-
Brazilian Journal of Otorhinolaryngology 2022
Topics: Aryldialkylphosphatase; Humans
PubMed: 34794918
DOI: 10.1016/j.bjorl.2021.08.009 -
International Journal of Molecular... Apr 2023Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON... (Review)
Review
Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON enzymes family consists of three members (PON-1, PON-2, and PON-3) that share a similar structure and location as a cluster on human chromosome 7. These enzymes exhibit anti-inflammatory and antioxidant properties with well-described roles in preventing cardiovascular disease. Perturbations in PON enzyme levels and their activity have also been linked with the development and progression of many neurological disorders and neurodegenerative diseases. The current review summarizes the available evidence on the role of PONs in these diseases and their ability to modify risk factors for neurological disorders. We present the current findings on the role of PONs in Alzheimer's disease, Parkinson's disease, and other neurodegenerative and neurological diseases.
Topics: Humans; Aryldialkylphosphatase; Neurodegenerative Diseases; Cardiovascular Diseases; Risk Factors; Alzheimer Disease
PubMed: 37108044
DOI: 10.3390/ijms24086881 -
Nutrients Jul 2022Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is... (Review)
Review
Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is sensitive to various modulating factors, such as genetic polymorphisms as well as pharmacological, dietary (including carotenoids), and lifestyle interventions. Carotenoids are nutritional pigments with antioxidant activity. The aim of this review was to gather evidence on their effect on the modulation of PON1 activity and gene expression. Carotenoids administered as naturally occurring nutritional mixtures may present a synergistic beneficial effect on PON1 status. The effect of carotenoids on the enzyme depends on age, ethnicity, gender, diet, and PON1 genetic variation. Carotenoids, especially astaxanthin, β-carotene, and lycopene, increase PON1 activity. This effect may be explained by their ability to quench singlet oxygen and scavenge free radicals. β-carotene and lycopene were additionally shown to upregulate PON1 gene expression. The putative mechanisms of such regulation involve PON1 CpG-rich region methylation, Ca(2+)/calmodulin-dependent kinase II (CaMKKII) pathway induction, and upregulation via steroid regulatory element-binding protein-2 (SREBP-2). More detailed and extensive research on the mechanisms of PON1 modulation by carotenoids may lead to the development of new targeted therapies for cardiovascular diseases.
Topics: Antioxidants; Aryldialkylphosphatase; Carotenoids; Gene Expression; Lycopene; beta Carotene
PubMed: 35889799
DOI: 10.3390/nu14142842 -
Current Opinion in Structural Biology Feb 2018Enzymes are flexible catalysts, and there has been substantial discussion about the extent to which this flexibility contributes to their catalytic efficiency. What has... (Review)
Review
Enzymes are flexible catalysts, and there has been substantial discussion about the extent to which this flexibility contributes to their catalytic efficiency. What has been significantly less discussed is the extent to which this flexibility contributes to their evolvability. Despite this, recent years have seen an increasing number of both experimental and computational studies that demonstrate that cooperativity and flexibility play significant roles in enzyme innovation. This review covers key developments in the field that emphasize the importance of enzyme dynamics not just to the evolution of new enzyme function(s), but also as a property that can be harnessed in the design of new artificial enzymes.
