A biochemical model of matrix metalloproteinase 9 activation and inhibition.
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.
Vempati
Prakash
P
Department of Biomedical Engineering, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA. prakashvempati1@jhu.edu
Karagiannis
Emmanouil D
ED
Popel
Aleksander S
AS
D001671:Biochemistry / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D008962:Models, Theoretical; D020033:Protein Isoforms; D013696:Temperature; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000737:chemistry
D020033:Protein Isoforms; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9