scholarly journals High-Risk Polymorphisms Associated with the Molecular Function of Human HMGCR Gene Infer the Impedance of Cholesterol Biosynthesis

2021 ◽  
Author(s):  
Keshob Chandra Das ◽  
Mohammad Uzzal Hossain ◽  
Md Moniruzzaman ◽  
Md Salimullah ◽  
Sharif Akhteruzzaman
Keyword(s):  
Solvent Accessibility ◽  
Cholesterol Biosynthesis ◽  
Functional Domain ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Instability ◽  
Structural Evaluation ◽  
Coa Reductase ◽  
Rate Limiting ◽  
Major Target

Abstract Background: HMG-CoA reductase or HMGCR (3-Hydroxy-3-methylglutaryl-CoA reductase) is a rate-limiting enzyme involved in cholesterol biosynthesis. HMGCR plays an important role in the possible occurrence of hypercholesterolemia leading to atherosclerosis and coronary heart disease. This enzyme is a major target for cholesterol lowering drugs such as “statins” which blocks the synthesis of mevalonate, a precursor for cholesterol biosynthesis. This study aims to characterize deleterious mutations and classify functional Single Nucleotide Polymorphisms (SNPs) of the HMGCR gene through analysis of functional and structural evaluation, domain association, solvent accessibility, and energy minimization studies. Results: Among 6,815 SNP entries from different databases, approximately 388 SNPs were found to be missense. Analysis showed that seven missense SNPs are more likely to have deleterious effects. A tertiary model of the mutant protein was constructed to determine the functional and structural effects of the HMGCR mutation. In addition, the location of the mutations suggests that they may have deleterious effects because most of the mutations are resides in the functional domain of the protein. The findings from the bunch of bioinformatics tools predicted that rs147043821 and rs193026499 missense SNPs could cause significant structural and functional instability in the mutated proteins of the HMGCR gene. Conclusion: Therefore, the results of the current study would undoubtedly be accommodating in future endeavors concerning drug discovery and therapeutics against hypercholesterolemia.

scholarly journals Association between the Polymorphisms of fads2a and fads2b and Poly-Unsaturated Fatty Acids in Common Carp (Cyprinus carpio)

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1780
Author(s):  
Yan Zhang ◽  
Xiao-Qing Sun ◽  
Yu-Qing Ye ◽  
Qi Wang ◽  
Qing-Song Li ◽  
...  
Keyword(s):  
Common Carp ◽  
Unsaturated Fatty Acids ◽  
Major Gene ◽  
Fatty Acid Desaturase ◽  
Mixed Linear Model ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Food Fish ◽  
Rate Limiting ◽  
Fatty Acid Desaturase 2

Fatty acid desaturase 2 (fads2) is one of the rate-limiting enzymes in PUFAs biosynthesis. Compared with the diploid fish encoding one fads2, the allo-tetraploid common carp, one most important food fish, encodes two fads2 genes (fads2a and fads2b). The associations between the contents of different PUFAs and the polymorphisms of fads2a and fads2b have not been studied. The contents of 12 PUFAs in common carp individuals were measured, and the polymorphisms in the coding sequences of fads2a and fads2b were screened. We identified five coding single nucleotide polymorphisms (cSNPs) in fads2a and eleven cSNPs in fads2b. Using the mixed linear model and analysis of variance, a synonymous fads2a cSNP was significantly associated with the content of C20:3n-6. One non-synonymous fads2b cSNP (fads2b.751) and one synonymous fads2b cSNP (fads2b.1197) were associated with the contents of seven PUFAs and the contents of six PUFAs, respectively. The heterozygous genotypes in both loci were associated with higher contents than the homozygous genotypes. The fads2b.751 genotype explained more phenotype variation than the fads2b.1197 genotype. These two SNPs were distributed in one haplotype block and associated with the contents of five common PUFAs. These results suggested that fads2b might be the major gene responding to common carp PUFA contents and that fads.751 might be the main effect SNP. These cSNPs would be potential markers for future selection to improve the PUFA contents in common carp.

