# MTHFD2: A Retrospective and a Glance into the Future

## TL;DR

This review summarizes 40 years of research on MTHFD2, highlighting its role in metabolism, cancer, and immune cells.

## Contribution

The paper offers a comprehensive retrospective and future outlook on MTHFD2 research.

## Key findings

- MTHFD2 plays key roles in the folate pathway and amino acid metabolism.
- It contributes to redox homeostasis and cancer cell metabolism.
- Non-canonical roles of MTHFD2 are being increasingly recognized.

## 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.