Some properties and a suggested reclassification of mevaldate reductase

Beedle, Alan S.; Rees, Huw H.; Goodwin, T. W.

doi:10.1042/bj1390205

Cited by 17 publications

(5 citation statements)

References 19 publications

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“…Multiple alternatively spliced transcript variants of this gene exist, all encoding the same protein. AKR1A1 is also known as mevaldate reductase and it reduces DL-glyceraldehyde to glycerol [51, 52] . Further, it has been shown to play an important role in ascorbic acid biosynthesis in mammalian species.…”

Section: Metabolism Of Carbonylsmentioning

confidence: 99%

Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls

Singh

Kapoor

Bhatnagar

2015

Chemico-Biological Interactions

130

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Extensive research has shown that increased production of reactive oxygen species (ROS) results in tissue injury under a variety of pathological conditions and chronic degenerative diseases. While ROS are highly reactive and can incite significant injury, polyunsaturated lipids in membranes and lipoproteins are their main targets. ROS-triggered lipid peroxidation reactions generate a range of reactive carbonyl species (RCS), and these RCS spread and amplify ROS-related injury. Several RCS generated in oxidizing lipids, such as 4-hydroxy trans-2-nonenal (HNE), 4-oxo-2-(E)-nonenal (ONE), acrolein, malondialdehyde (MDA) and phospholipid aldehydes have been shown to be produced under conditions of oxidative stress and contribute to tissue injury and dysfunction by depleting glutathione and other reductants leading to the modification of proteins, lipids, and DNA. To prevent tissue injury, these RCS are metabolized by several oxidoreductases, including members of the aldo-keto reductase (AKR) superfamily, aldehyde dehydrogenases (ALDHs), and alcohol dehydrogenases (ADHs). Metabolism via these enzymes results in RCS inactivation and detoxification, although under some conditions, it can also lead to the generation of signaling molecules that trigger adaptive responses. Metabolic transformation and detoxification of RCS by oxidoreductases prevent indiscriminate ROS toxicity, while at the same time, preserving ROS signaling. A better understanding of RCS metabolism by oxidoreductases could lead to the development of novel therapeutic interventions to decrease oxidative injury in several disease states and to enhance resistance to ROS-induced toxicity.

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Section: Metabolism Of Carbonylsmentioning

confidence: 99%

Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls

Singh

Kapoor

Bhatnagar

2015

Chemico-Biological Interactions

130

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“… 43 AKR1A1 is an enzyme of intermediary metabolism that converts d , l -glyceraldehyde to glycerol for triglyceride biosynthesis and also converts melvadate (aldehyde precursor of the primary alcohol in mevalonic acid) to mevaloinc acid for cholesterol biosynthesis. 44 AKR1A1 is ubiquitously expressed in human tissues and can therefore be coexpressed with induced P4501A1/1B1 and epoxide hydrolase. Recombinant AKR1A1 has the highest catalytic efficiency ( k cat / K m ) for the oxidation of B[ a ]P-7,8- trans -dihydrodiol and it is stereospecific for (−)-7 R ,8 R - trans -dihydrodiol, the major stereoisomer formed metabolically.…”

Section: Human Aldo-keto Reductases and Pah Trans mentioning

confidence: 99%

“…These are AKR1A1 (aldehyde reductase) and AKR1C1–AKR1C4 (hydroxysteroid dehydrogenases) . AKR1A1 is an enzyme of intermediary metabolism that converts d , l -glyceraldehyde to glycerol for triglyceride biosynthesis and also converts melvadate (aldehyde precursor of the primary alcohol in mevalonic acid) to mevaloinc acid for cholesterol biosynthesis . AKR1A1 is ubiquitously expressed in human tissues and can therefore be coexpressed with induced P4501A1/1B1 and epoxide hydrolase.…”

Section: Human Aldo-keto Reductases and Pah Trans-dihydrodiol Oxidationmentioning

confidence: 99%

Human Aldo-Keto Reductases and the Metabolic Activation of Polycyclic Aromatic Hydrocarbons

Penning

2014

Chem. Res. Toxicol.

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Aldo-keto reductases (AKRs) are promiscuous NAD(P)(H) dependent oxidoreductases implicated in the metabolic activation of polycyclic aromatic hydrocarbons (PAH). These enzymes catalyze the oxidation of non-K-region trans-dihydrodiols to the corresponding o-quinones with the concomitant production of reactive oxygen species (ROS). The PAH o-quinones are Michael acceptors and can form adducts but are also redox-active and enter into futile redox cycles to amplify ROS formation. Evidence exists to support this metabolic pathway in humans. The human recombinant AKR1A1 and AKR1C1–AKR1C4 enzymes all catalyze the oxidation of PAH trans-dihydrodiols to PAH o-quinones. Many human AKRs also catalyze the NADPH-dependent reduction of the o-quinone products to air-sensitive catechols, exacerbating ROS formation. Moreover, this pathway of PAH activation occurs in a panel of human lung cell lines, resulting in the production of ROS and oxidative DNA damage in the form of 8-oxo-2′-deoxyguanosine. Using stable-isotope dilution liquid chromatography tandem mass spectrometry, this pathway of benzo[a]pyrene (B[a]P) metabolism was found to contribute equally with the diol-epoxide pathway to the activation of this human carcinogen in human lung cells. Evaluation of the mutagenicity of anti-B[a]P-diol epoxide with B[a]P-7,8-dione on p53 showed that the o-quinone produced by AKRs was the more potent mutagen, provided that it was permitted to redox cycle, and that the mutations observed were G to T transversions, reminiscent of those observed in human lung cancer. It is concluded that there is sufficient evidence to support the role of human AKRs in the metabolic activation of PAH in human lung cell lines and that they may contribute to the causation of human lung cancer.

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“…26 A similar experiment was performed using pig liver and rat liver ''mevaldate reductase'' that show opposed hydride addition to the 5Re face of 10, 27 but this enzyme unspecifically reduces both (R)-and (S)-mevaldate 28 and was later reclassified as an aldehyde reductase that is not involved in the mevalonate pathway. 29 In contrast to the ''mevaldate reductase'', the HMG-CoA reductase is highly stereospecific with respect to the substrate's 3-positions and accepts only (3S)-3 or (3S)-9, whereas the enzyme is flexible for the stereochemistry of the thiohemiacetal and reacts on both diastereomers of (3S,5RS)-9. 30,31 This observation can be explained by thiol elimination from the diastereomeric mixture of 9 to yield mevaldic acid (10) as a single stereoisomer, but it has long been questioned if 10 is a true pathway intermediate, because 1 mevaldic acid was not observed as a free intermediate, 14,24,32 2 it is not or only very slowly converted into 4 by HMG-CoA reductase, 31,32 3 addition of an excess of 9 to an enzyme reaction with [2-14 C]-3 failed to reduce incorporation of radioactivity into 4, and barely no radioactivity was detected in re-isolated 9, 32 4 the enzyme reaction on HMG-CoA is not blocked by aldehyde scavengers such as semicarbazide.…”

Section: The Stereochemical Course Of the Mevalonate Pathwaymentioning

confidence: 99%