Exploring Single Nucleotide Polymorphisms in ITGAV for Gastric, Pancreatic and Liver Malignancies: An Approach towards Biomarker Discovery

2020 ◽  
Vol 23 ◽  
Author(s):  
Shreya Bhattacharya ◽  
Pragati Prasad Sah ◽  
Arundhati Banerjee ◽  
Sujay Ray
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Biomarker Discovery ◽  
Solvent Accessibility ◽  
Structure Stability ◽  
Nucleotide Polymorphisms ◽  
Liver Malignancies ◽  
Single Nucleotide ◽  
Integrin Αv

Background: Integrin αV, encoded by ITGAV gene is one of the most studied protein subunits, closely associated with liver, pancreatic and stomach cancer progression and metastasis via regulation of angiogenesis. Occurrence of Single Nucleotide Polymorphisms (SNPs) in cancer-associated proteins is a key determinant for varied susceptibility of an individual towards cancer. Methodology: The study investigated the deleterious effects of these cancer-associated SNPs on the protein’s structure, stability and cancer causing potential using an in silico approach. Numerous computational tools were employed that identified the most deleterious cancer-associated SNPs and those to get actively involved in post-translational modifications. Impact of these SNPs on the protein structure, function and stability was also examined. Conclusion and Future Scope: A total 63 non-synonymous SNPs in ITGAV gene were observed to be associated in these three gastrointestinal cancers and among this 63, 19 were the most deleterious ones. The structural and functional importance of residues altered by most damaging SNPs was analyzed through evolutionary conservation and solvent accessibility. The study also elucidated three-dimensional structures of the 19 most damaging mutants. The analysis of conformational variation identified 5SNPs (D379Y, G188E, G513V, L950P, and R540L) in integrin αV, which influence protein’s structure. Three calcium binding sites were predicted at residues: D379, G384 and G408 and a peptide binding site at residue: R369 in integrin αV. Therefore, SNPs D379Y, G384C, G408R and R369W have the potential to alter the binding properties of the protein. Screening and characterization of deleterious SNPs could advance novel biomarker discovery and therapeutic development in future.

scholarly journals A discoordinate increase in the cellular amount of 3-hydroxy-3-methylglutaryl-CoA reductase results in the loss of rate-limiting control over cholesterogenesis in a tumour cell-free system

1989 ◽  
Vol 258 (2) ◽  
pp. 421-425 ◽  
Author(s):  
N I Azrolan ◽  
P S Coleman
Keyword(s):  
Cholesterol Biosynthesis ◽  
Normal Liver ◽  
Preliminary Evidence ◽  
Free System ◽  
Normal Rat ◽  
Morris Hepatoma ◽  
Coa Reductase ◽  
Rate Limiting ◽  
Hydroxymethylglutaryl Coa Reductase ◽  
Tumour System

Cholesterol biosynthesis was characterized in cell-free post-mitochondrial supernatant systems prepared from both normal rat liver and Morris hepatoma 3924A. The rate of cholesterol synthesis per cell was 9-fold greater in the tumour system than in that from normal liver, and the tumour systems showed the loss of rate-limiting control at the hydroxymethylglutaryl-CoA reductase (HMGR)-catalysed step. The apparent absence of rate-limiting control over cell-free tumour cholesterogenesis was traced primarily to a discoordinate and dramatic increase in the amount of HMGR in the tumour relative to the liver system. Preliminary evidence for an altered control of the post-lanosterol portion of the pathway was also obtained with the tumour system.

scholarly journals TPH1 gene polymorphism rs211105 influences serotonin and tryptophan hydroxylase 1 concentrations in acute pancreatitis patients

2021 ◽  
Author(s):  
Jadwiga Snarska ◽  
Ewa Fiedorowicz ◽  
Dominika Rozmus ◽  
Konrad Wroński ◽  
Maria Latacz ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Metabolic Pathway ◽  
Tryptophan Hydroxylase ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Serotonin Synthesis ◽  
Single Nucleotide ◽  
Factors Affecting ◽  
Rate Limiting

Abstract Background The role of serotonin and its metabolic pathway in proper functioning of the pancreas has not been thoroughly investigated yet in acute pancreatitis (AP) patients. Tryptophan hydroxylase (TPH) as the rate-limiting enzyme of serotonin synthesis has been considered for possible associations in various diseases. Single-nucleotide polymorphisms (SNPs) in TPH genes have been already described in associations with psychiatric and digestive system disorders. This study aimed to explore the association of a rs211105 (T/G) polymorphism in TPH1 gene with tryptophan hydroxylase 1 concentrations in blood serum in a population of acute pancreatitis patients, and to investigate this association with acute pancreatitis susceptibility. Results Our data showed an association between the presence of the T allele at the position rs211105 (OR = 2.47, 95% CI: 0.94-6.50, p = 0.06) under conditions of a decreased AP incidence. For TT and GT genotypes in the control group, the lowest concentration of TPH was associated with higher serotonin levels (TT: Rs=-0.415, p=0.0018; GT: Rs=-0,457, p=0.0066), while for the AP group the highest levels of TPH among the TT genotype were associated with lower levels of serotonin (TT: Rs=-0.749, p<0.0001, and in the GG genotype higher levels of TPH were associated with higher levels of serotonin (GG: Rs=-0.738, p=0.037). Conclusions Here, a new insight in the potential role of a selected genetic factor in pancreatitis development was shown. Not only the metabolic pathway of serotonin, but also factors affecting serotonin synthesis may be interesting and important points in acute pancreatitis.

