STRUCTURAL ORGANIZATION OF THE HUMAN PON1 GENE

Serum paraoxonase/arylesterase (PON) is an ''A'' esterase found in the HDL(2) fraction of mammalian sera closely associated with apolipoprot eins Al and J. This enzyme hydrolyzes the active metabolites (oxons) o f several organophosphate (OF) insecticides as well as the P-F bond of the nerve agents soman and sarin. PON also destroys biologically acti ve, multioxygenated phospholipids. Two factors result in large individ ual variations in PON serum levels, a substrate-dependent activity pol ymorphism and large individual differences in PON protein levels that are stable over time. Animal model studies indicate that PON activity levels are likely to play a major role in determining sensitivity to O Ps. The arg(192) PON isoform appears to be a risk factor in coronary a rtery disease, We report here the characterization of a 28-kb contig e ncompassing 300 bp of 5' sequence, the entire coding region, and 2 kb of 3'-flanking sequence of the PON gene. The structural portion of the paraoxonase protein is encoded by nine exons that form the primary tr anscript through the use of typical splice donor and acceptor sites. D NA sequences of the regions surrounding all the coding exons have been determined, A polymorphic CA repeat is located in intron 4. (C) 1996 Academic Press, Inc.