The matrix metalloproteinases (MMPs) are a family of zinc proteinases that is collectively capable of degrading the major components of the extracellular matrix. A variety of synthetic peptides has been prepared which are models for the human MMP and their substrates to study structure-function relationships in this enzyme-substrate system. To elucidate the sequence specificity of the MMP, the k$\rm\sb{cat}/K\sb M$ values for the hydrolysis of over 50 synthetic octapeptides has been investigated. Similarities, as well as distinct differences have been found between the individual MMP with the largest differences occurring at subsites P$\rm\sb1, P\sb1\sp\prime$ and P$\sb3\sp\prime.$ Based on these data, quenched-fluorescence substrates with optimized sequences have been developed for five human MMP. The key features of these heptapeptides are a tryptophan on the P$\rm\sb n\sp\prime$ side and a dinitrophenol quenching group on the amino terminus. To assess the role of the triple helical conformation in the collagenase-collagen system, a series of triple helical peptides has been prepared and shown to compete with collagen in collagenase assays. This provides evidence for the existence of a triple helical recognition site distinct from the active site. All of the MMP are secreted as zymogens and it has been postulated that the portion of the propeptide surrounding a critical cysteine is responsible for maintaining latency. Conformational energy calculations and mutagenesis studies have suggested that this region adopts a specific conformation that stabilizes the latent form. Peptide models of this region of the propeptide have been prepared and shown to inhibit the MMP. CD and NMR studies, however, have failed to provide evidence for the predicted peptide conformation. Thus, the observed inhibition may reflect their propensity to adopt the propeptide conformation upon binding to the enzyme. / Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0222. / Major Professor: Harold E. Van Wart. / Thesis (Ph.D.)--The Florida State University, 1994.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_77350 |
| Contributors | Netzel-Arnett, Sarah Joann., Florida State University |
| Source Sets | Florida State University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | 215 p. |
| Rights | On campus use only. |
| Relation | Dissertation Abstracts International |
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