Defective MTR does not transfer CH3 group from MeCbl to HCYS

Stable Identifier
R-HSA-3322140
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Methionine synthase (MTR) catalyses the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to MTR-bound cob(I)alamin to form methylcobalamin (MeCbl). In the second step, the methyl group from MeCbl is transferred to homocysteine (HCYS), forming methionine (L-Met) (Leclerc et al. 1996). Under normal conditions, the enzyme-bound cobalamin shuttles between the cob(I)alamin and MeCbl forms. Every few hundred cycles, enzyme-bound cob(I)alamin is spontaneously oxidized to cob(II)alamin, inactivating MTR. Active MTR is regenerated by MTRR which, in conjunction with MTR, catalyzes reductive methylation of cob(II)alamin to MeCbl using SAM as a methyl donor.

Defects in MTR cause methylcobalamin deficiency type G (cblG, methionine synthase deficiency; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mutations causing cblG include P1173L, Ile881, H920D, R585*, E1204* and A1204P (Leclerc et al. 1996, Gulati et al. 1996, Watkins et al. 2002).

Literature References
PubMed ID Title Journal Year
12068375 Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L

Watkins, D, Ru, M, Hwang, HY, Kim, CD, Murray, A, Philip, NS, Kim, W, Legakis, H, Wai, T, Hilton, JF, Ge, B, Doré, C, Hosack, A, Wilson, A, Gravel, RA, Shane, B, Hudson, TJ, Rosenblatt, DS

Am. J. Hum. Genet. 2002
8968737 Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders

Leclerc, D, Campeau, E, Goyette, P, Adjalla, CE, Christensen, B, Ross, M, Eydoux, P, Rosenblatt, DS, Rozen, R, Gravel, RA

Hum Mol Genet 1996
8968736 Defects in human methionine synthase in cblG patients

Gulati, S, Baker, P, Li, YN, Fowler, B, Kruger, W, Brody, LC, Banerjee, R

Hum. Mol. Genet. 1996
Participants
Participates
Normal reaction
Functional status

Loss of function of MTRR:mutant MTR(MeCbl) [cytosol]

Status
Authored
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