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STUDIES ON THE INHIBITION OF PROTEASES, TYROSINASE AND RELATED ENZYMES BY NATURAL PRODUCTS AND SYNTHETIC COMPOUNDS

Ghani, Usman (2001) STUDIES ON THE INHIBITION OF PROTEASES, TYROSINASE AND RELATED ENZYMES BY NATURAL PRODUCTS AND SYNTHETIC COMPOUNDS. PhD thesis, University of Karachi, Karachi.

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Abstract

Proteinases play key roles in various physiological processes. However, excessive activity of proteinases leads to many diseases such as cancer, emphysema, bronchitis, arthritis, etc. Controlling or inhibiting the excessive proteolysis is an important step in treating various diseases. Similarly various diseases and clinical conditions such as hyper pigmentation, nevus a potential in controlling such ailments. A variety of natural and synthetic proteinase and tyrosinase inhibitors have potential commercial value, they can be developed and utilized as fruit-browning inhibitory agents and as safer insecticides In this work a number of new mechanism-based inhibitors of tyrosinase and chymotrypsin have been studied kinetically and structurally including some protein serine proteinase inhibitors. Chymotrypsin inhibitors such as analogues of meta and para benzoates and tyrosinase inhibitors such as defivatives of 1,3,4-thiadiazole and substituted hydrazides have been studied with their structure-activity relationship deduced. X-ray crystallographic methods were also utilized to determine the structure of chymotrypsin in complex with 7-hydroxycounarin and its mechanism of inhibtion Earlier studies indicate that the amino acid sequence of the inhibitor-II (TI-II) from tomato leaves has a two-domain organization. The sequence has two repeats, with each repeat containing one reactive loop located near the N-terminus of the repeat. Attempts were made to crystallize the TI-II in order to determine the crystal structure by molecular replacement and isomorphous replacement methods using a proposed search model of TI-II. The TI-II search model gave an approximate idea about the overall fold of the molecule and how the sequence repeats give rise to a two-domain organization and their association with each other A remarkable aspect of the canonical inhibitors of serine proteinases is that most of the enzyme binding loops of the members of the 18 families of serine proteinase inhibitors superpose well despite their different global structure. Interaction of the binding loops of TI-II and the polypeptide trypsin inhibitors with trypsin and chymotrypsin is in close agreement with that of the canonical inhibitors of serine proteinases as indicated by molecular modeling studies

Item Type:Thesis (PhD)
Uncontrolled Keywords:proteases, tyrosinase, enzymes, synthetic compounds, serine proteinase, polypeptide trypsin
Subjects:Physical Sciences (f) > Chemistry(f2)
ID Code:1338
Deposited By:Mr. Muhammad Asif
Deposited On:27 Jan 2007
Last Modified:04 Oct 2007 21:06

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