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Extramitochondrial Assembly of Mitochondrial Targeting Signal Disrupted Mitochondrial Enzyme Aldehyde Dehydrogenase.

ABSTRACT: Supramolecular assembly of metabolic enzymes has been studied both in vivo and in vitro for nearly a decade. Experimental evidence has suggested a close relationship between enzymatic activity and enzyme assembly/disassembly. However, most cases were studied with the cytosolic enzymes. Here, I report the evidence for a mitochondrial enzyme with its ability in forming visible intracellular structures. By removing the mitochondrial targeting sequence, yeast mitochondrial enzyme aldehyde dehydrogenase (Ald4p) exhibits reversible supramolecular assembly in the cytoplasm, thus creating a useful system for further characterization of the regulatory factors that modulate the assembly/disassembly of this mitochondrial enzyme.

SUBMITTER: Noree C

PROVIDER: S-EPMC5906672 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Extramitochondrial Assembly of Mitochondrial Targeting Signal Disrupted Mitochondrial Enzyme Aldehyde Dehydrogenase.

Noree Chalongrat C

Scientific reports 20180418 1

Supramolecular assembly of metabolic enzymes has been studied both in vivo and in vitro for nearly a decade. Experimental evidence has suggested a close relationship between enzymatic activity and enzyme assembly/disassembly. However, most cases were studied with the cytosolic enzymes. Here, I report the evidence for a mitochondrial enzyme with its ability in forming visible intracellular structures. By removing the mitochondrial targeting sequence, yeast mitochondrial enzyme aldehyde dehydrogen ...[more]

PMID: 29670139

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AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells.

Project description:Most ethanol is broken down in the liver in two steps by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) enzymes, which metabolize down ethanol into acetaldehyde and then acetate. Some individuals from the Asian population who carry a mutation in the aldehyde dehydrogenase gene (ALDH2*2) cannot metabolize acetaldehyde as efficiently, producing strong effects, including facial flushing, dizziness, hypotension, and palpitations. This results in an aversion to alcohol intake and protection against alcoholism. The large prevalence of this mutation in the human population strongly suggests that modulation of ALDH2 expression by genetic technologies could result in a similar phenotype. scAAV2 vectors encoding ALDH2 small hairpin RNA (shRNA) were utilized to validate this hypothesis by silencing ALDH2 gene expression in human cell lines. Human cell lines HEK-293 and HepG2 were transduced with scAAV2/shRNA, showing a reduction in ALDH2 RNA and protein expression with the two viral concentration assayed (1 × 104 and 1 × 105 vg/cell) at two different time points. In both cell lines, ALDH2 RNA levels were reduced by 90% and protein expression was inhibited by 90% and 52%, respectively, 5 days post infection. Transduced HepG2 VL17A cells (ADH+) exposed to ethanol resulted in a 50% increase in acetaldehyde levels. These results suggest that gene therapy could be a useful tool for the treatment of alcoholism by knocking down ALDH2 expression using shRNA technology delivered by AAV vectors.

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Targeting aldehyde dehydrogenase for prostate cancer therapies.

Project description:Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 - 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.

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Partially irreversible inactivation of mitochondrial aldehyde dehydrogenase by nitroglycerin.

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Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer.

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Robust assembly of the aldehyde dehydrogenase Ald4p in Saccharomyces cerevisiae.

Project description:As part of our studies of yeast aldehyde dehydrogenase (Ald4p) assembly, we identified a population of transformants (SWORD strain) that show more robust filament formation of GFP-tagged Ald4p (Ald4p-GFP) than that of a wild type ALD4::GFP strain. Sequencing of the ALD4 gene in the SWORD strain showed that the increased assembly was not due to changes to the ALD4 coding sequence, suggesting that a second mutation site was altering Ald4p assembly. Using short-read whole-genome sequencing, we identified spontaneous mutations in FLO9. Introduction of the SWORD allele of FLO9 into a wild-type ALD4::GFP yeast strain revealed that the changes to FLO9 were a contributor to the increased length of Ald4p-GFP filaments we observe in the SWORD strain and that this effect was not due to an increase in Ald4p protein levels. However, the expression of the FLO9 (SWORD) allele in wild-type yeast did not fully recapitulate the length control defect we observed in SWORD strains, arguing that there are additional genes contributing to the filament length phenotype. For our future work, this FLO9 from SWORD will be tested whether it could show global effect, promoting the assembly of some other filament-forming enzymes.

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Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications.

Project description:Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.

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The removal of cytosolic-type aldehyde dehydrogenase from preparations of sheep liver mitochondrial aldehyde dehydrogenase and the unusual properties of the purified mitochondrial enzyme in assays.

Project description:The pI approximately 5.2 isoenzymes of mitochondrial aldehyde dehydrogenase were separated from the other isoenzymes by pH-gradient chromatography on DEAE-Sephacel. The pI approximately 5.2 material is immunologically identical with cytosolic aldehyde dehydrogenase. It also shows sensitivity to 20 microM-disulfiram and insensitivity to 4M-urea in assays. These and other criteria seem to establish that the material is identical with the cytosolic enzyme. Mitochondrial enzyme that had been purified to remove pI approximately 5.2 isoenzymes shows concentration-dependent lag phases in assays. These effects are possibly due to the slow establishment of equilibrium between tetramer and either dimers or monomers, with the dissociated species being intrinsically more active than the tetramer.

| S-EPMC1144409 | biostudies-other

The plant pathogen enzyme AldC is a long-chain aliphatic aldehyde dehydrogenase.

Project description:Aldehyde dehydrogenases are versatile enzymes that serve a range of biochemical functions. Although traditionally considered metabolic housekeeping enzymes because of their ability to detoxify reactive aldehydes, like those generated from lipid peroxidation damage, the contributions of these enzymes to other biological processes are widespread. For example, the plant pathogen Pseudomonas syringae strain PtoDC3000 uses an indole-3-acetaldehyde dehydrogenase to synthesize the phytohormone indole-3-acetic acid to elude host responses. Here we investigate the biochemical function of AldC from PtoDC3000. Analysis of the substrate profile of AldC suggests that this enzyme functions as a long-chain aliphatic aldehyde dehydrogenase. The 2.5 Å resolution X-ray crystal of the AldC C291A mutant in a dead-end complex with octanal and NAD+ reveals an apolar binding site primed for aliphatic aldehyde substrate recognition. Functional characterization of site-directed mutants targeting the substrate- and NAD(H)-binding sites identifies key residues in the active site for ligand interactions, including those in the "aromatic box" that define the aldehyde-binding site. Overall, this study provides molecular insight for understanding the evolution of the prokaryotic aldehyde dehydrogenase superfamily and their diversity of function.

| S-EPMC7535917 | biostudies-literature

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