PDF(Pubmed)
Abstract：
Methionine adenosyltransferase (MAT) deficiency, characterized by isolated persistent hypermethioninemia (IPH), is caused by mutations in the MAT1A gene encoding MATαl, one of the major hepatic enzymes. Most of the associated hypermethioninemic conditions are inherited as autosomal recessive traits; however, dominant inheritance of hypermethioninemia is caused by an Arg264His (R264H) mutation. This mutation has been confirmed in a screening programme of newborns as the most common mutation in babies with IPH. Arg264 makes an inter-subunit salt bridge located at the dimer interface where the active site assembles. Here, it is demonstrated that the R264H mutation results in greatly reduced MAT activity, while retaining its ability to dimerize, indicating that the lower activity arises from alteration at the active site. The first crystallographic structure of the apo form of the wild-type MATαl enzyme is provided, which shows a tetrameric assembly in which two compact dimers combine to form a catalytic tetramer. In contrast, the crystal structure of the MATαl R264H mutant reveals a weaker dimeric assembly, suggesting that the mutation lowers the affinity for dimer-dimer interaction. The formation of a hetero-oligomer with the regulatory MATβV1 subunit or incubation with a quinolone-based compound (SCR0911) results in the near-full recovery of the enzymatic activity of the pathogenic mutation R264H, opening a clear avenue for a therapeutic solution based on chemical interventions that help to correct the defect of the enzyme in its ability to metabolize methionine.
摘要：
甲硫氨酸腺苷转移酶（MAT）缺乏症，以孤立性持续性高蛋氨酸血症（IPH）为特征，是由编码MATα1的MAT1A基因突变引起的，主要的肝酶之一。大多数相关的高蛋氨酸血症都是常染色体隐性遗传特征；然而，高蛋氨酸血症的显性遗传是由Arg264His（R264H）突变引起的。这种突变已在新生儿筛查计划中被证实为IPH婴儿中最常见的突变。Arg264形成位于活性位点组装的二聚体界面处的亚基间盐桥。这里,证明R264H突变导致MAT活性大大降低，同时保留其二聚化能力，表明较低的活性来自活性位点的改变。提供了野生型MATα1酶apo形式的第一晶体结构，其显示了四聚体组装,其中两个紧密二聚体结合以形成催化四聚体。相比之下,MATa1R264H突变体的晶体结构显示出较弱的二聚体组装，表明突变降低了二聚体-二聚体相互作用的亲和力。具有调节性MATβV1亚基的异源寡聚体的形成或与基于喹诺酮的化合物（SCR0911）的孵育导致致病性突变R264H的酶活性几乎完全恢复，为基于化学干预措施的治疗解决方案开辟了一条明确的途径，有助于纠正酶代谢蛋氨酸能力的缺陷。
