Molecular Evolution of the Aldo-keto Reductase Gene Superfamily

Seery, L.T.; Nestor, Padraig; Fitzgerald, Gerald A.

doi:10.1007/pl00006288

Cited by 29 publications

(20 citation statements)

References 44 publications

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“…We therefore investigated the possible induction of Akr1b8 expression -the structurally and functionally closest related protein (Seery et al 1998). Significantly, we found no indication for an expression of Akr1b8 in the vas deferens of neither knockout nor wild-type animals.…”

mentioning

confidence: 88%

“…Compensatory effects: Akr1b8 expression levels are not elevated in Akr1b7 knockout animals AKR1B8 (fibroblast growth factor induced protein-1) is the structurally and functionally closest related protein to AKR1B7 (Seery et al 1998). We therefore investigated whether Akr1b7-expressing organs show elevated expression levels of Akr1b8 mRNA by a compensatory mechanism.…”

Section: Akr1b7 Knockout Males Reveal Normal Spermatozoa Parametersmentioning

confidence: 99%

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AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

Baumann¹,

Davies²,

Peters³

et al. 2007

Reproduction

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AKR1B7 (aldo-keto reductase family 1, member 7; also known as mouse vas deferens protein) is a member of the AKR superfamily, and has been suggested to play a role in detoxifying processes on account of its preferred substrates, 4-hydroxynonenal and isocaproaldehyde. High levels of protein expression were found in the vas deferens and the adrenal gland, where sustained expression is dependent on androgen or ACTH respectively. Recently, a remarkable induction of AKR1B7 expression has been reported in the ovary following exogenous injections of LH. In the present study, we confirm this regulation physiologically during the estrous cycle, observing Akr1b7 expression to be restricted to the theca and stromal cells of the proestrus ovary. To further investigate the role of this detoxifying enzyme in both male and female reproduction, we generated knockout mice deficient in AKR1B7. Although AKR1B7 expression in the vas deferens is considerable and tightly regulated in the ovary of wild-type animals, homozygous mutant animals were found to be viable and no reproductive phenotype was observed. Ovarian follicle maturation and spermatozoa parameters remained normal in the absence of this protein. The determination of serum progesterone revealed an increase in hormone concentration in metestrus, while progesterone was found to be decreased in the estrus phase of the cycle in knockout females.

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confidence: 88%

Section: Akr1b7 Knockout Males Reveal Normal Spermatozoa Parametersmentioning

confidence: 99%

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

Baumann¹,

Davies²,

Peters³

et al. 2007

Reproduction

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“…The identification of AKRs in vertebrates, plants, protozoa, fungi, eubacteria, and archaebacteria suggests that this is an ancient superfamily of enzymes (3). Currently there are more than a hundred known AKR proteins classified into 12 families (4) (www.med.upenn.edu/akr).…”

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confidence: 99%

A cluster of eight hydroxysteroid dehydrogenase genes belonging to the aldo-keto reductase supergene family on mouse chromosome 13

Vergnes

Phan

Stolz

et al. 2003

Journal of Lipid Research

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A subclass of hydroxysteroid dehydrogenases (HSD) are NADP(H)-dependent oxidoreductases that belong to the aldo-keto reductase (AKR) superfamily. They are involved in prereceptor or intracrine steroid modulation, and also act as bile acid-binding proteins. The HSD family members characterized thus far in human and rat have a high degree of protein sequence similarity but exhibit distinct substrate specificity. Here we report the identification of nine murine AKR genes in a cluster on chromosome 13 by a combination of molecular cloning and in silico analysis of this region. These include four previously isolated mouse HSD genes (Akr1c18, Akr1c6, Akr1c12, Akr1c13), the more distantly related Akr1e1, and four novel HSD genes. These genes exhibit highly conserved exon/intron organization and protein sequence predictions indicate 75% amino acid similarity. The previously identified AKR protein active site residues are invariant among all nine proteins, but differences are observed in regions that have been implicated in determining substrate specificity. Differences also occur in tissue expression patterns, with expression of some genes restricted to specific tissues and others expressed at high levels in multiple tissues. Our findings dramatically expand the repertoire of AKR genes and identify unrecognized family members with potential roles in the regulation of steroid metabolism. -Vergnes, L., J. Phan, A. Stolz, and K. Reue. A cluster of eight hydroxysteroid dehydrogenase genes belonging to the aldo-keto reductase supergene family on mouse chromosome 13. J. Lipid Res. 2003. 44: 503-511.

