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Journal of Physiology and Pharmacology... Oct 2023Breast cancer (BRCA) is a serious life-threatening cancer, especially triple-negative breast cancer (TNBC). Alcohol dehydrogenase-1B (ADH1B) has recently been revealed...
Alcohol dehydrogenase-1B represses the proliferation, invasion and migration of breast cancer cells by inactivating the mitogen-activated protein kinase signalling pathway.
Breast cancer (BRCA) is a serious life-threatening cancer, especially triple-negative breast cancer (TNBC). Alcohol dehydrogenase-1B (ADH1B) has recently been revealed to be associated with poor prognosis of BRCA patients. This study identified the exact function of ADH1B on the progression of BRCA and TNBC. ADH1B effect on the prognosis of BRCA and TNBC patients was researched based on online databases and clinical samples. The function of ADH1B on the proliferation, invasion and migration, and growth of BRCA and TNBC cells was investigated by cell counting kit-8, Transwell, and in vivo assays. Western blot was utilized to determine the effect of ADH1B on the mitogen-activated protein kinase (MAPK) signalling pathway activity. As a result, ADH1B was down-regulated in BRCA and TNBC patients and cells, predicting unfavorable prognosis (P<0.05). ADH1B overexpression suppressed the proliferation, invasion and migration, and inactivated the MAPK signalling pathway in BRCA and TNBC cells (P<0.01). ADH1B synergized with Selumetinib (inhibitor of the MAPK signalling pathway) to attenuate the proliferation, invasion and migration of BRCA and TNBC cells (P<0.001). Conversely, Vacquinol-1 (activator of the MAPK signalling pathway) abolished the suppression of ADH1B on the proliferation, invasion and migration of BRCA and TNBC cells (P<0.05). ADH1B suppressed in vivo growth of TNBC cells (P<0.001). Thus, ADH1B may inhibit the proliferation, invasion and migration of BRCA and TNBC cells by inactivating the MAPK signalling pathway. It may be a promising target for the clinical treatment of BRCA and TNBC.
Topics: Humans; Alcohol Dehydrogenase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Mitogen-Activated Protein Kinases; Triple Negative Breast Neoplasms
PubMed: 38085522
DOI: 10.26402/jpp.2023.5.10 -
Chembiochem : a European Journal of... Jun 2022Multi-enzyme cascades enable the production of valuable chemical compounds, and fusion of the enzymes that catalyze these reactions can improve the reaction outcome. In...
Multi-enzyme cascades enable the production of valuable chemical compounds, and fusion of the enzymes that catalyze these reactions can improve the reaction outcome. In this work, P450 BM3 from Bacillus megaterium and an alcohol dehydrogenase from Sphingomonas yanoikuyae were fused to bifunctional constructs to enable cofactor regeneration and improve the in vitro two-step oxidation of (+)-valencene to (+)-nootkatone. An up to 1.5-fold increased activity of P450 BM3 was achieved with the fusion constructs compared to the individual enzyme. Conversion of (+)-valencene coupled to cofactor regeneration and performed in the presence of the solubilizing agent cyclodextrin resulted in up to 1080 mg L (+)-nootkatone produced by the fusion constructs as opposed to 620 mg L produced by a mixture of the separate enzymes. Thus, a two-step (+)-valencene oxidation was considerably improved through the simple method of enzyme fusion.
Topics: Alcohol Dehydrogenase; Bacillus megaterium; Bacterial Proteins; Cytochrome P-450 Enzyme System; NADPH-Ferrihemoprotein Reductase; Polycyclic Sesquiterpenes
PubMed: 35333425
DOI: 10.1002/cbic.202200065 -
Biomedica : Revista Del Instituto... Dec 2018Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of...
Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.
Topics: Adult; Aged; Alcohol Dehydrogenase; Carcinoma, Hepatocellular; Cytochrome P-450 CYP2E1; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Polymorphism, Genetic; Young Adult
PubMed: 30653870
DOI: 10.7705/biomedica.v38i4.3897 -
Bioorganic Chemistry Jun 2022In this study, we present the concept of co-immobilization of xylose dehydrogenase and alcohol dehydrogenase from Saccharomyces cerevisiae on an XN45 nanofiltration...
