Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 259, Issue -, Pages 51-62Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2016.05.036
Keywords
Paraoxonases; Oxidative stress; Anti-inflammatory; Organophosphate; Human disease
Funding
- NHGRI NIH HHS [U01 HG008657] Funding Source: Medline
- NHLBI NIH HHS [R01 HL067406] Funding Source: Medline
- NIEHS NIH HHS [P42 ES004696, R01 ES009883, P01 ES009601, P30 ES007033] Funding Source: Medline
- NIOSH CDC HHS [U50 OH007544] Funding Source: Medline
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Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high-density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual's functional Q192R genotype and activity levels. The three-dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa's pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3-to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson's disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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