UniProt functional annotation for Q99707



	UniProt functional annotation for Q99707

UniProt code: Q99707.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol (PubMed:27771510). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (PubMed:27771510). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510). {ECO:0000269|PubMed:27771510, ECO:0000303|PubMed:27771510}.

Catalytic activity: Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine = (6S)-5,6,7,8-tetrahydrofolate + L-methionine; Xref=Rhea:RHEA:11172, ChEBI:CHEBI:18608, ChEBI:CHEBI:57453, ChEBI:CHEBI:57844, ChEBI:CHEBI:58199; EC=2.1.1.13; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11173; Evidence={ECO:0000305};

Cofactor: Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; Note=Binds 1 zinc ion per subunit. {ECO:0000250};

Pathway: Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (MetH route): step 1/1.

Subunit: Monomer (PubMed:17288554). Dimer (PubMed:17288554). Forms a multiprotein complex with MMACHC, MMADHC AND MTRR (PubMed:17288554, PubMed:27771510). {ECO:0000269|PubMed:17288554, ECO:0000269|PubMed:27771510}.

Subcellular location: Cytoplasm.

Tissue specificity: Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta. Expressed at lower levels in lung, liver and kidney.

Domain: Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin (By similarity). {ECO:0000250}.

Disease: Homocystinuria-megaloblastic anemia, cblG complementation type (HMAG) [MIM:250940]: 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. {ECO:0000269|PubMed:8968736, ECO:0000269|PubMed:8968737}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:12375236}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous: L-homocysteine is bound via the zinc atom. {ECO:0000250}.

Similarity: Belongs to the vitamin-B12 dependent methionine synthase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol (PubMed:27771510). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (PubMed:27771510). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510). {ECO:0000269\|PubMed:27771510, ECO:0000303\|PubMed:27771510}.


Catalytic activity:		Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine = (6S)-5,6,7,8-tetrahydrofolate + L-methionine; Xref=Rhea:RHEA:11172, ChEBI:CHEBI:18608, ChEBI:CHEBI:57453, ChEBI:CHEBI:57844, ChEBI:CHEBI:58199; EC=2.1.1.13; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11173; Evidence={ECO:0000305};
Cofactor:		Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; Note=Binds 1 zinc ion per subunit. {ECO:0000250};
Pathway:		Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (MetH route): step 1/1.
Subunit:		Monomer (PubMed:17288554). Dimer (PubMed:17288554). Forms a multiprotein complex with MMACHC, MMADHC AND MTRR (PubMed:17288554, PubMed:27771510). {ECO:0000269\|PubMed:17288554, ECO:0000269\|PubMed:27771510}.
Subcellular location:		Cytoplasm.
Tissue specificity:		Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta. Expressed at lower levels in lung, liver and kidney.
Domain:		Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin (By similarity). {ECO:0000250}.
Disease:		Homocystinuria-megaloblastic anemia, cblG complementation type (HMAG) [MIM:250940]: 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. {ECO:0000269\|PubMed:8968736, ECO:0000269\|PubMed:8968737}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269\|PubMed:12375236}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Miscellaneous:		L-homocysteine is bound via the zinc atom. {ECO:0000250}.
Similarity:		Belongs to the vitamin-B12 dependent methionine synthase family. {ECO:0000305}.