation of homocysteine to methionine[1]. CHF is not used directly as a co-factor for biosynthetic reactions It is formed both enzymatically from MTHFS and the cyclohydrolase activity of MTHFD1 and non-enzymatically from both 5fTHF and 10fTHF9. 10fTHF binds tightly to and inhibits MTHFS in vitro[12,13], and increased MTHFS expression in cultured cells leads to increased rates of de novo purine biosynthesis[13]. 5fTHF is a feedback inhibitor of SHMT, and binds to and inhibits AICARFT15,16, but the purpose of the 5fTHF futile cycle in regulating SHMT and FOCM remains unresolved. This is due in part because 5mTHF, which is more abundant than 5fTHF, serves as a potent inhibitor of SHMT
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