Statins in Sepsis

2010 ◽  
Vol 23 (1) ◽  
pp. 38-49 ◽  
Author(s):  
Paul P. Dobesh ◽  
Stephanie M. Swahn, PharmD Candidate ◽  
Evan J. Peterson, PharmD Candidate ◽  
Keith M. Olsen
Keyword(s):  
Cholesterol Biosynthesis ◽  
Platelet Activating Factor ◽  
Population Based ◽  
Sepsis Syndrome ◽  
Positive Effects ◽  
Rate Limiting Step ◽  
Poor Outcomes ◽  
Coa Reductase ◽  
The Impact ◽  
Rate Limiting

Sepsis is a common intensive care unit event occurring in approximately 750 000 patients annually, with a case mortality rate approaching 50%. Sepsis is characterized by a chaotic and excessive release of inflammatory cytokines and procoagulants including tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, platelet-activating factor, and tissue factor. Efforts to inhibit individual cytokines in order to modify poor outcomes have been generally disappointing, suggesting the need to target multiple inflammatory mediators to obtain clinical benefit. Statins lower lipids by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which in turn inhibits the rate-limiting step in cholesterol biosynthesis. In addition to lowering total cholesterol, statins have pleiotropic effects on inflammation and immunity. Instead of impacting a single entity in the sepsis syndrome, statins may have positive effects on multiple inflammatory, immunomodulating, and coagulation targets involved in the development of infection and sepsis. There have been a number of institutional- and population-based studies that have evaluated the impact of statins in patients with infection and sepsis. Most of these studies, but not all, have demonstrated a number of positive outcomes in patients with statins, including reduction in mortality. Based on these data, statins are a promising therapy in the management of patients with sepsis and warrant larger and more rigorous clinical trials.

Association of Guanosine Triphosphate Cyclohydrolase 1 Gene Polymorphisms with Fibromyalgia Syndrome in a Korean Population

2013 ◽  
Vol 40 (3) ◽  
pp. 316-322 ◽  
Author(s):  
SEONG-KYU KIM ◽  
SEONG-HO KIM ◽  
SEONG-SU NAH ◽  
JI HYUN LEE ◽  
SEUNG-JAE HONG ◽  
...  
Keyword(s):  
Pain Sensitivity ◽  
Fibromyalgia Syndrome ◽  
No Production ◽  
Nucleotide Polymorphisms ◽  
Guanosine Triphosphate ◽  
Single Nucleotide ◽  
Lower Pain ◽  
Clinical Measures ◽  
Rate Limiting ◽  
Severity Indexes

Objective.Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor in nitric oxide (NO) production. Polymorphisms in theGCH1gene have been implicated in protection against pain sensitivity. The aim of our study was to determine whether single-nucleotide polymorphisms (SNP) in theGCH1gene affect susceptibility and/or pain sensitivity in fibromyalgia syndrome (FM).Methods.A total of 409 patients with FM and 422 controls were enrolled. The alleles and genotypes at 4 positions [rs3783641(T>A), rs841(C>T), rs752688(C>T), and rs4411417(T>C)] in theGCH1gene were analyzed. The associations of theGCH1SNP with susceptibility and clinical measures in patients with FM were assessed.Results.The frequencies of alleles and genotypes of the 4 SNP did not differ between patients with FM and healthy controls. Among 13 constructed haplotypes, we further examined 4 (CCTT, TTCT, TTCA, and CCTA) with > 1% frequency in both FM and controls. No associations ofGCH1polymorphisms with FM-related activity or severity indexes were found, although the number and total score of tender points in patients with FM differed among the 4 haplotypes (p = 0.03 and p = 0.01, respectively). The CCTA haplotype ofGCH1was associated with significantly lower pain sensitivity and occurred less frequently than the CCTT haplotype in patients with FM (p = 0.04, OR 0.45, 95% CI 0.21–0.96).Conclusion.Our study provides evidence that certainGCH1haplotypes may be protective against susceptibility and pain sensitivity in FM. Our data suggest that NO is responsible for pain sensitivity in the pathogenesis of FM.

