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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: Unpurified aldophosphamide and the analogs prepared from 6-methyl- and 5,5-dimethylcyclophosphamides were substrates for nicotinamide adenine dinucleotide-requiring enzymes, whereas incubation of 4-hydroxy-4-methylcycloph phosphamide in an unfractionated incubation mixture with liver soluble enzymes did not cause reduced nicotinamidine din nucleotide production.
Abstract: The initial metabolic products of cyclophosphamide (4-hydroxy-cyclophosphamide and aldophosphamide) were prepared biologically in unpurified form. Their toxicity to tumor cells were tested by bioassay techniques and in cell culture, and the deactivation abilities of various tissue-soluble fractions were quantitated. Liver and kidney cytosol effectively deactivated the primary metabolites, whereas cytosols from gastrointestinal tract mucosa, Walker ascites tumor, and spleen were less efficient. When [14C]cyclophosphamide was activated and incubated with liver cytosol, 34% of all radioactivity was identified as carboxyphosphamide, by mass spectrometry of the methyl ester. Measurement of alcohol dehydrogenase (EC 1.1.1.1) and aldehyde dehydrogenase (EC 1.2.1.3) activities by reduced nicotinamide adenine dinucleotide production revealed a qualitative correspondence between aldehyde dehydrogenase activity and deactivation ability. Unpurified aldophosphamide and the analogs prepared from 6-methyl- and 5,5-dimethylcyclophosphamides were substrates for nicotinamide adenine dinucleotide-requiring enzymes, whereas incubation of 4-hydroxy-4-methylcyclophosphamide in an unfractionated incubation mixture with liver soluble enzymes did not cause reduced nicotinamide adenine dinucleotide production. Activated 4-methylcyclophosphamide was deactivated by liver cytosol to the same extent as phosphoramide mustard (dose reduction factors, 2.2 and 2.7, respectively); that for liver cytosol and activated cyclophosphamide was 49.1. It was concluded that the selective action of cyclophosphamide when compared to other nitrogen mustards is largely dependent on the balance between the enzymatic production of nontoxic metabolites (principally carboxyphosphamide) and chemical decomposition of aldophosphamide to the ultimate alkylating agent (phosphoramide mustard).

93 citations

Journal ArticleDOI
TL;DR: It is demonstrated that NBP was well absorbed and extensively metabolized by multiple enzymes to various metabolites prior to urinary excretion, and can undergo β-oxidation to yield phthalide-3-acetic acid in rat liver homogenate.
Abstract: 3-n-Butylphthalide (NBP) is a cardiovascular drug currently used for the treatment of cerebral ischemia. The present study aims to investigate the metabolism, pharmacokinetics, and excretion of NBP in humans and identify the enzymes responsible for the formation of major metabolites. NBP underwent extensive metabolism after an oral administration of 200 mg NBP and 23 metabolites were identified in human plasma and urine. Principal metabolic pathways included hydroxylation on alkyl side chain, particularly at 3-, ω-1-, and ω-carbons, and further oxidation and conjugation. Approximately 81.6% of the dose was recovered in urine, mainly as NBP-11-oic acid (M5-2) and glucuronide conjugates of M5-2 and mono-hydroxylated products. 10-Keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), and M5-2 were the major circulating metabolites, wherein the areas under the curve values were 1.6-, 2.9-, 10.3-, and 4.1-fold higher than that of NBP. Reference standards of these four metabolites were obtained through microbial biotransformation by Cunninghamella blakesleana. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, especially CYP3A4, 2E1, and 1A2, were involved in the formation of M3-1, M3-2, and 11-hydroxy-NBP. Using M3-2 and 11-hydroxy-NBP as substrates, human subcellular fractions experiments revealed that P450, alcohol dehydrogenase, and aldehyde dehydrogenase catalyzed the generation of M2 and M5-2. Formation of M5-2 was much faster than that of M2, and M5-2 can undergo β-oxidation to yield phthalide-3-acetic acid in rat liver homogenate. Overall, our study demonstrated that NBP was well absorbed and extensively metabolized by multiple enzymes to various metabolites prior to urinary excretion.

