MTRR reduces cob(II)alamin to meCbl

Methionine synthase reductase (MTRR), in a stable complex with methionine synthase (MTR), catalyzes the reduction of cob(II)alamin to methylcobalamin (MeCbl), the cofactor form required for MTR activity. This reductive methylation reaction uses S adenosylmethionine (AdoMet, SAM) as a methyl donor. MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).<p>An important role for this reaction in the cell is maintenance of the pool of MeCbl-associated MTR. At a low rate, cobalamin bound to MTR is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR this reductive methylation reaction restores cob(II)alamin to MeCbl (Hall et al. 2000).<p>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.

蛋氨酸合酶还原酶（MTRR），与蛋氨酸合酶（MTR）形成稳定复合物，催化钴（II）钴胺素（Cob(II)alamin）还原为甲基钴胺素（MeCbl），这是维持MTR活性所需的辅因子形式。此还原性甲基化反应以S腺苷蛋氨酸（AdoMet，SAM）作为甲基供体。MTRR每亚基需1分子黄素单核苷酸（FMN）和1分子黄素腺嘌呤二核苷酸（FAD）以维持其活性（Wolthers & Scrutton 2007，Wolthers & Scrutton 2009）。该反应在细胞中发挥着至关重要的作用，即维持与MeCbl相关的MTR库的稳定。在低速率下，与MTR结合的钴胺素会自发氧化形成钴（II）钴胺素。当这种情况发生时，MTRR通过此还原性甲基化反应将钴（II）钴胺素恢复为MeCbl（Hall et al. 2000）。MTRR的缺陷会导致甲基钴胺素缺乏症类型E（cblE；MIM:236270）（Wilson et al. 1999）。cblE患者表现出巨幼细胞性贫血和高同型半胱氨酸血症。AdoMet在许多生物反应中用作甲基供体，其去甲基化产生同型半胱氨酸。甲基化过程由MTR与MTRR协同完成，但在cblE患者中，MTR结合的钴胺素无法被缺陷的MTRR还原形成功能性酶，因此同型半胱氨酸积累。导致cblE的MTRR突变包括Leu576del（Leclerc et al. 1998）和S454L（Zavadakova et al. 2005）。就频率而言，最常见的MTRR突变是c.903+469C>T突变，该突变在深部内含子中创建了一个新的剪接位点，导致MTRR mRNA中包含一个140 bp的插入（Homolova et al. 2010）。Wilson等发现，66A G多态性，导致Ile22Met（I22M）替换，与叶酸敏感神经管缺陷（FS NTD；MIM:601634）的易感性相关（Wilson et al. 1999b，Doolin et al. 2002）。维生素B₁₂血清缺乏会加剧这一效应。