Greig Kylie T, Antonchuk Jennifer, Metcalf Donald, Morgan Phillip O, Krebs Danielle L, Zhang Jian-Guo, Hacking Douglas F, Bode Lars, Robb Lorraine, Kranz Christian, de Graaf Carolyn, Bahlo Melanie, Nicola Nicos A, Nutt Stephen L, Freeze Hudson H, Alexander Warren S, Hilton Douglas J, Kile Benjamin T
Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Mol Cell Biol. 2007 Aug;27(16):5849-59. doi: 10.1128/MCB.00802-07. Epub 2007 Jun 4.
Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.
蛋白质的碳水化合物修饰包括N-连接和O-连接糖基化、蛋白聚糖形成、糖基磷脂酰肌醇锚定合成以及O-GlcNAc修饰。这些修饰中的每一种都需要糖核苷酸UDP-GlcNAc，它是通过己糖胺生物合成途径产生的。该途径中的一个关键步骤是由磷酸葡萄糖变位酶3（Pgm3）催化的GlcNAc-6-磷酸（GlcNAc-6-P）和GlcNAc-1-磷酸之间的相互转化。在本文中，我们描述了小鼠Pgm3的两个低表达等位基因，并表明Pgm3活性和全局UDP-GlcNAc水平的分级降低会产生特定的生理后果。缺乏Pgm3的小鼠在植入前死亡，而酶活性降低程度较轻的动物则不育，胰腺结构发生变化，并且贫血、白细胞减少和血小板减少。这些表型伴随着蛋白质糖基化的特定而非全面变化，这表明虽然某些蛋白质的功能是普遍需要的，但某些细胞类型的功能对Pgm3活性的降低特别敏感。
