New Insight in Human Lactonase PON2
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2017, Vol 1, Issue 5
Abstract
It is well established that oxidative stress from mitochondria plays an important role in apoptosis and also leads to premature aging and cancer [1]. There is growing scientific consensus that proteins with antioxidative functions, such as paraoxonases, can lower the incidence of these diseases. The paraoxonase (PON) gene family consists of three members: PON1, PON2, and PON3. PON genes are located in a gene cluster on chromosome 7q21.3-22.1 in human [2] and show about 70% sequence identity among them [3]. PON2 is a calcium-dependent glycoprotein of about 44 kDa, expressed ubiquitously, and associated with plasma membrane fractions. Recently, it has been demonstrated that PON2 is a type II Tran membrane protein, with its N-terminal region identified as a single Transmembrane domain, whereas the catalytic domain, corresponds to the C-terminus, located extracellularly to counteract lipid per oxidation [4]. PON2 has two main activities: a calcium-dependent hydrolytic activity, involved mainly in the hydrolysis of lactones, esters and aryl esters [2] and a redox function, which reduces the levels of ROS (reactive oxygen species) thus curbing cell oxidative stress and therefore displaying an anti-apoptotic effect. No clues are available about the molecular basis of this anti-ROS activity except the demonstration that PON2 can bind ubiquinone (coenzyme Q10) with high affinity only in the presence of Ca2+ [5]. In doing so coenzyme Q10 is substracted from interaction with O2 and production of ROS. Unlike PON1 and PON3, PON2 is an intracellular protein, expressed in a wide range of cell types, including pancreatic beta cells. Importantly, polymorphisms in the PON2 protein (S311C and A148G) have been associated by several studies with diabetes and its complications. Although a genetic association between PON2 and these conditions has been shown, the exact function of PON2 in humans is not known. It has been shown that all of the PONs can inactivate the lactone 3-Oxo-C12-HSL [2,6-8]. Among PONs, PON2 has the greatest lactonase activity against the bacterial quorumsensing (QS) molecules [2,9]. QS Is an interbacterial mode of communication accomplished through the coordinated production, secretion, and detection of chemical signals (QS signals) that trigger the expression of specific bacterial genes. The QS signals self-produced by P. aeruginosa are in the form of small molecules, termed acyl- homoserine lactones (acyl-HSLs) [10] among which 3-Oxo-C12-HSL is the master regulator [11]. It has been demonstrated that PON2 responds to the bacterial quorormone 3-Oxo-C12-acyl homoserine lactone by a rapid decrease of the lactonase activity via a putative post-translational modification (PTM) [12]. Therefore, Pseudomonas produced 3-Oxo-C12-HSL, organizes from one side the coordinated attack of bacterial cells against human tissues and on the other curbs the human defences by blocking PON2 activity, which is thought to represent the first line of defense against infections [9].
Authors and Affiliations
Giuseppe Manco
Keywords
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- EP ID EP572841
- DOI 10.26717/BJSTR.2017.01.000424
- Views 175
- Downloads 0
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