Monofunctional C1-tetrahydrofolate synthase, mitochondrial also known as formyltetrahydrofolate synthetase, is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

that in humans is encoded by the ''MTHFD1L''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

(methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like).

Function

One-carbon substituted forms of

tetrahydrofolate Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is ...

(THF) are involved in the

de novo synthesis In chemistry, ''de novo'' synthesis () refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation. For example, nucleotides are not needed in the diet as ...

purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purin ...

s and

thymidylate Thymidine monophosphate (TMP), also known as thymidylic acid (conjugate base thymidylate), deoxythymidine monophosphate (dTMP), or deoxythymidylic acid (conjugate base deoxythymidylate), is a nucleotide that is used as a monomer in DNA. It is an ...

and support cellular

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

reactions through the regeneration of methionine from

homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...

. MTHFD1L is an enzyme involved in THF synthesis in mitochondria. In contrast to

MTHFD1 MTHFD1 is a gene located in humans on chromosome 14 that encodes for a protein with three distinct enzymatic activities. C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase is an enzyme that in humans is encoded by the ''MTHFD ...

that has trifunctional methylenetetrahydrofolate dehydrogenase,

methenyltetrahydrofolate cyclohydrolase In enzymology, a methenyltetrahydrofolate cyclohydrolase () is an enzyme that catalyzes the chemical reaction :5,10-methenyltetrahydrofolate + H2O \rightleftharpoons 10-formyltetrahydrofolate Thus, the two substrates of this enzyme are 5,10-met ...

, and formyltetrahydrofolate synthetase enzymatic activities, MTHFD1L only has formyltetrahydrofolate synthetase activity.

Clinical significance

Certain variants of the MTHFD1L are associated

neural tube defect Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo ...

s. Different alleles of SNP rs7646 in the 3′ UTR of MTHFD1L are differentially regulated by microRNAs affecting MTHFD1L expression.

Model organisms

Model organisms have been used in the study of MTHFD1L function. A conditional

knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importa ...

line, called ''Mthfd1l^{tm1a(EUCOMM)Wtsi}'' was generated as part of the

International Knockout Mouse Consortium The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to cr ...

program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized

phenotypic screen In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...

to determine the effects of deletion. Twenty six tests were carried out on

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...

mice and two significant abnormalities were observed. The

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

embryos identified during gestation had

exencephaly Exencephaly is a type of cephalic disorder wherein the brain is located outside of the skull. This condition is usually found in embryos as an early stage of anencephaly. As an exencephalic pregnancy progresses, the neural tissue gradually degenerat ...

. None survived until

weaning Weaning is the process of gradually introducing an infant human or another mammal to what will be its adult diet while withdrawing the supply of its mother's milk. The process takes place only in mammals, as only mammals produce milk. The infa ...

. The remaining tests were carried out on

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

mutant adult mice and no further abnormalities were observed.

Function

Clinical significance

Model organisms

References

Further reading