Biochemistry Department, University of Missouri, Columbia, MO 65211, USA.
Acta Crystallogr F Struct Biol Commun. 2022 May 1;78(Pt 5):200-209. doi: 10.1107/S2053230X22004174. Epub 2022 Apr 25.
Phosphoglucomutase 1 (PGM1) plays a central role in glucose homeostasis in human cells. Missense variants of this enzyme cause an inborn error of metabolism, which is categorized as a congenital disorder of glycosylation. Here, two disease-related variants of PGM1, T337M and G391V, which are both located in domain 3 of the four-domain protein, were characterized via X-ray crystallography and biochemical assays. The studies show multiple impacts resulting from these dysfunctional variants, including both short- and long-range structural perturbations. In the T337M variant these are limited to a small shift in an active-site loop, consistent with reduced enzyme activity. In contrast, the G391V variant produces a cascade of structural perturbations, including displacement of both the catalytic phosphoserine and metal-binding loops. This work reinforces several themes that were found in prior studies of dysfunctional PGM1 variants, including increased structural flexibility and the outsized impacts of mutations affecting interdomain interfaces. The molecular mechanisms of PGM1 variants have implications for newly described inherited disorders of related enzymes.
磷酸葡萄糖变位酶 1（PGM1）在人类细胞的葡萄糖稳态中发挥核心作用。该酶的错义变体导致先天性代谢错误，被归类为糖基化先天性疾病。在这里，通过 X 射线晶体学和生化分析研究了两种位于四结构域蛋白结构域 3 的与疾病相关的 PGM1 变体，T337M 和 G391V。研究表明，这些功能失调变体导致多种影响，包括短程和长程结构扰动。在 T337M 变体中，这些结构扰动仅限于活性位点环的小位移，与酶活性降低一致。相比之下，G391V 变体产生一连串的结构扰动，包括催化磷酸丝氨酸和金属结合环的位移。这项工作强化了先前对功能失调的 PGM1 变体研究中发现的几个主题，包括结构灵活性增加以及影响结构域间界面的突变的巨大影响。PGM1 变体的分子机制对新描述的相关酶的遗传性疾病具有重要意义。
