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Theranostics 2021: Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing...
: Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. : We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed using cell line xenograft tumor studies. : The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both and This synergy was evident in homologous recombination (HR) proficient cell lines. : ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.
Topics: Aldehyde Dehydrogenase 1 Family; Aldehyde Oxidoreductases; Aldehydes; Animals; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Damage; Drug Synergism; Enzyme Inhibitors; Female; Gene Knockout Techniques; Humans; Mice; Ovarian Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 33664846
DOI: 10.7150/thno.51885 -
Journal of Biological Inorganic... Dec 2022Five tungstopterin-containing oxidoreductases were characterized from the hyperthermophile Pyrococcus furiosus. Each enzyme catalyzes the reversible conversion of one or...
Five tungstopterin-containing oxidoreductases were characterized from the hyperthermophile Pyrococcus furiosus. Each enzyme catalyzes the reversible conversion of one or more aldehydes to the corresponding carboxylic acid, but they have different specificities. The physiological functions of only two of these enzymes are known: one, termed GAPOR, is a glycolytic enzyme that oxidizes glyceraldehyde-3-phosphate, while the other, termed AOR, oxidizes multiple aldehydes generated during peptide fermentation. Two of the enzymes have known structures (AOR and FOR). Herein, we focus on WOR5, the fifth tungstopterin enzyme to be discovered in P. furiosus. Expression of WOR5 was previously shown to be increased during cold shock (growth at 72 ℃), although the physiological substrate is not known. To gain insight into WOR5 function, we sought to determine both its structure and identify its intracellular substrate. Crystallization experiments were performed with a concentrated cytoplasmic extract of P. furiosus grown at 72 ℃ and the structure of WOR5 was deduced from the crystals that were obtained. In contrast to a previous report, WOR5 is heterodimeric containing an additional polyferredoxin-like subunit with four [4Fe-4S] clusters. The active site structure of WOR5 is substantially different from that of AOR and FOR and the significant electron density observed adjacent to the tungsten cofactor of WOR5 was modeled as an aliphatic sulfonate. Biochemical assays and product analysis confirmed that WOR5 is an aliphatic sulfonate ferredoxin oxidoreductase (ASOR). A catalytic mechanism for ASOR is proposed based on the structural information and the potential role of ASOR in the cold-shock response is discussed.
Topics: Tungsten; Oxidoreductases; Aldehyde Oxidoreductases; Pyrococcus furiosus; Aldehydes
PubMed: 36269456
DOI: 10.1007/s00775-022-01965-0 -
Archives of Biochemistry and Biophysics Jan 2022Xenobiotic-metabolizing enzymes (XMEs) expressed in the olfactory epithelium (OE) are known to metabolize odorants. Aldehyde oxidase (AOX) recognizes a wide range of...
Xenobiotic-metabolizing enzymes (XMEs) expressed in the olfactory epithelium (OE) are known to metabolize odorants. Aldehyde oxidase (AOX) recognizes a wide range of substrates among which are substrates with aldehyde groups. Some of these AOX substrates are odorants, such as benzaldehyde and n-octanal. One of the mouse AOX isoforms, namely AOX2 (mAOX2), was shown to be specifically expressed in mouse OE but its role to metabolize odorants in this tissue remains unexplored. In this study, we investigated the involvement of mouse AOX isoforms in the oxidative metabolism of aldehyde-odorants in the OE. Mouse OE extracts effectively metabolized aromatic and aliphatic aldehyde-odorants. Gene expression analysis revealed that not only mAOX2 but also the mAOX3 isoform is expressed in the OE. Furthermore, evaluation of inhibitory effects using the purified recombinant enzymes led us to identify specific inhibitors of each isoform, namely chlorpromazine, 17β-estradiol, menadione, norharmane, and raloxifene. Using these specific inhibitors, we defined the contribution of mAOX2 and mAOX3 to the metabolism of aldehyde-odorants in the mouse OE. Taken together, these findings demonstrate that mAOX2 and mAOX3 are responsible for the oxidation of aromatic and aliphatic aldehyde-odorants in the mouse OE, implying their involvement in odor perception.
Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Aldehydes; Animals; Enzyme Inhibitors; Female; Male; Mice, Inbred C57BL; Odorants; Olfactory Mucosa; Oxidation-Reduction; Smell; Mice
PubMed: 34856193
DOI: 10.1016/j.abb.2021.109099 -
Environmental Toxicology and... Jul 2022Cardiovascular disease, the foremost cause of death worldwide, is an overarching disease term that encompasses a number of disorders involving the heart and circulatory... (Review)
Review
Cardiovascular disease, the foremost cause of death worldwide, is an overarching disease term that encompasses a number of disorders involving the heart and circulatory system, including atherosclerosis. Atherosclerosis is a primary cause of cardiovascular diseases and is caused by buildup of plaque and narrowing of blood vessels. Epidemiological studies have suggested that environmental pollutants are implicated in atherosclerosis disease progression. Among many environmental pollutants, acrolein (Acr) is an abundant reactive aldehyde and is ubiquitously present in cigarette smoke as well as food products (e.g., overheated oils and wine). Despite its ubiquitous presence and potential impact on the etiology of cardiovascular disease, a limited consensus has been made in regard to Acr exposure conditions to induce atherosclerosis in vivo. This mini-review summarizes in vivo atherosclerosis models using Acr to investigate biochemical and phenotypic changes related to atherosclerosis and in vitro mechanistic studies involving Acr and atherosclerosis.
