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The cholinesterases: A study in phar...

University of California, San Diego., Biomedical Sciences.

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The cholinesterases: A study in pharmacogenomics.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The cholinesterases: A study in pharmacogenomics./
Author:	Valle, Anne Marie.
Description:	163 p.
Notes:	Adviser: Palmer Taylor.
Contained By:	Dissertation Abstracts International68-12B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3291615
ISBN:	9780549374923

The cholinesterases: A study in pharmacogenomics.
Valle, Anne Marie.

The cholinesterases: A study in pharmacogenomics. - 163 p.

Adviser: Palmer Taylor.

Thesis (Ph.D.)--University of California, San Diego, 2008.

The cholinesterases are serine hydrolases that catalyze the hydrolysis of acetylcholine (ACh), the cholinergic neurotransmitter in the central and autonomic nervous systems and at neuromuscular synapses. Peripheral and central nervous system control of cardiovascular (CV) function mediated through cholinergic pathways is critical in the homeostatic maintenance of blood pressure and responsiveness to stress. The specific role for acetylcholinesterase (AChE; EC 3.1.1.7) lies in its ability to rapidly catalyze the hydrolysis of ACh. Butyrylcholinesterase (BChE; EC 3.1.1.8) catalyzes the hydrolysis of esters of choline including ACh, although it differs in its substrate and inhibitor specificities. The physiological role for BChE remains uncertain, but studies have shown a strong correlation between BChE activity and the metabolic syndrome.

ISBN: 9780549374923Subjects--Topical Terms:

1017730
Biology, Genetics.

The cholinesterases: A study in pharmacogenomics.
LDR:05090nam 2200373 a 45 001 856614
005 20100709
008 100709s2008 ||||||||||||||||| ||eng d
020 $a 9780549374923
035 $a (UMI)AAI3291615
035 $a AAI3291615
040 $a UMI $c UMI
100 1 $a Valle, Anne Marie. $3 1023442
245 1 4 $a The cholinesterases: A study in pharmacogenomics.
300 $a 163 p.
500 $a Adviser: Palmer Taylor.
500 $a Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7787.
502 $a Thesis (Ph.D.)--University of California, San Diego, 2008.
520 $a The cholinesterases are serine hydrolases that catalyze the hydrolysis of acetylcholine (ACh), the cholinergic neurotransmitter in the central and autonomic nervous systems and at neuromuscular synapses. Peripheral and central nervous system control of cardiovascular (CV) function mediated through cholinergic pathways is critical in the homeostatic maintenance of blood pressure and responsiveness to stress. The specific role for acetylcholinesterase (AChE; EC 3.1.1.7) lies in its ability to rapidly catalyze the hydrolysis of ACh. Butyrylcholinesterase (BChE; EC 3.1.1.8) catalyzes the hydrolysis of esters of choline including ACh, although it differs in its substrate and inhibitor specificities. The physiological role for BChE remains uncertain, but studies have shown a strong correlation between BChE activity and the metabolic syndrome.
520 $a This dissertation investigates the role variations in cholinesterase genes play in relation to cardiovascular function and the metabolic syndrome. AChE and BChE can be found in whole blood enabling a biochemical phenotypic characterization in addition to correlation of genotype with phenotypic physiologic responses. Analysis of enzymatic activity was determined spectrophotometrically in plasma and blood cells of twin subject registries from Australia and San Diego along with a general population subject registry from San Diego. Association studies revealed significant relationships between cholinesterase activity and certain cardiovascular endpoints.
520 $a For AChE, I looked at naturally occurring single nucleotide polymorphisms (SNPs) in the AChE gene in a human population in relation to catalytic properties and cardiovascular function. SNP discovery by re-sequencing of the AChE gene using genomic DNA of the general population registry and SNP genotyping was performed using genomic DNA of the San Diego twin subject registry. Nineteen SNPs have been identified: 7 SNPs in the coding region (cSNPs), 4 non-synonymous encoding for a different amino acid and 3 synonymous encoding the same amino acid; 12 are in untranslated regions (UTR) of the gene with 3 of these in a conserved region of intron 1. The non-synonymous cSNPs were inserted into a human AChE cDNA vector and transfected into human embryonic kidney (HEK) cells for protein expression. Characterization of the purified mutant enzymes encoded by the SNP polymorphisms revealed significant thermal and chemical stability differences when compared with the predominant AChE species.
520 $a For BChE, I examined whether BChE activity correlated with parameters of the metabolic syndrome and cardiovascular function. Linkage analysis with data from a dizygotic twin set showed suggestive linkage at the BChE locus, and statistical analysis revealed a high correlation between BChE activity and variables associated with cardiovascular risk and the metabolic syndrome. Statistical analysis revealed a significant relationship between two BChE SNPs and BChE activity. The pattern of within-pair twin correlations by zygosity and the ACE model-fitting findings suggested the major source of variation (65%) in BChE activity was attributable to additive genetic influences.
520 $a In summary the research presented here is important in defining the role of cholinesterase SNPs in disease susceptibility particularly in the realm of cardiovascular diseases and the metabolic syndrome, and individual risk associated with chemical terrorism with agents affecting cholinergic function. These enzymes, AChE and BChE, are readily accessible in blood samples however the tissues where activity most likely affects physiologic function are typically not accessible. However, my studies should reveal intrinsic differences in generalized expression parameters. Furthermore, this work underscores the importance of structure-based modeling for analytical and theoretical insights that can be ascertained based on the modeling of SNPs to a protein's crystal structure.
590 $a School code: 0033.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Neuroscience. $3 1017680
690 $a 0317
690 $a 0369
710 2 $a University of California, San Diego. $b Biomedical Sciences. $3 1021780
773 0 $t Dissertation Abstracts International $g 68-12B.
790 $a 0033
790 1 0 $a Bourne, Philip $e committee member
790 1 0 $a Lawson, Mark A. $e committee member
790 1 0 $a O'Connor, Daniel T. $e committee member
790 1 0 $a Schork, Nicholas J. $e committee member
790 1 0 $a Taylor, Palmer, $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3291615