MTHFD2: A Retrospective and a Glance into the Future

Costas Koufaris; Vicky Nicolaidou

doi:10.3390/ijms262211025

MTHFD2: A Retrospective and a Glance into the Future

Costas Koufaris
, Vicky Nicolaidou

Department of Life Sciences

Cyprus Cancer Research Institute (CCRI)

Research output: Contribution to journal › Review article › peer-review

Abstract

The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD⁺-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2’s metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.

Original language	English
Article number	11025
Journal	International Journal of Molecular Sciences
Volume	26
Issue number	22
DOIs	https://doi.org/10.3390/ijms262211025
Publication status	Published - Nov 2025

Keywords

MTHFD2
one-carbon metabolism
retrospective

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms262211025

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title = "MTHFD2: A Retrospective and a Glance into the Future",

abstract = "The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD+-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2{\textquoteright}s metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.",

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AU - Nicolaidou, Vicky

PY - 2025/11

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N2 - The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD+-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2’s metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.

AB - The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD+-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2’s metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.

KW - MTHFD2

KW - one-carbon metabolism

KW - retrospective

UR - https://www.scopus.com/pages/publications/105023129964

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DO - 10.3390/ijms262211025

M3 - Review article

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AN - SCOPUS:105023129964

SN - 1661-6596

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 22

M1 - 11025

ER -

MTHFD2: A Retrospective and a Glance into the Future

Abstract

Keywords

UN SDGs

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