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STUDIES ON UREASE ENZYME AND ALZHEIMER’S DISEASE

Amtul, Zareen (2002) STUDIES ON UREASE ENZYME AND ALZHEIMER’S DISEASE. PhD thesis, University of Karachi, Karachi.

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Abstract

Enzyme inhibition remains an important area of pharmaceutical research since these studies have led to the discovery of drugs useful in a variety of physiological conditions In the first part of the thesis, studies on urease inhibition were carried out. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. The present research describes the mechanism of action of two series of twenty-three new compounds i.e. Cystein Derivatives (CD) and Organogermanium Compounds (OG) against the enzyme urease. The synthetic CD and OG were assessed for the first time for kinetic parameters for urease inhibition. These compounds inhibited the activity of urease in a concentration dependent fashion. Dixon as well as Lineweaver-Burk Plots and their secondary replots indicate that the nature of the inhibition was of a noncompetitive type for all the 23 tested compounds. The inhibition was slightly potentiated by a lower pH and was not abolished in the presence of NH2OH (a scavenger of histidine residue). The tested compounds did not inhibit the growth of Bacillus pasteurii and Proteus mirabilis and therefore no correlation was observed between urease activity and the growth of urease producing bacteria. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed Another part of this thesis work was carried out on Alzheimer’s disease (AD) in Mayo Clinic Jackwonville, Florida. AD is the leading cause of dementia among the elderly. 5% of population over 65 and >20% over may have AD In the present investigation, a novel presenilin I (PSI) mutation, insR353, associated with frontal temporal dementia (FTD) phenotype was identified. Presenilins (PSs) are evolutionarily conserved, homologous, memberane proteins that participate in the Y-secretase cleavage that relaeases the Aβ from the APP (Golde and Younkin, 2001). Presenilin I (PSI) and presenilin 2 (PS2) mutations account for the majority of genetic forms of early onset familial Alzheimer’s Disease (FAD). These mutations increase the production of Aβ42, the more pathogenic form of Aβ (Hardy, 1997). Recently, it has been shown that dominant negative PSI proteins can be generated by mutation of either of two conserved aspartate (D257, D385) residues or deletion of amino acids 81-154 (delTM1-2) Murphy et al., 2000; Wolfe et al., 1999). These mutations appear to inhibit Y-secretase complex. Here we describe a naturally occurring PSI mutation, insR352 that in contrast to other characterized FAD-linked presenilin mutations, acts as a dominant negative PS markedly decreasing Y-secretase cleavage of both APP and Notch and thus decreasing amyloid β protein (Aβ) production. The distinct clinical phenotype associated with theis mutation suggests that chronic partial inhibition of Y-secretase activity may result in a neurodegenerative disorder

Item Type:Thesis (PhD)
Uncontrolled Keywords:urease enzyme, alzheimer’s disease, urease inhibition, anti-ulcer, cystein derivatives, organogermanium compounds, amyloid peptides, presenilin, secretase
Subjects:Physical Sciences (f) > Chemistry(f2)
ID Code:1310
Deposited By:Mr. Muhammad Asif
Deposited On:27 Jan 2007
Last Modified:04 Oct 2007 21:05

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