[Frontiers in Bioscience, Scholar, 7, 125-149, June 1, 2015]

Historical perspective of matrix metalloproteases

Ashleigh E. Pulkoski-Gross 1

1Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Classification of matrix metalloproteinases
4. Matrix metalloproteinase protein structure
    4.1. The signal peptide
    4.2. The propeptide domain
    4.3. The catalytic domain
    4.4. The hinge/linker region
    4.5. The hemopexin-like domain
    4.6. The membrane-type matrix metalloproteinases
    4.7. Additional domains
    4.8. Post-translational modifications of matrix metalloproteinases
5. The mechanism of action of matrix metalloproteinases
6. Matrix metalloproteinase evolution
7. Control of matrix metalloproteinases
    7.1. Regulation of gene expression
    7.2. Tissue inhibitors of metalloproteinases
8. MMPs unleashed: matrix metalloproteinases’ roles in disease
9. Reigning them in: early successes and major failures in targeting MMPs
10. The future of matrix metalloproteinases
11. References

1. ABSTRACT

Matrix metalloproteinases (MMPs) were identified as early as 1962. Since this seminal finding, this family of zinc-dependent endopeptidases has been studied extensively. This collective work has resulted in delineation of MMP gene and protein structures, the mechanisms of control of MMPs, the action of MMPs on their substrates, and of course their role in normal physiology and their crucial roles in pathophysiology. Stemming from the discovery that MMPs contribute to arthritis, heart disease, and cancer, amongst other diseases, attempts to develop treatment strategies incorporating MMP inhibition have been undertaken. The results of these endeavours have been mediocre, resulting in few FDA-approved MMP inhibitors mostly due to the broad-spectrum nature of these early inhibitors and unwanted side effects of MMP inhibition. The future of exploitation of MMPs in disease lies in the design of more targeted inhibitors; in order to accomplish this, we must all understand the subtle differences between each MMP and their contextual roles. In this chapter, we aim to overview major topics regarding MMPs and what direction we may go in the future.

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Key Words: Review, matrix metalloprotease, MMP structure, MMP regulation, MMP inhibitor, Review

Send correspondence to: Ashleigh Pulkoski-Gross, Stony Brook University, Stony Brook NY 11794 Tel: 631-632-1816, Fax: 631-632-1820, E-mail: ashleigh.pulkoski-gross@stonybrook.edu