Topics: Amino Acid Motifs; Animals; Aryldialkylphosphatase; Bacteria; Biocatalysis; Catalytic Domain; Evolution, Molecular; Humans; Models, Molecular; Phosphoric Monoester Hydrolases; Phylogeny; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Tetrahydrofolate Dehydrogenase; beta-Lactamases
PubMed: 29141202
DOI: 10.1016/j.sbi.2017.10.020 -
Annals of Global Health 2016Acute and chronic exposures to widely used organophosphorus (OP) insecticides are common. Children's detoxification mechanisms are not well developed until several years... (Review)
Review
Acute and chronic exposures to widely used organophosphorus (OP) insecticides are common. Children's detoxification mechanisms are not well developed until several years after birth. The increased cases of neurodevelopmental disorders in children, together with their increased susceptibility to OP neurotoxicity cannot be explained by genetic factors alone but could be related to gene-environment interactions. Paraoxonase-1 (PON1) is an enzyme that can detoxify OPs but its catalytic efficiency for hydrolysis to certain OPs is modulated by the Q192R polymorphism. Studies with animals have provided important information on the role of PON1 in protecting against gestational and postnatal toxicity to OPs. The PON1Q192 allele is less efficient in hydrolyzing certain OPs than the PON1R192 allele. Maternal PON1 status (PON1 activity levels, the most important measurement, and functional Q192R phenotype) modulates the detrimental effects of exposure to the OP chlorpyrifos oxon on fetal brain gene expression and biomarkers of exposure. Epidemiologic studies suggest that children from mothers with lower PON1 status who were in contact with OPs during pregnancy tend to show smaller head circumference at birth and adverse effects in cognitive function during childhood. Infants and children are vulnerable to OP toxicity. The detrimental consequences of OPs on neurodevelopment can lead to future generations with permanent cognitive problems and susceptibility to develop neurodegenerative diseases. Improved methods using mass spectrometry to monitor OP-adducted biomarker proteins are needed and will be extremely helpful in early life biomonitoring, while measurement of PON1 status as a biomarker of susceptibility will help identify mothers and children highly sensitive to OPs. The use of adductomics instead of enzymatic activity assays for biomonitoring OP exposures have proved to provide several advantages, including the use of dried blood spots, which would facilitate monitoring newborn babies and children.
Topics: Animals; Aryldialkylphosphatase; Environmental Exposure; Environmental Pollutants; Female; Gene-Environment Interaction; Humans; Insecticides; Polymorphism, Genetic; Pregnancy
PubMed: 27325068
DOI: 10.1016/j.aogh.2016.01.009 -
Journal of Biosciences 2021Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also... (Review)
Review
Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also demonstrated the significance of PON2 in the manifestation of cardiovascular and several other diseases, and hence, it is considered an important biomarker. Recent findings of its expression in brain tissue suggest its potential protective effect on oxidative stress and neuroinflammation. Polymorphisms of PON2 in humans are a risk factor in many pathological conditions, suggesting a possible mechanism of its anti-oxidative property probably through lactonase activity. However, exogenous factors may also modulate the expression and activity of PON2. Hence, this review aims to report the mechanism by which PON2 expression is regulated and its role in oxidative stress disorders such as neurodegeneration and tumor formation. The role of PON2 owing to its lactonase activity in bacterial infectious diseases and association of PON2 polymorphism with pathological conditions are also highlighted.
Topics: Aryldialkylphosphatase; Brain; Humans; Neoplasms; Oxidative Stress; Polymorphism, Genetic
PubMed: 34987135
DOI: No ID Found -
Molecules (Basel, Switzerland) Dec 2020Serum paraoxonase-1 (PON1) is the most studied member of the group of paraoxonases (PONs). This enzyme possesses three enzymatic activities: lactonase, arylesterase, and... (Review)
Review
Serum paraoxonase-1 (PON1) is the most studied member of the group of paraoxonases (PONs). This enzyme possesses three enzymatic activities: lactonase, arylesterase, and paraoxonase activity. PON1 and its isoforms play an important role in drug metabolism as well as in the prevention of cardiovascular and neurodegenerative diseases. Although all three members of the PON family have the same origin and very similar amino acid sequences, they have different functions and are found in different locations. PONs exhibit substrate promiscuity, and their true physiological substrates are still not known. However, possible substrates include homocysteine thiolactone, an analogue of natural quorum-sensing molecules, and the recently discovered derivatives of arachidonic acid-bioactive δ-lactones. Directed evolution, site-directed mutagenesis, and kinetic studies provide comprehensive insights into the active site and catalytic mechanism of PON1. However, there is still a whole world of mystery waiting to be discovered, which would elucidate the substrate promiscuity of a group of enzymes that are so similar in their evolution and sequence yet so distinct in their function.