Topics: Acrolein; Aldehydes; Atherosclerosis; Cardiovascular Diseases; Environmental Pollutants; Hazardous Substances; Humans
PubMed: 35613694
DOI: 10.1016/j.etap.2022.103890 -
International Journal of Environmental... Jan 2023Formaldehyde, a colorless and highly irritating substance, causes cancer of the nasopharynx and leukemia. Furthermore, it is one of the environmental mutagens to which...
INTRODUCTION
Formaldehyde, a colorless and highly irritating substance, causes cancer of the nasopharynx and leukemia. Furthermore, it is one of the environmental mutagens to which humans are most abundantly exposed. Acetaldehyde was recently classified as carcinogen class 1B and mutagen class 2 in Annex VI EC regulation. Occupational exposure to the two aldehydes occurs in a wide variety of occupations and industries. The aim of this study is to deepen exposure to the two aldehydes in the non-traditional productive sectors of bakeries and pastry producers.
METHODS
The evaluation of exposure to formaldehyde and acetaldehyde was conducted in Italy in 2019, in specific tasks and positions of 11 bakeries and pastry producers (115 measures, of which 57.4% were in fixed positions and the rest were personal air sampling). The measurements were performed using Radiello© radial diffusion samplers. A logarithmic transformation of the data was performed, and the correlation between the two substances was calculated. Moreover, linear models considering the log-formaldehyde as the outcome and adjusting for log-acetaldehyde values were used.
RESULTS
The study identified high levels of acetaldehyde and formaldehyde exposure in the monitored workplaces. Higher mean values were observed in the leavening phase (8.39 µg/m and 3.39 µg/m for log-transformed data acetaldehyde and formaldehyde, respectively). The adjusted univariate analyses show statistically significant factors for formaldehyde as the presence of yeast, the presence of type 1 flour, the use of barley, the use of fats, the type of production, the use of spelt, and the presence of type 0 flour.
CONCLUSIONS
The measurements confirmed the release of formaldehyde and acetaldehyde in bakeries and pastry industries, especially in some phases of the work process, such as leavening.
Topics: Humans; Acetaldehyde; Formaldehyde; Occupational Exposure; Aldehydes; Allergens
PubMed: 36767350
DOI: 10.3390/ijerph20031983 -
Natural Product Reports Jan 2021Covering: up to April 2020Fungal benzene carbaldehydes with salicylaldehydes as predominant representatives carry usually hydroxyl groups, prenyl moieties and alkyl side... (Review)
Review
Covering: up to April 2020Fungal benzene carbaldehydes with salicylaldehydes as predominant representatives carry usually hydroxyl groups, prenyl moieties and alkyl side chains. They are found in both basidiomycetes and ascomycetes as key intermediates or end products of various biosynthetic pathways and exhibit diverse biological and pharmacological activities. The skeletons of the benzene carbaldehydes are usually derived from polyketide pathways catalysed by iterative fungal polyketide synthases. The aldehyde groups are formed by direct PKS releasing, reduction of benzoic acids or oxidation of benzyl alcohols.
Topics: Aldehydes; Alkylation; Antifungal Agents; Antineoplastic Agents; Benzene; Fungal Proteins; Fungi; Humans; Molecular Structure; Polyketide Synthases
PubMed: 32779678
DOI: 10.1039/d0np00026d -
FEMS Microbiology Reviews May 2021Many bacteria produce storage biopolymers that are mobilized under conditions of metabolic adaptation, for example, low nutrient availability and cellular stress.... (Review)
Review
Many bacteria produce storage biopolymers that are mobilized under conditions of metabolic adaptation, for example, low nutrient availability and cellular stress. Polyhydroxyalkanoates are often found as carbon storage in Bacteria or Archaea, and of these polyhydroxybutyrate (PHB) is the most frequently occurring PHA type. Bacteria usually produce PHB upon availability of a carbon source and limitation of another essential nutrient. Therefore, it is widely believed that the function of PHB is to serve as a mobilizable carbon repository when bacteria face carbon limitation, supporting their survival. However, recent findings indicate that bacteria switch from PHB synthesis to mobilization under stress conditions such as thermal and oxidative shock. The mobilization products, 3-hydroxybutyrate and its oligomers, show a protective effect against protein aggregation and cellular damage caused by reactive oxygen species and heat shock. Thus, bacteria should have an environmental monitoring mechanism directly connected to the regulation of the PHB metabolism. Here, we review the current knowledge on PHB physiology together with a summary of recent findings on novel functions of PHB in stress resistance. Potential applications of these new functions are also presented.
