Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An apparent conservative mutation, Leu to Val, at the second residue of the rat liver mitochondrial aldehyde dehydrogenase (ALDH) presequence resulted in a precursor protein that was not imported into mitochondria. Additional mutants were made to substitute various amino acids with nonpolar side chains for Leu2. The Ile, Phe, and Trp mutants were imported to an extent similar to that of the native precursor, but the Ala mutant was imported only about one-fourth as well. It was shown that the N-terminal methionine was removed from the L2V mutant in a reaction catalyzed by methionine aminopeptidase. The N-terminal methionine of native pALDH and the other mutant presequences was blocked, presumably by acetylation. Because of the difference in co-translational modification, the L2V mutant sustained a significant loss in the available hydrophobic surface of the presequence. Import competence was restored to the L2V mutant when it was translated using a system that did not remove Met1. The removal of an Arg-Gly-Pro helix linker segment (residues 11-14) from the L2V mutant, which shifted three leucine residues toward the N-terminus, also restored import competence. These results lead to the conclusion that a minimum amount of hydrophobic surface area near the N-termini of mitochondrial presequences is an essential property to determine their ability to be imported. As a result, both electrostatic and hydrophobic components must be considered when trying to understand the interactions between precursor proteins and proteins of the mitochondrial import apparatus.
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PMID:The loss in hydrophobic surface area resulting from a Leu to Val mutation at the N-terminus of the aldehyde dehydrogenase presequence prevents import of the protein into mitochondria. 1021 35

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
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PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Vitamin D signaling in mammary cancer stem cells (MCSCs), which are implicated in the initiation and progression of breast cancer, is poorly understood. In this study, we examined vitamin D signaling in mammospheres which are enriched in MCSCs from established breast cancer cell lines. Breast cancer cells positive for aldehyde dehydrogenase (ALDH(+)) had increased ability to form mammospheres compared to ALDH(-) cells. These mammospheres expressed MCSC-specific markers and generated transplantable xenografts in nude mice. Vitamin D receptor (VDR) was significantly down-regulated in mammospheres, as well as in ALDH(+) breast cancer cells. TN aggressive human breast tumors as well as transplantable xenografts obtained from SKBR3 expressed significantly lower levels of VDR but higher levels of CD44 expression. Snail was up-regulated in mammospheres isolated from breast cancer cells. Inhibition of VDR expression by siRNA led to a significant change in key EMT-specific transcription factors and increased the ability of these cells to form mammospheres. On the other hand, over-expression of VDR led to a down-regulation of Snail but increased expression of E-cad and significantly compromised the ability of cells to form mammospheres. Mammospheres were relatively insensitive to treatment with 1,25-dihydroxyvitamin D (1,25D), the active form of vitamin D, compared to more differentiated cancer cells grown in presence of serum. Treatment of H-Ras transformed HMLE(HRas) cells with DETA NONOate, a nitric oxide (NO)-donor led to induction of MAP-kinase phosphatase -1 (MKP-1) and dephosphorylation of ERK1/2 in the mammospheres. Combined treatment of these cells with 1,25D and a low-concentration of DETA NONOate led to a significant decrease in the overall size of mammospheres and reduced tumor volume in nude mice. Our findings therefore, suggest that combination therapy using 1,25D with drugs specifically targeting key survival pathways in MCSCs warrant testing in prospective clinical trial for treatment of aggressive breast cancer.
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PMID:Down-regulation of vitamin D receptor in mammospheres: implications for vitamin D resistance in breast cancer and potential for combination therapy. 2334 35