# 5,10-Methylenetetrahydrofolate Reductasethe Key Allosteric Regulator in One-Carbon Metabolism

## TL;DR

This paper explores the role of MTHFR in one-carbon metabolism, focusing on its regulation and recent structural insights into its function.

## Contribution

The paper provides new insights into the regulatory mechanisms and structural features of MTHFR in eukaryotes.

## Key findings

- MTHFR is central to directing methyl groups in the methionine cycle.
- Eukaryotic MTHFR activity is regulated by SAM levels to balance one-carbon needs.
- Recent structural findings reveal a unique inactivation mechanism by SAM.

## Abstract

Collectively known as one-carbon metabolism (OCM), both
the folate
and methionine cycles are highly regulated to meet cellular demands.
These cycles are key in the production and recycling of methyl groups
to be used in many essential cellular processes such as the production
of nucleotides, as well as S-adenosyl-l-methionine
(SAM) the global methyl donor for DNA, RNA, and post translational
modifications. Within the folate cycle, 5,10-methylenetetrahydrofolate
is the main species through which methyl groups enter OCM. Therefore,
5,10-methylenetetrahydrofolate reductase (MTHFR), which reduces 5,10-methylenetetrahydrofolate
into 5-methyltetrahydrofolate, is the central enzyme that directs
methyl groups for use within the methionine cycle. MTHFR is an enzyme
found in all domains of life, but unlike in prokaryotes, eukaryotic
MTHFR activity is highly regulated by the level of SAM, to balance
the one-carbon needs of the cell. In this perspective, we review the
catalytic mechanism of MTHFR, evolutionary differences, and the regulatory
mechanisms that have evolved to alter its activity. We also discuss
recent structural findings that reveal a unique mechanism for inactivation
by SAM as a feedback loop and its consequences for understanding inherited
MTHFR deficiency.