In this study, we present the concept of co-immobilization of xylose dehydrogenase and alcohol dehydrogenase from Saccharomyces cerevisiae on an XN45 nanofiltration membrane for application in the process of xylose bioconversion to xylonic acid with simultaneous cofactor regeneration and membrane separation of reaction products. During the research, the effectiveness of the co-immobilization of enzymes was confirmed, and changes in the properties of the membrane after the processes were determined. Using the obtained biocatalytic system it was possible to obtain 99% xylonic acid production efficiency under optimal conditions, which were 5 mM xylose, 5 mM formaldehyde, ratio of NAD+:NADH 1:1, and 60 min of reaction. Additionally, the co-immobilization of enzymes made it possible to improve stability of the co-immobilized enzymes and to carry out xylose conversion in six consecutive cycles and after 7 days of storage at 4 °C with over 90% efficiency. The presented data confirm the effectiveness of the co-immobilization, improvement of the stability and reusability of the biocatalysts, and show that the obtained enzymatic system is promising for use in xylose bioconversion and simultaneous regeneration of nicotinamide cofactor.
Topics: Alcohol Dehydrogenase; Aldehyde Reductase; Biocatalysis; Regeneration; Xylose
PubMed: 35395447
DOI: 10.1016/j.bioorg.2022.105781 -
Bioengineered 2015N(6)-carboxymethyl-NAD (N(6)-CM-NAD) can be used to immobilize NAD onto a substrate containing terminal primary amines. We previously immobilized N(6)-CM-NAD onto...
N(6)-carboxymethyl-NAD (N(6)-CM-NAD) can be used to immobilize NAD onto a substrate containing terminal primary amines. We previously immobilized N(6)-CM-NAD onto sepharose beads and showed that Thermotoga maritima glycerol dehydrogenase could use the immobilized cofactor with cofactor recycling. We now show that Saccharomyces cerevisiae alcohol dehydrogenase, rabbit muscle L-lactate dehydrogenase (type XI), bovine liver L-glutamic dehydrogenase (type III), Leuconostoc mesenteroides glucose-6-phosphate dehydro-genase, and Thermotoga maritima mannitol dehydrogenase are active with soluble N(6)-CM-NAD. The products of all enzymes but 6-phospho-D-glucono-1,5-lactone were formed when sepharose-immobilized N(6)-CM-NAD was recycled by T. maritima glycerol dehydrogenase, indicating that N(6)-immobilized NAD is suitable for use by a variety of different dehydrogenases. Observations of the enzyme active sites suggest that steric hindrance plays a greater role in limiting or allowing activity with the modified cofactor than do polarity and charge of the residues surrounding the N(6)-amine group on NAD.
Topics: Alcohol Dehydrogenase; Animals; Cattle; Glutamate Dehydrogenase; L-Lactate Dehydrogenase; NAD; Oxidoreductases; Rabbits; Sepharose; Sugar Alcohol Dehydrogenases
PubMed: 25611453
DOI: 10.1080/21655979.2014.1004020 -
Chembiochem : a European Journal of... Dec 2021Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study...
Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64-95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95->99 % and up to 98 % yield.
Topics: Alcohol Dehydrogenase; Alcohols; Halogenation; Lactobacillus; Molecular Structure; Pyridines
PubMed: 34520599
DOI: 10.1002/cbic.202100392 -
The Turkish Journal of Gastroenterology... Jul 2022Alcohol dehydrogenase and acetaldehyde dehydrogenases have been associated with hepatocellular carcinoma, but how alcohol dehydrogenase and acetaldehyde dehydrogenases...
BACKGROUND
Alcohol dehydrogenase and acetaldehyde dehydrogenases have been associated with hepatocellular carcinoma, but how alcohol dehydrogenase and acetaldehyde dehydrogenases alter the prognosis of hepatocellular carcinoma have not been completely elucidated.
METHODS
Metabolic activities, gene polymorphisms, and content of alcohol dehydrogenase and acetaldehyde dehydrogenases were determined in 68 fibrotic livers from hepatocellular carcinoma patients. These characteristics were then correlated with clinical features and prognosis in these patients.
