前蛋白转化酶(PC)是调节细胞中蛋白质底物的稳态的丝氨酸内切蛋白酶。PCs家族有9个成员-PC1/3、PC2、PC4、PACE4、PC5/6、PC7、Furin、SKI-1/S1P,PCSK9前七个PC被称为碱性前蛋白转化酶,因为它们倾向于在多碱性簇之后裂解。SKI-1/S1P需要额外存在疏水性残基进行处理,而PCSK9在自动激活后催化死亡,并使用替代直接裂解的机制发挥其功能。所有PC都通过规范的分泌途径,到达各种底物所在的不同隔室。尽管PC成员不共享相同的亚蜂窝定位,大多数细胞器计数一种或多种前蛋白转化酶,包括ER,高尔基堆栈,内体,分泌颗粒,和质膜。这些酶在系统水平上的广泛表达说明了它们在大量生物学功能的稳态中的重要性。其中,PCs切割激素和生长因子的前体并激活受体和转录因子。值得注意的是,前蛋白转化酶的酶活性失调与主要的人类病理有关,比如心血管疾病,癌症,糖尿病,感染,炎症,自身免疫性疾病,和帕金森。在当前的COVID-19大流行中,弗林蛋白酶作为赋予SARS-CoV-2高致病性的关键参与者进一步引起了关注。这里,我们回顾了ProproteinConvertases家族及其在分泌途径中最重要的底物。有关PC复杂功能的知识对于确定靶向此类酶的潜在药物策略很重要。
Proprotein Convertases (PCs) are serine endoproteases that regulate the homeostasis of protein substrates in the cell. The PCs family counts 9 members-PC1/3, PC2, PC4, PACE4, PC5/6, PC7, Furin, SKI-1/S1P, and PCSK9. The first seven PCs are known as Basic Proprotein Convertases due to their propensity to cleave after polybasic clusters. SKI-1/S1P requires the additional presence of hydrophobic residues for processing, whereas PCSK9 is catalytically dead after autoactivation and exerts its functions using mechanisms alternative to direct cleavage. All PCs traffic through the canonical secretory pathway, reaching different compartments where the various substrates reside. Despite PCs members do not share the same subcellular localization, most of the cellular organelles count one or more Proprotein Convertases, including ER, Golgi stack, endosomes, secretory granules, and plasma membranes. The widespread expression of these enzymes at the systemic level speaks for their importance in the homeostasis of a large number of biological functions. Among others, PCs cleave precursors of hormones and growth factors and activate receptors and transcription factors. Notably, dysregulation of the enzymatic activity of Proprotein Convertases is associated to major human pathologies, such as cardiovascular diseases, cancer, diabetes, infections, inflammation, autoimmunity diseases, and Parkinson. In the current COVID-19 pandemic, Furin has further attracted the attention as a key player for conferring high pathogenicity to SARS-CoV-2. Here, we review the Proprotein Convertases family and their most important substrates along the secretory pathway. Knowledge about the complex functions of PCs is important to identify potential drug strategies targeting this class of enzymes.