# MTHFD2L

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**NAD-dependent methylenetetrahydrofolate dehydrogenase 2-like protein** (MTHFD2L), also known as **bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2**, is an [enzyme](/source/Enzyme) that in humans is encoded by the *MTHFD2L* [gene](/source/Gene) on chromosome 4.[1][2] This enzyme localizes to the [inner mitochondrial membrane](/source/Inner_mitochondrial_membrane), where it performs the [NADP+](/source/NADP%2B)-dependent [dehydrogenase](/source/Dehydrogenase)/cyclo[hydrolase](/source/Hydrolase) activity as part of the mitochondrial pathway to convert [folate](/source/Folate) to [formate](/source/Formate).[3] It is associated with fluctuations in [cytokine](/source/Cytokine) secretion in response to [viral infections](/source/Viral_infection) and [vaccines](/source/Vaccine).[4]

## Structure

The *MTHFD2L* gene consists of nine [exons](/source/Exon) and is conserved among mammals. This gene encodes a 340-[residue](/source/Amino_acid) protein that is [homologous](/source/Homology_(biology)) to the mitochondrial bifunctional dehydrogenase/cyclohydrolase ([MTHFD2](/source/MTHFD2)) and to the [N-terminal](/source/N-terminal) dehydrogenase/cyclohydrolase domains of [cytoplasmic](/source/Cytoplasm) and [mitochondrial](/source/Mitochondria) [C1-THF syntheses](/source/Formate%E2%80%93tetrahydrofolate_ligase) ([MTHFD1](/source/MTHFD1) and [MTHFD1L](/source/MTHFD1L), respectively). The MTHFD2L protein contains a predicted N-terminal mitochondrial [targeting sequence](/source/Targeting_sequence) and four [amino acids](/source/Amino_acid) (Lys-93, Arg-206, Gly-211, and Arg-238) necessary for the protein's dehydrogenase/cyclohydrolase activity. Three classes of MTHFD2L [RNA](/source/RNA) transcripts have been detected at equal levels in adult human [brain](/source/Brain) and [placenta](/source/Placenta), though their [translation](/source/Translation) into stable proteins [in vivo](/source/In_vivo) has not been confirmed.[3]

## Function

MTHFD2L is a member of the tetrahydrofolate dehydrogenase/cyclohydrolase family.[2] This enzyme is expressed in all adult tissues and localizes to the mitochondria, specifically as a [peripheral membrane protein](/source/Peripheral_membrane_protein) in the [mitochondrial matrix](/source/Mitochondrial_matrix) side of the inner mitochondrial membrane. Within the mitochondria, it participates the conversion of folate to formate as part of the mitochondrial pathway for 1-carbon [metabolism](/source/Metabolism).[3][4] In the final step of this pathway, the NADP+-dependent CH2-THF dehydrogenase/CH+-THF cyclohydrolase activity of bifunctional MTHFD2L complements the 10-CHO-THF synthetase activity of monofunctional MTHFD1L.[3][5] The formate produced via the mitochondrial pathway can contribute to [purine](/source/Purine) and [thymidine](/source/Thymidine) synthesis and [homocysteine](/source/Homocysteine) re[methylation](/source/Methylation) into [methionine](/source/Methionine), as well as be converted into 1-carbon units to fuel the cytoplasmic pathway of folate metabolism.[5]

## Clinical significance

In a [GWAS](/source/Genome-wide_association_study) study concerning variations in [cytokine](/source/Cytokine) responses observed in [smallpox](/source/Smallpox) [vaccine](/source/Vaccine) recipients, a number of SNPs associated with variations in [IL-1β](/source/IL-1%CE%B2) secretion were identified in or within the vicinity of the *MTHFD2L* gene. Identification of the genetic elements controlling cytokine secretion in response to viral infection or vaccination can improve next-generation vaccines to provide robust immune protection while avoiding adverse effects.[4]

## See also

- [MTHFD1](/source/MTHFD1)
- [MTHFD1L](/source/MTHFD1L)
- [MTHFD2](/source/MTHFD2)

## References

1. ["Entrez Gene: MTHFD2L methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2-like"](https://www.ncbi.nlm.nih.gov/gene/441024)

1. ["UniProtKB: Q9H903 (MTD2L_HUMAN)"](https://www.uniprot.org/uniprot/Q9H903)

1. Bolusani S, Young BA, Cole NA, Tibbetts AS, Momb J, Bryant JD, Solmonson A, Appling DR (Feb 2011). "Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues". *The Journal of Biological Chemistry*. **286** (7): 5166–74. [doi:10.1074/jbc.M110.196840](https://doi.org/10.1074/jbc.M110.196840). [PMC 3037629](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037629). [PMID 21163947](https://pubmed.ncbi.nlm.nih.gov/21163947)

1. Kennedy RB, Ovsyannikova IG, Pankratz VS, Haralambieva IH, Vierkant RA, Poland GA (Sep 2012). "Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients". *Human Genetics*. **131** (9): 1403–21. [doi:10.1007/s00439-012-1174-2](https://doi.org/10.1007/s00439-012-1174-2). [PMC 4170585](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170585). [PMID 22610502](https://pubmed.ncbi.nlm.nih.gov/22610502)

1. Watkins D, Rosenblatt DS (Jul 2012). "Update and new concepts in vitamin responsive disorders of folate transport and metabolism". *Journal of Inherited Metabolic Disease*. **35** (4): 665–70. [doi:10.1007/s10545-011-9418-1](https://doi.org/10.1007/s10545-011-9418-1). [PMID 22108709](https://pubmed.ncbi.nlm.nih.gov/22108709). [S2CID 1258801](https://api.semanticscholar.org/CorpusID:1258801)

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Adapted from the Wikipedia article [MTHFD2L](https://en.wikipedia.org/wiki/MTHFD2L) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/MTHFD2L?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.