MTRR

Methionine is an essential amino acid required for protein synthesis and one-carbon metabolism. Its synthesis is catalyzed by the enzyme methionine synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cob(I)alamin cofactor. The protein encoded by this gene regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. Patients of the cbl-E complementation group of disorders of folate/cobalamin metabolism are defective in reductive activation of methionine synthase. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq]

Full Name

5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Function

Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin (PubMed:17892308).

Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species (Probable). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510).

Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (By similarity).

Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme (PubMed:16769880).

Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (PubMed:16769880).

Biological Process

DNA methylation Source: UniProtKB
Folic acid metabolic process Source: BHF-UCL
Homocysteine catabolic process Source: BHF-UCL
Homocysteine metabolic process Source: GO_Central
Methionine biosynthetic process Source: BHF-UCL
Negative regulation of cystathionine beta-synthase activity Source: BHF-UCL
S-adenosylmethionine cycle Source: BHF-UCL

Cellular Location

Cytoplasm

Involvement in disease

Homocystinuria-megaloblastic anemia, cblE complementation type (HMAE):
An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia. Cells from patients with HMAE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent.
Neural tube defects, folate-sensitive (NTDFS):
The most common NTDs are open spina bifida (myelomeningocele) and anencephaly.