Disease relevance of ALD6

• In addition, screening of the deletion strains for hypersensitivity to SFK2 yielded ZWF1, encoding glucose-6-phosphate dehydrogenase, which has been shown to play an overlapping role with Ald6p in NADPH production [1].
• The full-length DNAs for two Saccharomyces cerevisiae aldehyde dehydrogenase (ALDH) genes were cloned and expressed in Escherichia coli [2].
• To confirm the correlation between inhibition of class 3 ALDH and reduction of cell proliferation, we exposed hepatoma cells to antisense oligonucleotides (ODNs) against ALDH3 [3].

High impact information on ALD6

• This screen yielded a number of genes not previously implicated in salt stress, including ALD6, which encodes an NADP(+)-dependent aldehyde dehydrogenase, and UTR1, which encodes an NAD+ kinase [1].
• Measurements of NADP(H) levels revealed that NADPH may not be rapidly utilized in the zwf1Delta ald6Delta mutant in glucose medium, perhaps because of a reduction in fatty acid synthesis associated with loss of Ald6p [4].
• We performed a differential screen on wild-type and Deltaatg7/apg7 autophagy-deficient cells and found that cytosolic acetaldehyde dehydrogenase (Ald6p) decreased under nitrogen starvation [5].
• Ald6p enzymatic activity may be disadvantageous for survival under nitrogen starvation; therefore, yeast cells may preferentially eliminate Ald6p via autophagy [5].
• Using pulse-chase and subcellular fractionation, we have also demonstrated that Ald6p was preferentially transported to vacuoles via autophagosomes [5].

Chemical compound and disease context of ALD6

• We demonstrated previously that restoring endogenous lipid peroxidation in hepatoma cells by enriching them with arachidonic acid causes a decrease of mRNA, protein and enzyme activity of ALDH3 and that this decrease reduces cell growth and/or causes cell death, depending on basal class 3 ALDH activity [3].

Biological context of ALD6

• We found that overexpression of the ALD6 gene coding for cytosolic acetaldehyde dehydrogenase, which utilizes NADP(+) as its cofactor, restores the Met(+) phenotype of the zwf1Delta strain [6].
• The absence of Ald6p was compensated by the mitochondrial isoforms and this involves the transcriptional activation of ALD4 [7].
• The gene is situated on the right arm of chromosome XV, bears the systematic name YOR374w and the deduced product shows significant homology to other members of the S. cerevisiae aldehyde dehydrogenase (ALDH) family [8].
• Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae [5].
• MBT sulfoxide, from oxidation of MBT with magnesium monoperoxyphthalate in water, is one of the most potent inhibitors known for mALDH and yeast ALDH in vitro (IC50 0.08-0.09 microM) [9].

Anatomical context of ALD6

• More of chimeric ALDH1 precursor was imported into mitochondria compared to its parent precursor ALDH1 [10].
• ATE inhibited ALDH1 activity in ALDH1-transfected L1210 T cells resistant to hydroperoxycyclophosphamide (HCPA) and inhibited growth synergistically in the presence of HCPA [11].
• Intact antibiotics which contain the MTT moiety did not cause an inhibition of yeast ALDH unless the antibiotics were first treated with potassium hydroxide and then incubated with microsomes [12].
• ALDH-mediated oxidation of a synthetic standard of the hydroxy/aldehyde derivative of MA resulted in formation of this new metabolite, which was also a major product formed by rat hepatocytes incubated with MA [13].
• Previous studies by gene disrupted in our laboratory revealed that the Saccharomyces cerevisiae cytosol ALDH1 played an important role in ethanol metabolism as did the class 2 mitochondrial enzyme [14].

Associations of ALD6 with chemical compounds

• The ALD6 gene product is indispensable for providing NADPH in yeast cells lacking glucose-6-phosphate dehydrogenase activity [6].
• The deletion of ALD6 and ALD5 decreased acetate formation in both strains, demonstrating for the first time that the mitochondrial Ald5p isoform is involved in the biosynthesis of acetate during anaerobic growth on glucose [7].
• Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae: role of the cytosolic Mg(2+) and mitochondrial K(+) acetaldehyde dehydrogenases Ald6p and Ald4p in acetate formation during alcoholic fermentation [15].
• Growth on glucose was not affected in the mutants lacking ALD7 (in contrast to the behaviour of ald6 mutants), whereas growth on ethanol was severely impaired [8].
• This approach was found to enrich the analysis since GND1, ZWF1 and ALD6, encoding the most important enzymes for regeneration of NADPH under anaerobic conditions, were down-regulated together with eight other genes encoding NADP(H)-dependent enzymes [16].

Regulatory relationships of ALD6

• Using quantitative PCR analysis, ALD6 was found to be the most highly expressed among the ALD2 to ALD6 genes [17].

Other interactions of ALD6

• Another multicopy suppressor identified in our screen, the ZMS1 gene encoding a putative transcription factor, regulates the level of ALD6 expression [6].
• Deletion of the aldehyde dehydrogenase gene, ALD6, in wild-type and GPD2 overexpressing strains (GPD2-OP) decreased acetic acid production by three- and four-fold, respectively [18].
• Although no significant differences in the transcriptional levels of ALD2 to ALD6 encoding acetaldehyde dehydrogenase (ALD) between 2DGR19 and NCYC1245 were observed, ALD activity in 2DGR19 was lower [17].
• Of the seven proteins that were identified, two were previously not known to be under HOG pathway control: Ald6p, an isoform of aldehyde dehydrogenase and Dak1p, a putative dihydroxyacetone kinase [19].
• Neither ALDH5 nor the other ALDH-like proteins identified from the genomic sequence contributed to the in vitro oxidation of acetaldehyde [2].

Analytical, diagnostic and therapeutic context of ALD6

• Identification of Ald6p as the target of a class of small-molecule suppressors of FK506 and their use in network dissection [1].
• Activity staining of isoelectric focusing gels showed that cytosolic ALDH1 contributed 30 to 70% of the overall activity, depending on the cofactor used, while mitochondrial ALDH2 contributed the rest [2].
• Two methods were employed to detect autophagy: a biochemical approach based on depletion of the protein acetaldehyde dehydrogenase Ald6p and a morphological strategy consisting of visualization of autophagic bodies and autophagosomes, which are intermediate vesicles in the autophagic process, by transmission electron microscopy [20].
• Using thin-layer chromatography and high-pressure liquid chromatography techniques, a product with polarity intermediate between that of the dialdehyde trans,trans-muconaldehyde and the diacid trans,trans-muconic acid (MA) was detected in the ALDH incubation mixtures [21].

References