Vempati Prakash, Karagiannis Emmanouil D, Popel Aleksander S
Department of Biomedical Engineering, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
J Biol Chem. 2007 Dec 28;282(52):37585-96. doi: 10.1074/jbc.M611500200. Epub 2007 Sep 11.
Matrix metalloproteinases (MMPs) are a class of extracellular and membrane-bound proteases involved in an array of physiological processes, including angiogenesis. We present a detailed computational model of MMP9 activation and inhibition. Our model is validated to existing biochemical experimental data. We determine kinetic rate constants for the processes of MMP9 activation by MMP3, MMP10, MMP13, and trypsin; inhibition by the tissue inhibitors of metalloproteinases (TIMPs) 1 and 2; and MMP9 deactivation. This computational approach allows us to investigate discrepancies in our understanding of the interaction of MMP9 with TIMP1. Specifically, we find that inhibition due to a single binding event cannot describe MMP9 inhibition by TIMP1. Temporally accurate biphasic inhibition requires either an additional isomerization step or a second lower affinity isoform of MMP9. We also theoretically characterize the MMP3/TIMP2/pro-MMP9 and MMP3/TIMP1/pro-MMP9 systems. We speculate that these systems differ significantly in their time scales of activation and inhibition such that MMP9 is able to temporarily overshoot its final equilibrium value in the latter. Our numerical simulations suggest that the ability of pro-MMP9 to complex TIMP1 increases this overshoot. In all, our analysis serves as a summary of existing kinetic data for MMP9 and a foundation for future models utilizing MMP9 or other MMPs under physiologically well defined microenvironments.
基质金属蛋白酶（MMPs）是一类参与包括血管生成在内的一系列生理过程的细胞外和膜结合蛋白酶。我们提出了一个详细的MMP9激活和抑制的计算模型。我们的模型已根据现有的生化实验数据进行了验证。我们确定了MMP3、MMP10、MMP13和胰蛋白酶激活MMP9过程的动力学速率常数；金属蛋白酶组织抑制剂（TIMPs）1和2的抑制作用；以及MMP9失活的动力学速率常数。这种计算方法使我们能够研究我们对MMP9与TIMP1相互作用理解上的差异。具体而言，我们发现单次结合事件导致的抑制无法描述TIMP1对MMP9的抑制作用。时间上精确的双相抑制需要一个额外的异构化步骤或MMP9的第二种低亲和力异构体。我们还从理论上对MMP3/TIMP2/pro-MMP9和MMP3/TIMP1/pro-MMP9系统进行了表征。我们推测这些系统在激活和抑制的时间尺度上有显著差异，以至于在后者中MMP9能够暂时超过其最终平衡值。我们的数值模拟表明，pro-MMP9与TIMP1形成复合物的能力增加了这种超调。总之，我们的分析总结了MMP9现有的动力学数据，并为未来在生理上定义明确的微环境下利用MMP9或其他MMPs的模型奠定了基础。
