The Department of Cell Biology & Genetics, Chongqing Medical University, Chongqing 400016, China; Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
The Department of Cell Biology & Genetics, Chongqing Medical University, Chongqing 400016, China.
Bioorg Chem. 2020 Jul;100:103836. doi: 10.1016/j.bioorg.2020.103836. Epub 2020 Apr 10.
In eucaryotic cells, methionine synthase reductase (MSR/MTRR) is capable of dominating the folate-homocysteine metabolism as an irreplaceable partner in electron transfer for regeneration of methionine synthase. The N-terminus of MTRR containing a conserved domain of FMN_Red is closely concerned with the oxidation-reduction process. Maternal substitution of I22M in this domain can bring about pregnancy with high risk of spina bifida. A new variation of Arg2del was identified from a female conceiving a fetus with spina bifida cystica. Although the deletion is far from the N-terminal FMN_Red domain, the biochemical features of the variant had been seriously investigated. Curiously, the deletion of arginine(s) of MTRR could not affect the electron relay, if only the FMN_Red domain was intact, but by degrees reduced the ability to promote MTR catalysis in methionine formation. Confirmation of the interaction between the isolated MTRR N-terminal polypeptide and MTR suggested that the native MTRR N-terminus might play an extra role in MTR function. The tandem arginines at the end of MTRR N-terminus conferring high affinity to MTR were indispensable for stimulating methyltransferase activity perhaps via triggering allosteric effect that could be attenuated by removal of the arginine(s). It was concluded that MTRR could also propel MTR enzymatic reaction relying on the tandem arginines at N-terminus more than just only implicated in electron transfer in MTR reactivation cycle. Perturbance of the enzymatic cooperation due to the novel deletion could possibly invite spina bifida in clinics.
在真核细胞中，蛋氨酸合成酶还原酶（MSR/MTRR）作为蛋氨酸合成酶电子传递中不可替代的伙伴，能够主导叶酸-同型半胱氨酸代谢。MTRR 的 N 端包含 FMN_Red 保守结构域，与氧化还原过程密切相关。该结构域中的 I22M 发生母体替代可能导致神经管缺陷高风险的妊娠。从患有囊性脊柱裂胎儿的女性中鉴定出 Arg2del 的新变异。尽管该缺失远离 N 端 FMN_Red 结构域，但已对该变体的生化特征进行了深入研究。奇怪的是，如果仅 FMN_Red 结构域完整，MTRR 缺失精氨酸（s）不会影响电子传递，但会逐渐降低其促进蛋氨酸形成中 MTR 催化的能力。MTRR 分离的 N 端多肽与 MTR 之间相互作用的证实表明，天然 MTRR N 端可能在 MTR 功能中发挥额外作用。MTRR N 端末端的串联精氨酸赋予对 MTR 的高亲和力，对于刺激甲基转移酶活性是不可或缺的，可能通过触发变构效应，而这种效应可以通过去除精氨酸（s）而减弱。因此，MTRR 也可以依靠 N 端的串联精氨酸来推动 MTR 酶促反应，而不仅仅是参与 MTR 再激活循环中的电子传递。由于新的缺失导致酶的协同作用受到干扰，可能会在临床上导致脊柱裂。
