Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. Examples of how members of these classes of etiologic agents can cooperate to produce illness were shown. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis were examined using concepts about cooperation. The Western diet so closely associated with these illnesses often is low in copper. Copper deficiency decreases the activity of methionine synthase which contributes to elevation of homocysteine, and of paraoxonase which impairs hydrolysis of homocysteine thiolactone, an inhibitor of lysyl oxidase. This copper-dependent enzyme initiates the cross-linking of collagen and elastin in arteries and bone. High homocysteine also impairs superoxide dismutase, a copper-dependent enzyme important in oxidative defense. Some genes affecting paraoxonase activity may respond to dietary copper. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis are inextricably entwined.
Cell Mol Biol (Noisy-le-grand) 2006 Dec 31
PMID:How dietary deficiency, genes and a toxin can cooperate to produce arteriosclerosis and ischemic heart disease. 1754

Cholinergic Status, the total soluble circulation capacity for acetylcholine hydrolysis, was tested for putative involvement in individual variabilities of the recruitment of immune cells in response to endotoxin challenge. Young (average age 26) and elderly (average age 70) volunteers injected with either Escherichia coli endotoxin or saline on two different occasions were first designated Enhancers and Suppressors if they showed increase or decrease, respectively, in plasma acetylcholinesterase (AChE) activity 1.5 h after endotoxin administration compared to saline. Enhancers showed significant co-increases in plasma butyrylcholinesterase (BChE) and paraoxonase (PON1) activities, accompanied by rapid recovery of lymphocyte counts. Young Enhancers alone showed pronounced post-exposure increases in the pro-inflammatory cytokine interleukin-6 (IL-6), and upregulation of the normally rare, stress-induced AChE-R variant, suggesting age-associated exhaustion of the cholinergic effects on recruiting innate immune reactions to endotoxin challenge. Importantly, IL-6 injected to young volunteers or administered in vitro to primary mononuclear blood cells caused upregulation of AChE, but not BChE or PON1, excluding it from being the sole cause for this extended response. Interestingly, Suppressors but not Enhancers showed improved post-exposure working memory performance, indicating that limited cholinergic reactions may be beneficial for cognition. Our findings establish Cholinergic Status modulations as early facilitators and predictors of individual variabilities in the peripheral response to infection.
J Mol Med (Berl) 2007 Nov
PMID:Cholinergic status modulations in human volunteers under acute inflammation. 1765 67

Organophosphate hydrolases (OPHs), involved in hydrolytic cleavage of structurally diverse organophosphates are coded by a plasmid borne, highly conserved organophosphate degrading (opd) gene. An inverted repeat sequence found in the signal coding region of the opd gene was found to be responsible for inducing a stable stem loop structure with a DeltaG of -23.1 kcal/mol. This stem loop structure has shown significant influence on the expression levels of organophosphate hydrolase (OPH) in E. coli. When the signal coding region comprising the inverted repeat sequence was deleted a approximately 3.28 fold increase in the expression levels of OPH was noticed in E. coli BL21 cells. Mutations in the inverted repeat region, especially at the third position of the codon, to a non-complementary base destabilized the secondary structure of opd mRNA. When such opd variant, opd' was expressed, the expression levels were found to be similar to expression levels coded by the construct generated by deleting the signal peptide coding region. Deletion of signal peptide did not influence the folding and activity of OPH. Though high level induction has resulted in accumulation of OPH as inclusion bodies, modulation of expression levels by reducing the copy number of the expression plasmid, inducer concentration and growth temperature has produced majority of the protein in soluble and active form.
Mol Biol Rep 2009 Mar
PMID:mRNA secondary structure modulates the translation of organophosphate hydrolase (OPH) in E. coli. 1815 14

