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Aldehyde dehydrogenase
About: Aldehyde dehydrogenase is a research topic. Over the lifetime, 3365 publications have been published within this topic receiving 107683 citations.
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TL;DR: Activity with betaine aldehyde was considerably higher than that with 4-aminobutyraldehyde, the best known substrate, and human E3 isozyme and betaineAldehyde dehydrogenase are the same enzyme.
74 citations
TL;DR: Ex vivo sensitivity of murine pluripotent hematopoietic stem cells and myeloid progenitor cells to 4-hydroperoxycyclophosphamide, ASTA Z 7557, phosphoramide mustard, acrolein, melphalan, and cis-platinum was determined and the phenotypic basis for the relative insensitivity of CFU-S to oxazaphosphorines is the aldehyde dehydrogenase activity contained by these cells
73 citations
TL;DR: It is concluded that both dehydrogenases are involved in the metabolism of natural compounds and due to their broad substrate specificity fortuitously also play a role inThe metabolism of the xenobiotic compounds 1,2-dichloroethane and 2-chloroethanol.
Abstract: SUMMARY: An inducible methanol dehydrogenase showing high activity with 2-chloroethanol was purified from 2-chloroethanol-grown cells of the 1, 2-dichloroethane utilizing bacterium Xanthobacter autotrophicus GJ10. The enzyme consisted of a 60 kDa polypeptide that was associated with a 10 kDa polypeptide and contained pyrrolo-quinoline quinone (PQQ) as a prosthetic group. Chloroethanol-grown cells of strain GJ10 also contained an inducible NAD-dependent chloroacetaldehyde dehydrogenase. Its involvement in the metabolism of 2-chloroethanol was inferred from its absence in a 2-chloroethanol non-utilizing mutant. Three different isolates of X. autotrophicus that do not utilize 2-chloroethanol for growth produced chloroethanol dehydrogenase and chloroacetaldehyde dehydrogenase activities at similar levels as strain GJ10. It is concluded that both dehydrogenases are involved in the metabolism of natural compounds and due to their broad substrate specificity fortuitously also play a role in the metabolism of the xenobiotic compounds 1,2-dichloroethane and 2-chloroethanol.
73 citations
73 citations
TL;DR: Results indicate that metabolites of disulfiram can covalently inactivate P-gp, and suggest covalent modification of drug transporters could be a useful approach for inhibiting their activities during chemotherapy.
Abstract: The human multidrug resistance P-glycoprotein (P-gp) uses ATP to transport a wide variety of structurally unrelated cytotoxic compounds out of the cell. The relatively high expression of P-gp in organs such as the intestine, kidney, blood-brain/testes barrier and in some tumor cells can compromise chemotherapy treatments for patients with cancer or AIDS/HIV. It has been difficult to inhibit P-gp during chemotherapy with noncovalent inhibitors because the relatively high levels of inhibitors have severe side effects. An alternative approach to inhibit P-gp would be to covalently modify cysteine residues within the NBDs. In this study, we tested whether metabolites of disulfiram, a drug currently used to treat chronic alcoholism, could inhibit P-gp. We show that the disulfiram metabolites, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the verapamil-stimulated ATPase activity of P-gp with IC50 values (concentrations that result in 50% inhibition of activity) of 9 and 4.8 microM, respectively. Similarly, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the activity of aldehyde dehydrogenase with IC50 values of 3.2 and 1.7 microM, respectively. Inhibition of P-gp by the metabolites was not reversed by addition of the reducing compound, dithiothreitol. We then determined which endogenous cysteine residue was responsible for inhibiting P-gp activity after exposure to the disulfiram metabolites. Treatment of P-gp mutants containing a single cysteine residue showed that inactivation was primarily due to modification of Cys1074 in NBD2. These results indicate that metabolites of disulfiram can covalently inactivate P-gp. Covalent modification of drug transporters could be a useful approach for inhibiting their activities during chemotherapy.
73 citations