5-Formyltetrahydrofolate promotes conformational remodeling in a methylenetetrahydrofolate reductase active site and inhibits its activity

Yamada, Keiko; Mendoza, Johnny; Koutmos, Markos

doi:10.1016/j.jbc.2022.102855

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…High doses of folic acid supplementation come with the mental health risks covered in previous sections, and as reviewed decades ago by Young and Ghadirian [288]. In a small clinical study, there is also new evidence to suggest that folic acid and folinic acid can either inhibit transport of 5-methyl-THF across the BBB [289], or diminish its synthesis. Consistent with this outcome, there is a more recent report that folinic acid acts as an inhibitor of MTHFR in lower organisms by changing the conformation of the active site [290], though no similar study of the mammalian enzyme has yet been conducted.…”

Section: Dysregulation Of the Folate Cycle: Neuroprotective Strategiesmentioning

confidence: 89%

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Miller

2024

Explor Neuroprot Ther

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Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

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Section: Dysregulation Of the Folate Cycle: Neuroprotective Strategiesmentioning

confidence: 89%

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Miller

2024

Explor Neuroprot Ther

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“…1b) 7 . In contrast, bacterial MTHFR lacks the regulatory domain and manifests as a homooligomer consisting only of catalytic subunits 11,12,13 . The catalytic component of all MTHFRs bind FAD within the core of a β 8 α 8 barrel structure, also known as a TIM-barrel.…”

Section: Introductionmentioning

confidence: 99%

Structural basis ofS-adenosylmethionine-dependent Allosteric Transition from Active to Inactive States in Methylenetetrahydrofolate Reductase

Yamada,

Mendoza,

Koutmos

2023

Preprint

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Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and AdoMet-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures ofChaetomium thermophilumMTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form ofcMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites inhMTHFR, three of which are novel. Based on the structural framework provided by ourcMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.

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“…1b) 7 . In contrast, bacterial MTHFR lacks the regulatory domain and manifests as a homooligomer consisting only of catalytic subunits [11][12][13] . The catalytic component of most MTHFRs binds FAD within the core of a β 8 α 8 barrel structure, also known as a TIM barrel.…”

mentioning

confidence: 99%

Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

Yamada,

Mendoza,

Koutmos

2024

Nat Commun

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Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and S-adenosylmethionine (AdoMet)-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures of Chaetomium thermophilum MTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form of cMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites in hMTHFR, three of which were previously unidentified. Based on the structural framework provided by our cMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.

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5-Formyltetrahydrofolate promotes conformational remodeling in a methylenetetrahydrofolate reductase active site and inhibits its activity

Cited by 3 publications

References 44 publications

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Structural basis ofS-adenosylmethionine-dependent Allosteric Transition from Active to Inactive States in Methylenetetrahydrofolate Reductase

Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

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