Abstract
Spanning three decades in research, Paraoxonases (PON1) carried potential of dealing with neurotoxicity of organophosphates entering the circulation and preventing cholinergic crisis. In the past few years, the Paraoxonase multigene family (PON1, PON2, PON3) has been shown to play an important role in pathogenesis of cardiovascular disorders including coronary artery disease (CAD). The PON genes are clustered in tandem on the long arm of human chromosome 7 (q21, 22). All of them have been shown to act as antioxidants. Of them, PON3 is the least studied member as its exact physiological substrate is still not clear. This has further led to limitation in our understanding of its role in pathogenesis of CAD and development of the potential therapeutic agents which might modulate its activity, expression in circulation and tissues. In the present review, we discuss the structure and activity of human PON3 enzyme and its Single nucleotide variants that could potentially lead to new clinical strategies in prevention and treatment of CAD.
Highlights
Cardiovascular diseases (CVDs) are the foremost cause of worldwide mortality, including India, and by 2020 coronary artery disease (CAD) is expected to become the largest contributor to this growing burden [1,2].Ethnic and regional variations prevail for risk factors of developing CVD
The present review is an attempt to discuss the role of Paraoxonase 3 (PON3) enzyme in CAD etio-pathogenesis beyond the thought of conventional Paraoxonases like paraoxonase 1 (PON1) (OP-hydrolyzing enzymes) which flock against cholinergic crisis
Paraoxonases act as crucial endogenous enzymes against oxidative stress which have been implicated in the pathogenesis of cardiovascular diseases
Summary
Cardiovascular diseases (CVDs) are the foremost cause of worldwide mortality, including India, and by 2020 coronary artery disease (CAD) is expected to become the largest contributor to this growing burden [1,2]. Research over time has shown a definite role of genetic factors in susceptibility to CAD and significant advances have been made in identifying potential candidate genes which predispose individuals towards the disease. In context of population genetics, the measurement of Paraoxonase activity and concentration (PON status) are considered to be more important than studying PON polymorphisms alone [17] when the role of these genes is dissected to determine any association with the progression of disease. PON1 (E.C. 3.1.8.1) was the first identified paraoxonase to play a role in CAD It hydrolyzes diazinon, chlorpyrifos (an oxon metabolite) and nerve gases [19] (e.g., sarin and soman). It is an HDL-associated enzyme synthesized mainly in the liver and prevents LDL-C from oxidative modification [20]
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