RESULTS
The median survival time of the ALDH-high activity group (727 days) was increased by 128% compared with that of ALDH-low activity group (319 days), and there was a significant negative correlation between the activity of acetaldehyde dehydrogenases and the level of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. There was no difference in survival time between ALDH2-high and ALDH2-low expression group, though the activity of acetaldehyde dehydrogenases had correlation with the content of ALDH2 (r = 0.6887, P < .001). Mutation at ALDH2rs671 significantly decreased both the activity and content of acetalde- hyde dehydrogenases, but the polymorphism had no relationship with progression of hepatocellular carcinoma patients. In addition, the activity and 3 polymorphisms of alcohol dehydrogenase had no effect on overall survival. Mutation at ADH1Crs698 significantly decreased both the activity and content of alcohol dehydrogenase (P < .05), mutation at ADH1C rs2241894 had an inverse effect, and mutation at ADH1B rs1229984 increased activity but did not affect content. The activity of alcohol dehydrogenase had a moderate cor- relation with the content of ADH1A and ADH1C in livers (P < .05).
CONCLUSION
Low activity of acetaldehyde dehydrogenases in livers correlates with poor prognosis and clinical progression in hepatocel- lular carcinoma patients, and both gene polymorphisms and content influence its metabolic activity.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Aldehyde Oxidoreductases; Carcinoma, Hepatocellular; Ethanol; Humans; Liver Neoplasms; Polymorphism, Genetic; Prognosis
PubMed: 35879918
DOI: 10.5152/tjg.2022.21340 -
Cell Reports Jan 2023Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is...
Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.
Topics: Humans; Aldehyde Oxidoreductases; Focal Adhesion Kinase 1; Neoplasms; Nitric Oxide; Phosphorylation; Protein Processing, Post-Translational; Tumor Microenvironment; Alcohol Dehydrogenase
PubMed: 36656716
DOI: 10.1016/j.celrep.2023.111997 -
Scientific Reports Jul 2021Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals...
Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals genetically susceptible to the carcinogenic effect of alcohol might have higher pancreatic cancer risk after drinking alcohol. The current study investigated the association between alcohol use and pancreatic cancer with 419 pancreatic cancer cases and 963 controls recruited by a hospital-based case-control study in Taiwan. Gene-environment interaction between alcohol use and polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on pancreatic risk was evaluated. Our results showed no significant association between alcohol drinking and an increased pancreatic cancer risk, even at high levels of alcohol consumption. Even among those genetically susceptible to the carcinogenic effect of alcohol (carriers of ADH1B*2/*2(fast activity) combined with ALDH2*1/*2(slow activity) or ALDH2*2/*2(almost non-functional)), no significant association between alcohol use and pancreatic cancer was observed. Overall, our results suggested that alcohol drinking is not a significant contributor to the occurrence of pancreatic cancer in Taiwan.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; Asian People; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Taiwan
PubMed: 34267279
DOI: 10.1038/s41598-021-94111-w -
Chembiochem : a European Journal of... Jan 2019To expand the arsenal of industrially applicable oxidative enzymes, fusions of alcohol dehydrogenases with an NADPH-oxidase were designed. Three different alcohol...
To expand the arsenal of industrially applicable oxidative enzymes, fusions of alcohol dehydrogenases with an NADPH-oxidase were designed. Three different alcohol dehydrogenases (LbADH, TbADH, ADHA) were expressed with a thermostable NADPH-oxidase fusion partner (PAMO C65D) and purified. The resulting bifunctional biocatalysts retained the catalytic properties of the individual enzymes, and acted essentially like alcohol oxidases: transforming alcohols to ketones by using dioxygen as mild oxidant, while merely requiring a catalytic amount of NADP . In small-scale reactions, the purified fusion enzymes show good performances, with 69-99 % conversion, 99 % ee with a racemic substrate, and high cofactor and enzyme total turnover numbers. As the fusion enzymes essentially act as oxidases, we found that commonly used high-throughput oxidase-activity screening methods can be used. Therefore, if needed, the fusion enzymes could be easily engineered to tune their properties.
Topics: Alcohol Dehydrogenase; Alcohol Oxidoreductases; Animals; Armoracia; Benzyl Alcohols; Biocatalysis; Cattle; Cyclohexanols; Escherichia coli; Levilactobacillus brevis; Micrococcus; Multifunctional Enzymes; NADPH Oxidases; Oxidation-Reduction; Protein Engineering; Recombinant Fusion Proteins; Thermoanaerobacter
PubMed: 30184296
DOI: 10.1002/cbic.201800421