Defective MTRR does not convert cob(II)alamin to MeCbl

Stable Identifier
Reaction [transition]
Homo sapiens
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Methionine synthase reductase (MTRR) is involved in reducing cob(II)alamin (B12r) to methylcobalamin (MeCbl), the cofactor form used by methionine synthase (MTR). Regeneration of functional MTR requires reductive methylation via a reaction catalysed by MTRR in which S-adenosylmethionine (AdoMet, SAM) is used as a methyl donor. MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers et al. 2007). MTRR exists in a stable complex with MTR, bound through their FMN-binding and C-terminal activation domains respectively (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).

When methionine synthase (MTR) is functioning properly, cobalamin (Cbl) is continuously shuttled between two forms, cob(I)alamin and MeCbl. There are 2 half reactions: transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to enzyme-bound cob(I)alamin to form MeCbl; and transfer of the methyl group from MeCbl to homocysteine (HYCS) to form AdoMet, methionine and regenerate cob(I)alamin. From time to time (every few hundred cycles), the enzyme-bound cobalamin is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR in conjunction with MTR catalyzes the reductive methylation of cob(II)alamin to form MeCbl. If MTRR is defective, cob(II)alamin accumulates and methionine synthase is inactivated.

Defects in MTRR cause methylcobalamin deficiency type E (cblE; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. AdoMet is used as a methyl donor in many biological reactions and its demethylation produces homocysteine. Remethylation is carried out by MTR in conjunction with MTRR but in cblE patients, MTR-bound cobalamin cannot be reduced by defective MTRR to form a functional enzyme thus homocysteine accumulates. Mutations in MTRR that cause cblE include Leu576del (Leclerc et al. 1998) and S454L (Zavadakova et al. 2005). In terms of frequency, the most common MTRR mutation is a c.903+469C>T mutation which creates a novel splice site deep in an intron and results in inclusion of a 140-bp insertion in MTRR mRNA (Homolova et al. 2010). Wilson et al. showed that a 66A G polymorphism, resulting in an Ile22Met (I22M) substitution, is associated with susceptibility to folate sensitive neural tube defects (FS NTD; MIM:601634) (Wilson et al. 1999b, Doolin et al. 2002). Serum deficiency of vitamin B12 increased the effect.

Literature References
PubMed ID Title Journal Year
17892308 Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry

Wolthers, KR, Lou, X, Toogood, HS, Leys, D, Scrutton, NS

Biochemistry 2007
12375236 Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida

Doolin, MT, Barbaux, S, McDonnell, M, Hoess, K, Whitehead, AS, Mitchell, LE

Am. J. Hum. Genet. 2002
15714522 cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression

Zavadakova, P, Fowler, B, Suormala, T, Novotna, Z, Mueller, P, Hennermann, JB, Zeman, J, Vilaseca, MA, Vilarinho, L, Gutsche, S, Wilichowski, E, Horneff, G, Kozich, V

Hum. Mutat. 2005
10484769 Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism

Wilson, A, Leclerc, D, Rosenblatt, DS, Gravel, RA

Hum. Mol. Genet. 1999
9501215 Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria

Leclerc, D, Wilson, A, Dumas, R, Gafuik, C, Song, D, Watkins, D, Heng, HH, Rommens, JM, Scherer, SW, Rosenblatt, DS, Gravel, RA

Proc. Natl. Acad. Sci. U.S.A. 1998
19243433 Cobalamin uptake and reactivation occurs through specific protein interactions in the methionine synthase-methionine synthase reductase complex

Wolthers, KR, Scrutton, NS

FEBS J. 2009
10444342 A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida

Wilson, A, Platt, R, Wu, Q, Leclerc, D, Christensen, B, Yang, H, Gravel, RA, Rozen, R

Mol. Genet. Metab. 1999
20120036 The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria

Homolova, K, Zavadakova, P, Doktor, TK, Schroeder, LD, Kozich, V, Andresen, BS

Hum. Mutat. 2010
12555939 CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families

Zavadakova, P, Fowler, B, Zeman, J, Suormala, T, Pristoupilov√°, K, Kozich, V, Zavad'√°kov√°, P

J. Inherit. Metab. Dis. 2002
17477549 Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation

Wolthers, KR, Scrutton, NS

Biochemistry 2007
Normal reaction
Functional status

Loss of function of mutant MTRR:MTR(cob(II)alamin) [cytosol]

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