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“…These enzymes, designated DKGR A and B, reduce 2,5-diketo-D-gluconic acid rather inefficiently, exhibiting K m values for substrate greater than 1 mM and catalytic efficiencies (k cat / K m ) less than 20 mM Ϫ1 s Ϫ1 . The enzymes are members of the aldo-keto reductase superfamily (14,30). Like almost all other aldo-keto reductases, the known DKGRs are specific for NADPH (14,30).…”

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confidence: 99%

“…The enzymes are members of the aldo-keto reductase superfamily (14,30). Like almost all other aldo-keto reductases, the known DKGRs are specific for NADPH (14,30). Recently, additional aldo-keto reductases that can convert 2,5-diketo-D-gluconic acid to 2-keto-L-gulonic acid have been isolated from Escherichia coli through a search of the genome sequence for homologues (40,41).…”

mentioning

confidence: 99%

DNA from Uncultured Organisms as a Source of 2,5-Diketo- d -Gluconic Acid Reductases

Eschenfeldt

Stols²,

Rosenbaum

et al. 2001

Appl Environ Microbiol

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Total DNA of a population of uncultured organisms was extracted from soil samples, and by using PCR methods, the genes encoding two different 2,5-diketo-D-gluconic acid reductases (DKGRs) were recovered. Degenerate PCR primers based on published sequence information gave internal gene fragments homologous to known DKGRs. Nested primers specific for the internal fragments were combined with random primers to amplify flanking gene fragments from the environmental DNA, and two hypothetical full-length genes were predicted from the combined sequences. Based on these predictions, specific primers were used to amplify the two complete genes in single PCRs. These genes were cloned and expressed in Escherichia coli. The purified gene products catalyzed the reduction of 2,5-diketo-D-gluconic acid to 2-keto-L-gulonic acid. Compared to previously described DKGRs isolated from Corynebacterium spp., these environmental reductases possessed some valuable properties. Both exhibited greater than 20-fold-higher k cat /K m values than those previously determined, primarily as a result of better binding of substrate. The K m values for the two new reductases were 57 and 67 M, versus 2 and 13 mM for the Corynebacterium enzymes. Both environmental DKGRs accepted NADH as well as NADPH as a cosubstrate; other DKGRs and most related aldo-keto reductases use only NADPH. In addition, one of the new reductases was more thermostable than known DKGRs.Interest in 2,5-diketo-D-gluconic acid reductases (DKGRs) is related to a new biotechnological process for the production of vitamin C (ascorbic acid) from glucose. Conversion of glucose to ascorbic acid is a complicated process that involves selective epimerization, oxidation, and lactonization reactions. The natural biosynthetic pathways are long and incorporate many energy-consuming reactions (8,21,38). The present commercial process for ascorbic acid production (the Reichstein process) couples a single biological step-the microbial oxidation of sorbitol to sorbose-with a subsequent, multistep, chemical conversion of blocked derivatives of sorbose to ascorbic acid (7,26). An alternative commercial process that has been proposed (2, 10, 34) consists of biological conversion of glucose to 2-keto-L-gulonic acid, which is then lactonized chemically to ascorbic acid (Fig. 1). The biological metabolism involved is simpler than that of natural biosynthetic routes and requires less metabolic energy (less ATP and NADPH). In this process, glucose is first converted to 2,5-diketo-D-gluconic acid by endogenous oxidases of a suitable bacterial strain, with molecular oxygen as the ultimate electron acceptor. 2,5-Diketo-D-gluconic acid is then reduced enzymatically to 2-keto-L-gulonic acid by a heterologous DKGR expressed in the production strain. The NADPH required for the reaction is generated by the metabolism of the host strain. Finally, chemical lactonization of 2-keto-L-gulonic acid generates ascorbic acid.To date, only two DKGRs have been extensively characterized, both isolated from a species of Co...

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Molecular Evolution of the Aldo-keto Reductase Gene Superfamily

Cited by 29 publications

References 44 publications

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success

A cluster of eight hydroxysteroid dehydrogenase genes belonging to the aldo-keto reductase supergene family on mouse chromosome 13

DNA from Uncultured Organisms as a Source of 2,5-Diketo- d -Gluconic Acid Reductases

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