93 citations

Journal ArticleDOI
TL;DR: The strikingly different responses to PB administration between the various mRNA species in each of the genotypes suggest that the regulation of specific gene expression by PB may involve multiple pathways.

93 citations

Journal ArticleDOI
TL;DR: Although the ald1disruptant (ald1Δ) strain still had the ability to grow on n-hexadecane to some extent, its aldehyde dehydrogenase activity toward n-tetradecanal was reduced to half the level of the wild-type strain.
Abstract: The microbial degradation of petrochemicals has attracted much interest due to its potential for the development of bioremediation processes for oil spill environments, as well as for the production of fine and moderately priced chemicals. Acinetobacter spp. are known to utilize long-chain n-alkanes and to accumulate intracellular wax esters (8), which are enveloped by a single membrane (25) and serve as cell reserves. The composition of intracellular wax esters as to carbon chain length or the degree of unsaturation can be controlled by altering the growth substrate or temperature (5, 16, 17). Therefore, Acinetobacter spp. are expected to have great potential for industrial utilization. Recently, the hydroxylation of n-alkanes, involving rubredoxin and rubredoxin reductase, has been found to be indispensable for n-alkane degradation by Acinetobacter sp. strain ADP1 (9, 19). From these facts, together with this evidence of the existence of a membrane-bound aldehyde dehydrogenase (2, 12, 27), the main pathway of n-alkane oxidation to acyl coenzyme A (acyl-CoA) via carboxylic acid is assumed to proceed through the membrane-bound enzymes in these Acinetobacter strains. This pathway is analogous to that confirmed in the alkBAC operon of Pseudomonas oleovorans (29), although the genetic organization of the alk genes is different from that in Acinetobacter spp. (9, 19). On the other hand, a variety of enzymes that catalyze the oxidation of n-alkanes and related compounds have also been found in soluble fractions of cell extracts of Acinetobacter spp. (1, 11, 7, 30), but their physiological significance in n-alkane metabolism has not been confirmed. In this study, we found a long-chain aldehyde dehydrogenase, Ald1, in a soluble fraction of Acinetobacter sp. strain M-1 cells. In order to determine the physiological role of Ald1 in Acinetobacter sp. strain M-1, we cloned the Ald1-encoding gene, ald1, and expressed and characterized the recombinant enzyme. From these results together with those of investigation of an ald1 disruptant strain, Ald1 was confirmed to play a significant role in n-alkane utilization, especially in intracellular wax ester synthesis.

93 citations

Journal ArticleDOI
TL;DR: The crystal structure of retinal dehydrogenase type II cocrystallized with nicotinamide adenine dinucleotide (NAD) has been determined and it appears to utilize a disordered loop in the substrate access channel to discriminate between retinaldehyde and short-chain aldehydes.
Abstract: Retinoic acid, a hormonally active form of vitamin A, is produced in vivo in a two step process: retinol is oxidized to retinal and retinal is oxidized to retinoic acid. Retinal dehydrogenase type II (RalDH2) catalyzes this last step in the production of retinoic acid in the early embryo, possibly producing this putative morphogen to initiate pattern formation. The enzyme is also found in the adult animal, where it is expressed in the testis, lung, and brain among other tissues. The crystal structure of retinal dehydrogenase type II cocrystallized with nicotinamide adenine dinucleotide (NAD) has been determined at 2.7 A resolution. The structure was solved by molecular replacement using the crystal structure of a mitochondrial aldehyde dehydrogenase (ALDH2) as a model. Unlike what has been described for the structures of two aldehyde dehydrogenases involved in the metabolism of acetaldehyde, the substrate access channel is not a preformed cavity into which acetaldehyde can readily diffuse. Retinal dehydr...

92 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023260
2022192
202170
202081
201980
201895