Hysteretic Behavior of Proprotein Convertase 1/3 (PC1/3)

The proprotein convertases (PCs) are calcium-dependent proteases responsible for processing precursor proteins into their active forms in eukariotes. The PC1/3 is a pivotal enzyme of this family that participates in the proteolytic maturation of prohormones and neuropeptides inside the regulated secretory pathway. In this paper we demonstrate that mouse proprotein convertase 1/3 (mPC1/3) has a lag phase of activation by substrates that can be interpreted as a hysteretic behavior of the enzyme for their hydrolysis. This is an unprecedented observation in peptidases, but is frequent in regulatory enzymes with physiological relevance. The lag phase of mPC1/3 is dependent on substrate, calcium concentration and pH. This hysteretic behavior may have implications in the physiological processes in which PC1/3 participates and could be considered an additional control step in the peptide hormone maturation processes as for instance in the transformation of proinsulin to insulin.

前蛋白转化酶（proprotein convertases, PCs）是一类钙依赖性蛋白酶，负责在真核生物中将前体蛋白加工为活性形式。PC1/3是该家族中的关键酶，参与调节性分泌通路内激素原与神经肽的蛋白水解成熟过程。本研究证实，小鼠前蛋白转化酶1/3（mouse proprotein convertase 1/3, mPC1/3）存在底物介导的激活迟滞期，这一现象可被解读为该酶在底物水解过程中的迟滞行为。这是肽酶领域前所未有的观测结果，但在具有生理相关性的调节酶中较为常见。mPC1/3的激活迟滞期依赖于底物、钙离子浓度与pH值。这种迟滞行为可能对PC1/3参与的生理过程具有重要意义，同时可被视为肽激素成熟过程中的额外调控步骤，例如胰岛素原向胰岛素的转化过程。