Metabolism of the extracellular matrix (ECM) is important in many normal physiological processes, such as wound healing and aging, as well as in many disease states, such as rheumatoid arthritis and cancer cell metastasis. Collagen is the major protein component of the ECM, and comprises one-third of the total protein found in mammalian organisms. Two distinct collagenases are known to exist in humans, human fibroblast collagenase (HFC) and human neutrophil collagenase (HNC). These collagenases are members of a family of ECM degrading enzymes called the matrix metalloproteinases (MMP). The MMP are secreted from cells as inactive zymogens which, subsequently, become activated in the extracellular milieu. / The zinc content of five human pro-MMP has been quantitated, and the role of zinc in these MMP has been assessed. Each of these MMP is found to contain one zinc atom which is catalytically important. The catalytic zinc atom of HFC is shown to be sequestered in the latent state and exposed in the active state. Studies of the activation and inhibition of HFC and HNC by seven classes of agents reveal a common biochemical theme and multiple active forms. Two pathways are identified in the activation of HFC and HNC, chemical modification of a cysteine sulfhydryl and removal of the N-terminal propeptide. The key sulfhydryl group is found to be sequestered in the latent state of pro-HFC and is released from this sequestered environment upon activation. A model is proposed, the "cysteine switch" model, which accounts for the multiple modes of HFC activation and for the observed properties of the latent and active forms. The implication of the cysteine switch mechanism of activation for the MMP family in vivo is that it permits flexibility and selectivity in the control of the enzymes responsible for metabolism of the ECM. / Source: Dissertation Abstracts International, Volume: 53-11, Section: B, page: 5704. / Major Professor: Harold E. Van Wart. / Thesis (Ph.D.)--The Florida State University, 1992.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_76819 |
| Contributors | Springman, Eric B., Florida State University |
| Source Sets | Florida State University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | 267 p. |
| Rights | On campus use only. |
| Relation | Dissertation Abstracts International |
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