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Regulation of human mitochondrial aldehyde dehydrogenase (ALDH-2) activity by electrophiles in vitro.

ABSTRACT: Recently, mitochondrial aldehyde dehydrogenase (ALDH-2) was reported to reduce ischemic damage in an experimental myocardial infarction model. ALDH-2 activity is redox-sensitive. Therefore, we here compared effects of various electrophiles (organic nitrates, reactive fatty acid metabolites, or oxidants) on the activity of ALDH-2 with special emphasis on organic nitrate-induced inactivation of the enzyme, the biochemical correlate of nitrate tolerance. Recombinant human ALDH-2 was overexpressed in Escherichia coli; activity was determined with an HPLC-based assay, and reactive oxygen and nitrogen species formation was determined by chemiluminescence, fluorescence, protein tyrosine nitration, and diaminonaphthalene nitrosation. The organic nitrate glyceryl trinitrate caused a severe concentration-dependent decrease in enzyme activity, whereas incubation with pentaerythritol tetranitrate had only minor effects. 4-Hydroxynonenal, an oxidized prostaglandin J(2), and 9- or 10-nitrooleate caused a significant inhibition of ALDH-2 activity, which was improved in the presence of Mg(2+) and Ca(2+). Hydrogen peroxide and NO generation caused only minor inhibition of ALDH-2 activity, whereas peroxynitrite generation or bolus additions lead to severe impairment of the enzymatic activity, which was prevented by the thioredoxin/thioredoxin reductase (Trx/TrxR) system. In the presence of glyceryl trinitrate and to a lesser extent pentaerythritol tetranitrate, ALDH-2 may be switched to a peroxynitrite synthase. Electrophiles of different nature potently regulate the enzymatic activity of ALDH-2 and thereby may influence the resistance to ischemic damage in response to myocardial infarction. The Trx/TrxR system may play an important role in this process because it not only prevents inhibition of ALDH-2 but is also inhibited by the ALDH-2 substrate 4-hydroxynonenal.

SUBMITTER: Oelze M

PROVIDER: S-EPMC3058968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMalignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.e. cancer stem cells (CSC), exists in malignant melanoma. Rather, it is suggested that multiple cell populations are implicated in initiation and progression of the disease, making it of importance to identify subpopulations with elevated aggressive properties.Methods and findingsIn several other cancer forms, Aldehyde Dehydrogenase (ALDH), which plays a role in stem cell biology and resistance, is a valuable functional marker for identification of cells that show enhanced aggressiveness and drug-resistance. Furthermore, the presence of ALDH(+) cells is linked to poor clinical prognosis in these cancers. By analyzing cell cultures, xenografts and patient biopsies, we showed that aggressive melanoma harboured a large, distinguishable ALDH(+) subpopulation. In vivo, ALDH(+) cells gave rise to ALDH(-) cells, while the opposite conversion was rare, indicating a higher abilities of ALDH(+) cells to reestablish tumour heterogeneity with respect to the ALDH phenotype. However, both ALDH(+) and ALDH(-) cells demonstrated similarly high abilities for clone formation in vitro and tumour initiation in vivo. Furthermore, both subpopulations showed similar sensitivity to the anti-melanoma drugs, dacarbazine and lexatumumab.ConclusionsThese findings suggest that ALDH does not distinguish tumour-initiating and/or therapy-resistant cells, implying that the ALDH phenotype is not associated with more-aggressive subpopulations in malignant melanoma, and arguing against ALDH as a "universal" marker. Besides, it was shown that the ability to reestablish tumour heterogeneity is not necessarily linked to the more aggressive phenotype.

Project description:The completion of the grape genome sequencing project has paved the way for novel gene discovery and functional analysis. Aldehyde dehydrogenases (ALDHs) comprise a gene superfamily encoding NAD(P)(+)-dependent enzymes that catalyze the irreversible oxidation of a wide range of endogenous and exogenous aromatic and aliphatic aldehydes. Although ALDHs have been systematically investigated in several plant species including Arabidopsis and rice, our knowledge concerning the ALDH genes, their evolutionary relationship and expression patterns in grape has been limited.A total of 23 ALDH genes were identified in the grape genome and grouped into ten families according to the unified nomenclature system developed by the ALDH Gene Nomenclature Committee (AGNC). Members within the same grape ALDH families possess nearly identical exon-intron structures. Evolutionary analysis indicates that both segmental and tandem duplication events have contributed significantly to the expansion of grape ALDH genes. Phylogenetic analysis of ALDH protein sequences from seven plant species indicates that grape ALDHs are more closely related to those of Arabidopsis. In addition, synteny analysis between grape and Arabidopsis shows that homologs of a number of grape ALDHs are found in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the speciation of the grape and Arabidopsis. Microarray gene expression analysis revealed large number of grape ALDH genes responsive to drought or salt stress. Furthermore, we found a number of ALDH genes showed significantly changed expressions in responses to infection with different pathogens and during grape berry development, suggesting novel roles of ALDH genes in plant-pathogen interactions and berry development.The genome-wide identification, evolutionary and expression analysis of grape ALDH genes should facilitate research in this gene family and provide new insights regarding their evolution history and functional roles in plant stress tolerance.

Project description:Background and aimsStresses such as drought or salinity induce the generation of reactive oxygen species, which subsequently cause excessive accumulation of aldehydes in plant cells. Aldehyde dehydrogenases (ALDHs) are considered as 'aldehyde scavengers' to eliminate toxic aldehydes caused by oxidative stress. The completion of the genome sequencing projects of the halophytes Eutrema parvulum and E. salsugineum has paved the way to explore the relationships and the roles of ALDH genes in the glycophyte Arabidopsis thaliana and halophyte model plants.MethodsProtein sequences of all plant ALDH families were used as queries to search E. parvulum and E. salsugineum genome databases. Evolutionary analyses compared the phylogenetic relationships of ALDHs from A. thaliana and Eutrema. Expression patterns of several stress-associated ALDH genes were investigated under different salt conditions using reverse transcription-PCR. Putative cis-elements in the promoters of ALDH10A8 from A. thaliana and E. salsugineum were compared in silico.Key resultsSixteen and 17 members of ten ALDH families were identified from E. parvulum and E. salsugineum genomes, respectively. Phylogenetic analysis of ALDH protein sequences indicated that Eutrema ALDHs are closely related to those of Arabidopsis, and members within these species possess nearly identical exon-intron structures. Gene expression analysis under different salt conditions showed that most of the ALDH genes have similar expression profiles in Arabidopsis and E. salsugineum, except for ALDH7B4 and ALDH10A8. In silico analysis of promoter regions of ALDH10A8 revealed different distributions of cis-elements in E. salsugineum and Arabidopsis.ConclusionsGenomic organization, copy number, sub-cellular localization and expression profiles of ALDH genes are conserved in Arabidopsis, E. parvulum and E. salsugineum. The different expression patterns of ALDH7B4 and ALDH10A8 in Arabidopsis and E. salsugineum suggest that E. salsugineum uses modified regulatory pathways, which may contribute to salinity tolerance.

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Regulation of human mitochondrial aldehyde dehydrogenase (ALDH-2) activity by electrophiles in vitro.

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