Topics: Amino Acid Sequence; Animals; Arachidonic Acid; Aryldialkylphosphatase; Carboxylic Ester Hydrolases; Catalytic Domain; Homocysteine; Humans; Mice; Protein Binding; Protein Conformation; Sequence Alignment; Substrate Specificity
PubMed: 33348669
DOI: 10.3390/molecules25245980 -
Current Neuropharmacology 2019Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1)... (Review)
Review
BACKGROUND
Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms.
OBJECTIVES
1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities.
METHODS
The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity.
RESULTS
The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity.
CONCLUSION
Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.
Topics: Aryldialkylphosphatase; Humans; Mental Disorders; Neurologists; Nitrosative Stress; Oxidative Stress; Psychiatry
PubMed: 30592255
DOI: 10.2174/1570159X17666181227164947 -
Frontiers in Bioscience (Landmark... Jan 2021Some organophosphorus compounds (OPs), which are used in the manufacturing of insecticides and nerve agents, are racemic mixtures with at least one chiral center with a... (Review)
Review
Some organophosphorus compounds (OPs), which are used in the manufacturing of insecticides and nerve agents, are racemic mixtures with at least one chiral center with a phosphorus atom. Acute exposure of humans to these mixtures induces the covalent modification of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) and causes a cholinergic syndrome or organophosphate-induced delayed polyneuropathy syndrome (OPIDP). These irreversible neurological effects are due to the stereoselective interaction of the racemic OPs with these B-esterases (AChE and NTE) and such interactions have been studied in vivo, ex vivo and in vitro, using stereoselective hydrolysis by A-esterases or phosphotriesterases (PTEs) and the PTE from Pseudomonas diminuta, and paraoxonase-1 (PON1) from mammalian serum. PON1 has a limited hydrolytic potential of the racemic OPs, while the bacterial PTE exhibits a significant catalytic activity on the less toxic isomers P(+) of the nerve agents. Avian serum albumin also shows a hydrolyzing capacity of chiral OPs with oxo and thio forms. There are ongoing environmental and bioremediation efforts to design and produce recombinants as bio-scavengers of OPs.
Topics: Animals; Aryldialkylphosphatase; Catalysis; Hydrolysis; Mammals; Organophosphorus Compounds; Phosphoric Triester Hydrolases; Stereoisomerism
PubMed: 33049692
DOI: 10.2741/4916 -
PloS One 2022Obesity in asthmatics has been associated with higher airway oxidative stress in which dysfunctional mitochondria are a potential contributing source of excess free...
BACKGROUND
Obesity in asthmatics has been associated with higher airway oxidative stress in which dysfunctional mitochondria are a potential contributing source of excess free radicals. Paraoxonase 2 (PON2) plays an important role in reducing mitochondrial-derived oxidative stress and could, therefore, have therapeutic potential in these patients.
OBJECTIVES
We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: a) protein levels of Paraoxonase 2 and b) to test the potential protective effect of quercetin supplementation in cells under oxidative stress conditions.
RESULTS
Compared to lean controls, obese asthmatics had significantly lower PON2 airway epithelial levels (respectively, 1.08 vs. 0.47 relative units normalized by GAPDH) (p-value < 0.006). Treating HBECs in vitro for 24 hrs. with 25μM quercetin significantly increased PON2 protein levels: 15.5 treated cells vs. 9.8 untreated cells (relative units normalized by GAPDH) (p value = 0.004). Notably, compared to untreated cells, quercetin supplementation reduces mitochondrial superoxide and hydrogen peroxide production on HBECs cells exposed to different oxidative stress triggers such as 1-2 Naphthoquinone (1-2 NQ) and hydrogen peroxide, suggesting that PON2 might play a protective role ameliorating oxidative injury on human airway epithelium.
CONCLUSION
Compared to lean controls, obese asthmatics have significantly reduced PON2 levels in airway epithelial cells. Treatment with quercetin in vitro increased PON2 protein levels and prevented oxidative stress from different types of stimuli. Hence, quercetin supplementation may be a potential therapeutic strategy to prevent obesity-mediated airway oxidative stress in obese asthmatics.
Topics: Aryldialkylphosphatase; Asthma; Humans; Hydrogen Peroxide; Obesity; Oxidative Stress; Quercetin
PubMed: 35286330
DOI: 10.1371/journal.pone.0261504