scholarly journals A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation

2021 ◽  
Vol 14 (10) ◽  
pp. 981
Author(s):  
Ngoc Tan Cao ◽  
Ngoc Anh Nguyen ◽  
Chan Mi Park ◽  
Gun Su Cha ◽  
Ki Deok Park ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Liver Microsomes ◽  
Red Yeast Rice ◽  
High Catalytic Activity ◽  
Hmg Coa Reductase ◽  
Drug Candidates ◽  
New Strategy ◽  
Statin Drug ◽  
Coa Reductase ◽  
Rate Limiting

Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in cholesterol biosynthesis. Statin therapy reduces morbidity and mortality in those who are at high risk of cardiovascular disease. Monacolin J is a statin compound, which is an intermediate in the lovastatin biosynthesis pathway, in the fungus Aspergillus terreus. It is also found in red yeast rice, which is made by culturing rice with the yeast Monascus purpureus. Monacolin J has a hydroxyl substituent at position C’-8 of monacolin L. Here, a new statin derivative from monacolin J was made through the catalysis of CYP102A1 from Bacillus megaterium. A set of CYP102A1 mutants of monacolin J hydroxylation with high catalytic activity was screened. The major hydroxylated product was C-6′a-hydroxymethyl monacolin J, whose structure was confirmed using LC–MS and NMR analysis. The C-6′a-hydroxymethyl monacolin J has never been reported before. It showed a greater ability to inhibit HMG-CoA reductase than the monacolin J substrate itself. Human liver microsomes and human CYP3A4 also showed the ability to catalyze monacolin J in producing the same product of the CYP102A1-catalyzed reaction. This result motivates a new strategy for the development of a lead for the enzymatic and chemical processes to develop statin drug candidates.

scholarly journals TPH1 Gene Polymorphism (rs211105) Influences Serotonin and Tryptophan Hydroxylase 1 Concentrations in Acute Pancreatitis Patients

2021 ◽  
Author(s):  
Jadwiga Snarska ◽  
Ewa Fiedorowicz ◽  
Dominika Rozmus ◽  
Konrad Wroński ◽  
Maria Latacz ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Metabolic Pathway ◽  
Tryptophan Hydroxylase ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Serotonin Synthesis ◽  
Single Nucleotide ◽  
Factors Affecting ◽  
Rate Limiting

Abstract Background: The role of serotonin and its metabolic pathway in the proper functioning of the pancreas has not been thoroughly investigated yet in the aspect of AP (acute pancreatitis). Tryptophan hydroxylase (TPH) as the rate-limiting enzyme of serotonin synthesis has been considered for possible associations in various diseases. Single-nucleotide polymorphisms (SNPs) in TPH genes have been already described in associations with psychiatric and digestive system disorders. Aim of this study was to explore association of rs211105 (T/G) polymorphism in TPH1 gene with tryptophan hydroxylase 1 concentrations in blood serum in population of acute pancreatitis patients, and to investigate this association with acute pancreatitis susceptibility. Results: To date, we have found an association between the presence of the T allele at the position rs211105 (OR = 2.47, 95% CI: 0.94-6.50, p = 0.06) under conditions of a decreased AP incidence. For TT and GT genotype in control group, the lowest concentration of TPH was associated with higher serotonin levels (TT: Rs=-0.415, p=0.0018; GT: Rs=-0,457, p=0.0066), while for AP group: the highest levels of TPH among TT genotype were associated with lower levels of serotonin (TT: Rs=-0.749, p=0.0000), and in GG genotype higher levels of TPH were associated with higher levels of serotonin (GG: Rs=-0.738, p=0.037).Conclusions: Here, the new insight of the potential role of selected genetic factor in pancreatitis development was brought. Not only the metabolic pathway of serotonin, but also factors affecting serotonin synthesis may be interesting and important point in acute pancreatitis.

scholarly journals Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Amit Datta ◽  
Md. Habibul Hasan Mazumder ◽  
Afrin Sultana Chowdhury ◽  
Md. Anayet Hasan
Keyword(s):  
Prostate Cancer ◽  
Solvent Accessibility ◽  
3D Models ◽  
Structural Effect ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Snp Data ◽  
Project Hope ◽  
Ribonuclease L

A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3′ and 5′ UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.

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