Organophosphates are the largest class of known insecticides, several of which are potent nerve agents. Consequently, organophosphate-degrading enzymes are of great scientific interest as bioscavengers and biodecontaminants. Recently, a hyperthermophilic phosphotriesterase (known as SsoPox), from the Archaeon Sulfolobus solfataricus, has been isolated and found to possess a very high lactonase activity. Here, we report the three-dimensional structures of SsoPox in the apo form (2.6 A resolution) and in complex with a quorum-sensing lactone mimic at 2.0 A resolution. The structure also reveals an unexpected active site topology, and a unique hydrophobic channel that perfectly accommodates the lactone substrate. Structural and mutagenesis evidence allows us to propose a mechanism for lactone hydrolysis and to refine the catalytic mechanism established for phosphotriesterases. In addition, SsoPox structures permit the correlation of experimental lactonase and phosphotriesterase activities and this strongly suggests lactonase activity as the cognate function of SsoPox. This example demonstrates that promiscuous activities probably constitute a large and efficient reservoir for the creation of novel catalytic activities.
J Mol Biol 2008 Jun 20
PMID:Structural basis for natural lactonase and promiscuous phosphotriesterase activities. 1848 46

We have engineered bacterial outer membrane vesicles (OMVs) with dramatically enhanced functionality by fusing several heterologous proteins to the vesicle-associated toxin ClyA of Escherichia coli. Similar to native unfused ClyA, chimeric ClyA fusion proteins were found localized in bacterial OMVs and retained activity of the fusion partners, demonstrating for the first time that ClyA can be used to co-localize fully functional heterologous proteins directly in bacterial OMVs. For instance, fusions of ClyA to the enzymes beta-lactamase and organophosphorus hydrolase resulted in synthetic OMVs that were capable of hydrolyzing beta-lactam antibiotics and paraoxon, respectively. Similarly, expression of an anti-digoxin single-chain Fv antibody fragment fused to the C terminus of ClyA resulted in designer "immuno-MVs" that could bind tightly and specifically to the antibody's cognate antigen. Finally, OMVs displaying green fluorescent protein fused to the C terminus of ClyA were highly fluorescent and, as a result of this new functionality, could be easily tracked during vesicle interaction with human epithelial cells. We expect that the relative plasticity exhibited by ClyA as a fusion partner should prove useful for: (i) further mechanistic studies to identify the vesiculation machinery that regulates OMV secretion and to map the intracellular routing of ClyA-containing OMVs during invasion of host cells; and (ii) biotechnology applications such as surface display of proteins and delivery of biologics.
J Mol Biol 2008 Jun 27
PMID:Engineered bacterial outer membrane vesicles with enhanced functionality. 1851 Oct 69

Paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) that prevents low-density lipoprotein (LDL) oxidation. PON1Q192R polymorphism is associated with a risk of coronary heart disease and low HDL levels in case-control studies, but the issue is yet unresolved. Mexico has shown an increase in cardiovascular diseases, and some genetic factors may play a role. Our purpose was to evaluate the association between PON1Q192R and L55M polymorphisms and serum lipid profile in a healthy Mexican population. Ninety unrelated male inhabitants from southeastern Mexico with Mayan ascendancy agreed to participate. Demographic characteristics, lifestyle and medical history were obtained by questionnaire. Lipid profile was determined by enzymatic methods, PON1 activity by using paraoxon and phenylacetate and PON1 genotype by real-time PCR. HDL-cholesterol (HDL-C) levels were associated with genotype: 192RR homozygote subjects had lower HDL-C levels than 192QQ homozygotes, and individuals with 192RR and 192QR genotypes had an odds ratio (OR)=7.05 (95% confidence interval (CI)=1.29-38.34) of having HDL-C <60 mg/dL. Individuals with higher paraoxonase activity (>600.18 U/L) had a slight risk (OR=4.9, 95% CI=0.83-22.02) of having HDL-C <60 mg/dL. PON155LM polymorphism was associated with higher LDL-cholesterol. PON1Q192R polymorphism showed a role in modulating lipid profile: 192RR homozygotes showed the least favorable lipoprotein levels.
Exp Mol Pathol 2008 Oct
PMID:PON1Q192R polymorphism is associated with lipid profile in Mexican men with Mayan ascendancy. 1858 59