Topics: Aldehydes; Bacteria; Stress, Physiological
PubMed: 33118006
DOI: 10.1093/femsre/fuaa058 -
The Journal of Organic Chemistry May 2022Six- and seven-membered ring-fused, functionalized cyclopentadienes can be obtained in moderate to excellent yields by a cascade process entailing the Au(I)-catalyzed...
Six- and seven-membered ring-fused, functionalized cyclopentadienes can be obtained in moderate to excellent yields by a cascade process entailing the Au(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization of propargyl vinyl ethers, the hetero-Diels-Alder reaction with dialkylazodicarboxylates, and the spontaneous conversion of cycloaddition products into cyclopentadienes by a highly regioselective cleavage of a C-N bond. Depending on the treatment of the crude reaction mixtures, two types of products can be obtained: cyclopentadienes with pendant hydrazine and aldehyde moieties that intramolecularly react to form hemiaminals are obtained in 43-52% overall yields when the crude reaction mixtures are left over KCO in a DCM solution. Instead, by reducing the aldehyde group just after addition of the heterodienophile, the regioselective C-N bond cleavage generates the corresponding cyclopentadienes bearing a hydrazine and an alcohol appendage in excellent yields (66-82%) over four steps, all in one pot. Two examples from the latter class of compounds were also converted into ring-fused, functionalized cyclopentadienes, bearing a protected amino group, by the selective N-N cleavage of the hydrazine moiety.
Topics: Aldehydes; Catalysis; Cycloaddition Reaction; Cyclopentanes; Gold; Hydrazines; Stereoisomerism
PubMed: 35442687
DOI: 10.1021/acs.joc.2c00296 -
Biotechnology Advances 2022From Egyptian mummies to the Chanel n°5 perfume, fatty aldehydes have long been used and keep impacting our senses in a wide range of foods, beverages and perfumes.... (Review)
Review
From Egyptian mummies to the Chanel n°5 perfume, fatty aldehydes have long been used and keep impacting our senses in a wide range of foods, beverages and perfumes. Natural sources of fatty aldehydes are threatened by qualitative and quantitative variability while traditional chemical routes are insufficient to answer the society shift toward more sustainable and natural products. The production of fatty aldehydes using biotechnologies is therefore the most promising alternative for the flavors and fragrances industry. In this review, after drawing the portrait of the origin and characteristics of fragrant fatty aldehydes, we present the three main classes of enzymes that catalyze the reaction of fatty alcohols oxidation into aldehydes, namely alcohol dehydrogenases, flavin-dependent alcohol oxidases and copper radical alcohol oxidases. The constraints, challenges and opportunities to implement these oxidative enzymes in the flavors and fragrances industry are then discussed. By setting the scene on the biocatalytic production of fatty aldehydes, and providing a critical assessment of its potential, we expect this review to contribute to the development of biotechnology-based solutions in the flavors and fragrances industry.
Topics: Alcohols; Aldehydes; Fatty Alcohols; Odorants; Oxidation-Reduction; Oxidoreductases; Perfume
PubMed: 34147589
DOI: 10.1016/j.biotechadv.2021.107787 -
International Journal of Biological... Jun 2023Biocatalysts have been gaining extra attention in recent decades due to their industrial-relevance properties, which may hasten the transition to a cleaner environment.... (Review)
Review
Biocatalysts have been gaining extra attention in recent decades due to their industrial-relevance properties, which may hasten the transition to a cleaner environment. Carboxylic acid reductases (CARs) are large, multi-domain proteins that can catalyze the reduction of carboxylic acids to corresponding aldehydes, with the presence of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH). This biocatalytic reaction is of great interest due to the abundance of carboxylic acids in nature and the ability of CAR to convert carboxylic acids to a wide range of aldehydes essentially needed as end products such as vanillin or reaction intermediates for several compounds production such as alcohols, alkanes, and amines. This modular enzyme, found in bacteria and fungi, demands an activation via post-translational modification by the phosphopantetheinyl transferase (PPTase). Recent advances in the characterization and structural studies of CARs revealed valuable information about the dynamics, mechanisms, and unique features of the enzymes. In this comprehensive review, we summarize the previous findings on the phylogeny, structural and mechanistic insight of the domains, post-translational modification requirement, strategies for the cofactors regeneration, the extensively broad aldehyde-related industrial application properties of CARs, as well as their recent immobilization approaches.
Topics: Oxidoreductases; Biotechnology; Aldehydes; Carboxylic Acids
PubMed: 37080403
DOI: 10.1016/j.ijbiomac.2023.124526