Human serum paraoxonase/arylesterase is of pharmacogenetic interest because it catalyzes the hydrolysis of both aromatic carboxylic acid esters and organophosphates, such as DPF (diisopropylfluorophosphate), paraoxon, soman, sarin, and presumably, some carbamates. Two genetically determined polymorphic forms of the serum esterase, which we call types A and B, differ particularly in their paraoxonase activities; the B-type being several-fold times more effective than the A-type in paraoxonase activity. We have cloned the gene determining the structure of this enzyme and plan to identify the DNA structural basis of the two polymorphic forms of the esterase. We will search for additional variant forms of the esterase using blood cellular DNA and the polymerase chain reaction (PCR) to examine the coding DNA sequence from people with serum arylesterases that differ quantitatively or in qualitative properties from the common A and B allozymic forms. Individuals will also be sought who have a genetically determined complete esterase deficiency, i.e., who have a total lack of any arylesterase activity, to help determine what functions this esterase may have in normal metabolism and what its physiological substrates might be. The purified esterase will be characterized in further detail, particularly its active center amino acid components, physical properties, substrate specificity, and its structural homology with other esterases having cysteine in their active centers. Its close association with the HDL- complex in serum will also be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM046979-01
Application #
3306501
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1992-01-06
Project End
1994-12-31
Budget Start
1992-01-06
Budget End
1992-12-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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