Human Paraoxonase 1 as a Pharmacologic Agent: Limitations and Perspectives

Bajaj, Priyanka; Tripathy, Rajan K.; Aggarwal, Geetika; Pande, Abhay H.

doi:10.1155/2014/854391

Cited by 14 publications

(9 citation statements)

References 84 publications

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“…It is however exceptionally difficult to separate PON1 from other HDL components, such as apolipoprotein AI (apoAI) and phospholipase A2 (PLA2), without subjecting it to conditions which might affect its catalytic activity (Ben-David et al, 2015 ). Similarly, the increased polarity of recombinant PON1 would be expected to compromise its ability to hydrolyze hydrophobic substrates (Harel et al, 2004 ; Draganov et al, 2005 ; Bajaj et al, 2014 ). More lipophilic recombinant PON1 might be expected to have improved functionality, but is more difficult to isolate, a factor which will prove important in the development of recombinant PON1 for therapeutic use (Bajaj et al, 2014 ).…”

Section: Paraoxonasementioning

confidence: 99%

“…Similarly, the increased polarity of recombinant PON1 would be expected to compromise its ability to hydrolyze hydrophobic substrates (Harel et al, 2004 ; Draganov et al, 2005 ; Bajaj et al, 2014 ). More lipophilic recombinant PON1 might be expected to have improved functionality, but is more difficult to isolate, a factor which will prove important in the development of recombinant PON1 for therapeutic use (Bajaj et al, 2014 ). Interestingly, HDL from avian species, which lacks paraoxonase activity, does not protect human LDL against lipid peroxidation (Mackness et al, 1998 ).…”

Section: Paraoxonasementioning

confidence: 99%

“…Parenteral administration of partially purified PON1 can ameliorate experimental atherosclerosis. Recombinant PON1 might also be used for this purpose, if its properties can be retained during isolation (Draganov et al, 2005 ; Bajaj et al, 2014 ). Intraperitoneal injection of recombinant PON1 in mice increased cholesterol efflux capacity and HDL aryl esterase and lactonase activities, and decreased macrophage mediated LDL oxidation (Rosenblat et al, 2011 ).…”

Section: Paraoxonasementioning

confidence: 99%

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Antioxidant properties of HDL

2015

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High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL.

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Section: Paraoxonasementioning

confidence: 99%

Section: Paraoxonasementioning

confidence: 99%

Section: Paraoxonasementioning

confidence: 99%

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Antioxidant properties of HDL

2015

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“…One of the significant factors which protect serum lipids against oxidation is paraoxonase (paraoxon hydrolase; EC: 3.1.8.1; PON1) . PON1, which exhibit anti‐inflammatory and antioxidant activities, is an esterase enzyme released by the liver and related to HDL in the blood . In vivo studies, PON1 has been shown to reverse the biological effects of oxidized LDL and to protect LDL against oxidation .…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Studies on the Toxic Effects of Antibacterial Drugs as Human Serum Paraoxonase 1 Inhibitor

2019

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The core purpose of the current study was to investigate the interactions of widely used broad‐spectrum antibacterial drugs developed in response to the increasing rate of antibiotic‐resistant various bacteria and to contribute to the field of drug design. Also, it is to broaden the current knowledge of paraoxonase 1 enzyme (EC: 3.1.8.1; PON1) which is a crucial drug‐target enzyme. For this aim, first, we purified PON1 from human serum using rapid chromatographic techniques including, enzyme precipitation, IEX (ion‐exchange) chromatography, and SEC (size exclusion chromatography), quickly. Following this, we researched the inhibitory effects of some antibacterial drugs. Finally, molecular docking tests were performed and analyzed in silico data. PON1 was found to be effectively inhibited by tigecycline, linezolid, ciprofloxacin lactate, and ertapenem sodium (Kis in the ranging from 0.018 to 125.540 mM). Drugs showed two different inhibition mechanisms: Linezolid was competitive; others were non‐competitive. While Glide GScore of the linezolid for 1 V04 and 3SRE receptors were detected to be –4.442 and –4.915 kcal/mol in the SP mode, monitored as –3.548 and –3.791 kcal/mol in the XP mode, respectively

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“…We encountered a study on refolding of rhPON1. Bajaj et al 45 investigated hPON1 as a pharmacologic agent. They refolded the rh-PON1 enzyme in vitro and detected a dramatic increase in the yield of the active enzyme.…”

mentioning

confidence: 99%

Purification, refolding, and characterization of recombinant human paraoxonase-1

Demir¹,

Beydemır²

2015

Turk J Chem

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Abstract:A high density lipoprotein (HDL)-linked enzyme with antioxidant and antiatherogenic properties, paraoxonase-1(PON1), prevents the formation of atherosclerotic lesions in humans. In the present study, a recombinant hPON1 gene was produced using a small ubiquitin-related modifier (SUMO) fusion protein expression system. To that end, the hPON1 gene was amplified from human liver-ready cDNA, cloned into the expression vector pET SUMO, and expressed in Escherichia coli BL21 (DE3). The predominance of the expressed fusion SUMO-hPON1 protein was inclusion bodies and purified using 6xHis affinity chromatography under natural and denaturing conditions. Subsequently, the enzyme was purified and refolded directly on the affinity matrix under redox conditions to obtain a bioactive protein in a single step. The inclusion bodies were solubilized with urea, guanidine hydrochloride, and Triton X-100 and refolded in vitro. After purification, 0.045 mg/mL protein in soluble fraction and 0.108 mg/mL protein from inclusion bodies were obtained. Optimum temperature, pH, and ionic strength for rhPON1 activity were determined as 40• C, 10.0, and 100 mM, respectively. The kinetic parameters K m and V max for rhPON1 were determined as 0.94 mM and 110.01 EU/mL, respectively, by using Lineweaver-Burk plots.

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Human Paraoxonase 1 as a Pharmacologic Agent: Limitations and Perspectives

Cited by 14 publications

References 84 publications

Antioxidant properties of HDL

Antioxidant properties of HDL

In Vitro and In Silico Studies on the Toxic Effects of Antibacterial Drugs as Human Serum Paraoxonase 1 Inhibitor

Purification, refolding, and characterization of recombinant human paraoxonase-1

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