Inflammation Program and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Veterans Administration Medical Center, Iowa City, IA 52240, USA; Veterans Administration Medical Center, Iowa City, IA 52240, USA; 2501 Crosspark Road D168- MTF, Coralville, IA 52241, USA.
Arch Biochem Biophys. 2018 Mar 15;642:1-9. doi: 10.1016/j.abb.2018.02.001. Epub 2018 Feb 3.
Members of Chordata peroxidase subfamily [1] expressed in mammals, including myeloperoxidase (MPO), eosinophil peroxidase (EPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO), express conserved motifs around the heme prosthetic group essential for their activity, a calcium-binding site, and at least two covalent bonds linking the heme group to the protein backbone. Although most studies of the biosynthesis of these peroxidases have focused on MPO, many of the features described occur during biosynthesis of other members of the protein subfamily. Whereas MPO biosynthesis includes events typical for proteins generated in the secretory pathway, the importance and consequences of heme insertion are events uniquely associated with peroxidases. This Review summarizes decades of work elucidating specific steps in the biosynthetic pathway of human MPO. Discussion includes cotranslational glycosylation and subsequent modifications of the N-linked carbohydrate sidechains, contributions by molecular chaperones in the endoplasmic reticulum, cleavage of the propeptide from proMPO, and proteolytic processing of protomers and dimerization to yield mature MPO. Parallels between the biosynthesis of MPO and TPO as well as the impact of inherited mutations in the MPO gene on normal biosynthesis will be summarized. Lastly, specific gaps in our knowledge revealed by this review of our current understanding will be highlighted.
Chordata 过氧化物酶亚家族 [1] 在哺乳动物中表达的成员，包括髓过氧化物酶 (MPO)、嗜酸性粒细胞过氧化物酶 (EPO)、乳过氧化物酶 (LPO) 和甲状腺过氧化物酶 (TPO)，表达了对其活性至关重要的血红素辅基周围的保守基序、一个钙结合位点和至少两个将血红素基团与蛋白质骨架连接的共价键。尽管大多数关于这些过氧化物酶生物合成的研究都集中在 MPO 上，但许多描述的特征都发生在蛋白质亚家族其他成员的生物合成过程中。虽然 MPO 的生物合成包括在分泌途径中产生的蛋白质的典型事件，但血红素插入的重要性和后果是与过氧化物酶特有相关的事件。这篇综述总结了几十年来阐明人 MPO 生物合成途径特定步骤的工作。讨论包括共翻译糖基化和随后对 N-连接碳水化合物侧链的修饰、内质网中分子伴侣的贡献、从 proMPO 中切割原肽、以及原聚体的蛋白水解加工和二聚化以产生成熟的 MPO。将总结 MPO 和 TPO 的生物合成之间的平行性以及 MPO 基因中的遗传突变对正常生物合成的影响。最后，将突出显示通过对我们当前理解的审查揭示的我们知识中的具体差距。