The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.
Mol Med
PMID:Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. 1861 56

Autism spectrum disorders (ASD) comprise a complex and heterogeneous group of conditions of unknown aetiology, characterized by significant disturbances in social, communicative and behavioural functioning. Recent studies suggested a possible implication of the high-density lipoprotein associated esterase/lactonase paraoxonase 1 (PON1) in ASD. In the present study, we aimed at investigating the PON1 status in a group of 50 children with ASD as compared to healthy age and sex matched control participants. We evaluated PON1 bioavailability (i.e. arylesterase activity) and catalytic activity (i.e. paraoxonase activity) in plasma using spectrophotometric methods and the two common polymorphisms in the PON1 coding region (Q192R, L55M) by employing Light Cycler real-time PCR. We found that both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with less active variants of the PON1 gene was found. The PON1 phenotype, inferred from the two-dimensional enzyme analysis, had a similar distribution in the ASD group and the control group. In conclusion, both the bioavailability and the catalytic activity of PON1 are impaired in ASD, despite no association with the Q192R and L55M polymorphisms in the PON1 gene and a normal distribution of the PON1 phenotype.
J Cell Mol Med 2010 Mar
PMID:Paraoxonase 1 activities and polymorphisms in autism spectrum disorders. 1862 74

This study was performed to investigate the lipid-lowering, antioxidant, and hepato-protective effects of pinitol in dose-dependent manners in hamsters fed-high fat and high cholesterol (HFHC) diet. Pinitol supplementation (0.05%, P-I and 0.1% pinitol, P-II) with an HFHC diet (10% coconut oil plus 0.2% cholesterol) for 10 wks significantly lowered the white adipose tissue weights, hepatic lipid droplets, plasma glucose, total-cholesterol, nonHDL-cholesterol, total-cholesterol/HDL-cholesterol ratio, and hepatic lipid levels. Whereas it significantly increased the brown adipose tissue weight, plasma HDL-cholesterol, apolipoprotein A-I (apo A-I) concentrations, paraoxonase (PON) activity, and/or mRNA expression, compared to the HFHC control group. Plasma insulin and adiponectin levels were significantly lower and higher, respectively, in both P-I and P-II groups than the HFHC control group. Dietary pinitol significantly inhibited hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT), and cytochrome P4502E1 (CYP2E1) activities without altering their mRNA expressions compared to the control group. Pinitol significantly elevated the hepatic antioxidant enzyme activities, whereas it also significantly reduced the hepatic lipid peroxide and H2O2 production. Accordingly, these results indicate that both 0.05 and 0.1% pinitol supplementation may improve the lipid and antioxidant metabolism in HFHC diet-fed hamsters. In particular, pinitol supplementation was very effective on the elevation of antiatherogenic factors, including plasma HDL-cholesterol, apo A-I, adiponectin, and PON.
Mol Nutr Food Res 2009 Jun
PMID:Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. 1920 1

Serum paraoxonase (PON1) plays an important role in protecting low-density lipoprotein against oxidative modification. In this study, the full-length cDNA sequence (1,416 bp) of porcine PON1 was cloned by reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. It was found to contain a 1,068 bp open reading frame encoding a deduced protein of 355 amino acids with a calculated molecular weight of 40.02 kDa. The genomic structure and sequence of porcine PON1 were also analyzed using a bacterial artificial chromosome clone of a Chinese Erhualian pig. The porcine PON1 gene contained nine exons and eight introns spanning approximately 29 kb, and was located on chromosome nine between microsatellite markers SWR915 and SW944 by IMpRH mapping. Porcine PON1 was highly expressed in kidney, followed by liver, lung and small intestine, expressed at an extremely low level in heart, and was hardly expressed in spleen, lymph, muscle of the anterior limb, cerebrum, fat, cerebellum or hypothalamus.
Mol Biol Rep 2010 Mar
PMID:Sequence identification, chromosomal mapping and tissue specific expression of the porcine paraoxonase 1 (PON1) gene. 1934 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>