Structural comparisons lead to the definition of a new superfamily of NAD(P)(H)-accepting oxidoreductases: the single-domain reductases/epimerases/dehydrogenases (the ‘RED’ family)

Labesse, Gilles; Vidal-Cros, Anne; Chomilier, Jacques; Gaudry, Michel; Mornon, Jean‐Paul

doi:10.1042/bj3040095

Cited by 73 publications

(62 citation statements)

References 18 publications

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“…The substrates required to test this suggestion are not currently available and would need to be chemically synthesized. By sequence similarity, BAN is most closely related to DFR, and both are members of the Reductase Epimerase Dehydrogenase family of proteins that include epimerases (Labesse et al, 1994;Jornvall et al, 1995). Potentially, BAN could be an enzyme that epimerizes the 3-OH group, either at the dihydroquercetin or leucocyanidin step.…”

Section: Discussionmentioning

confidence: 99%

Identification and Biochemical Characterization of Mutants in the Proanthocyanidin Pathway in Arabidopsis

et al. 2002

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Proanthocyanidin (PA), or condensed tannin, is a polymeric flavanol that accumulates in a number of tissues in a wide variety of plants. In Arabidopsis, we found that PA precursors (detected histochemically using OsO 4 ) accumulate in the endothelial cell layer of the seed coat from the two-terminal cell stage of embryo development onwards. To understand how PA is made, we screened mature seed pools of T-DNA-tagged Arabidopsis lines to identify mutants defective in the synthesis of PA and found six tds (tannin-deficient seed) complementation groups defective in PA synthesis. Mutations in these loci disrupt the amount (tds1, tds2, tds3, tds5, and tds6) or location and amount of PA (tds4) in the endothelial cell layer. The PA intermediate epicatechin has been identified in wild type and mutants tds1, tds2, tds3, and tds5 (which do not produce PA) and tds6 (6% of wild-type PA), whereas tds4 (2% of wild-type PA) produces an unidentified dimethylaminocinnamaldehyde-reacting compound, indicating that the mutations may be acting on genes beyond leucoanthocyanidin reductase, the first enzymatic reduction step dedicated to PA synthesis. Two other mutants were identified, an allele of tt7, which has a spotted pattern of PA deposition and produces only 8% of the wild-type level of type PA as propelargonidin, and an allele of tt8 producing no PA. Spotted patterns of PA deposition observed in seed of mutants tds4 and tt7-3 result from altered PA composition and distribution in the cell. Our mutant screen, which was not exhaustive, suggests that the cooperation of many genes is required for successful PA accumulation.Flavonoids are a diverse group of plant secondary metabolites that accumulate in a wide variety of plant tissues and include anthocyanins, flavonols, and the polymeric flavanols known as proanthocyanidins (PAs; Fig. 1). Like their flavanol constituents, PAs are rich in hydrophobic aromatic rings and hydroxyl groups that can interact with biological molecules, particularly proteins, by hydrogen bonds and hydrophobic interactions. Because PAs are polymeric, their interaction with proteins is much stronger than that of monomeric flavanols, presumably because of a "chelate" effect where polymeric PAs can interact with large proteins at multiple sites, increasing the strength of overall molecular interaction as well as minimizing dissociation of the complex once it is formed (Fersht, 1985). This strong interaction of PAs with proteins is probably the basis of their main role in plants and their uses by man.Because PA content of dietary plants can have both positive and negative effects on animal nutrition (Waghorn and Jones, 1989), an important agricultural objective is to manipulate the level of PA in pasture legumes (Morris and Robbins, 1997). When present in bloat-safe forage legumes, PA can bind to and cause the precipitation of dietary proteins, inhibiting the formation of stable proteinaceous foams, thereby preventing bloat (Tanner et al., 1995). Increasing the PA content of pastures such as alfalfa (Medicago s...

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Section: Discussionmentioning

confidence: 99%

Identification and Biochemical Characterization of Mutants in the Proanthocyanidin Pathway in Arabidopsis

et al. 2002

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“…The search for related three-dimensional structures indicated extended similarities with the short-chain dehydrogenases\reductases (SDR) superfamily (Rafferty et al, 1995 ;Jo$ rnvall et al, 1995), or the reductases\epimerases\dehydrogenases (RED) superfamily (Labesse et al, 1994), to which InhA belongs, the closest structure being the KAR from Brassica napus (PDB1EDO), with 40 % identity. Most residues critical for cofactor binding and catalysis are well conserved in MabA sequence (Fig.…”

Section: Structural Analysis Of the Maba Proteinmentioning

confidence: 99%

MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II

et al. 2002

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The fatty acid elongation system FAS-II is involved in the biosynthesis of mycolic acids, which are very long-chain fatty acids of the cell envelope specific to Mycobacterium tuberculosis and other mycobacteria. A potential component of FAS-II, the protein MabA (FabG1), was overexpressed and purified. Sedimentation equilibrium analyses revealed that MabA undergoes a dimer to tetramer self-association with a dissociation constant of 22 µM.

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“…GMD is a member of the short-chain dehydrogenase/reductase family of proteins (12) and in general has structural features compatible with enzymes belonging to the reductase-epimerase-dehydrogenase superfamily (13). GMD sequences are well conserved among organisms; they all contain three conserved amino acids, Ser/Thr, Tyr, and Lys, involved in catalysis and a glycine-rich motif at the N terminus that is involved in cofactor binding.…”

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confidence: 99%

Differential Role of NADP+ and NADPH in the Activity and Structure of GDP-D-mannose 4,6-Dehydratase from Two Chlorella Viruses

Fruscione¹,

Sturla²,

Duncan

et al. 2008

Journal of Biological Chemistry

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GDP-D-mannose 4,6-dehydratase (GMD) is a key enzyme involved in the synthesis of 6-deoxyhexoses in prokaryotes and eukaryotes. Paramecium bursaria chlorella virus-1 (PBCV-1) encodes a functional GMD, which is unique among characterized GMDs because it also has a strong stereospecific NADPHdependent reductase activity leading to GDP-D-rhamnose formation (Tonetti, M., Zanardi, D., Gurnon, J., Fruscione, F., Armirotti, A., Damonte, G., Sturla, L., De Flora, A., and Van Etten, J.L. (2003) J. Biol. Chem. 278, 21559 -21565). In the present study we characterized a recombinant GMD encoded by another chlorella virus, Acanthocystis turfacea chlorella virus 1 (ATCV-1), demonstrating that it has the expected dehydratase activity. However, it also displayed significant differences when compared with PBCV-1 GMD. In particular, ATCV-1 GMD lacks the reductase activity present in the PBCV-1 enzyme. Using recombinant PBCV-1 and ATCV-1 GMDs, we determined that the enzymatically active proteins contain tightly bound NADPH and that NADPH is essential for maintaining the oligomerization status as well as for the stabilization and function of both enzymes. Phylogenetic analysis indicates that PBCV-1 GMD is the most evolutionary diverged of the GMDs. We conclude that this high degree of divergence was the result of the selection pressures that led to the acquisition of new reductase activity to synthesize GDP-D-rhamnose while maintaining the dehydratase activity in order to continue to synthesize GDP-L-fucose.GDP-D-mannose 4,6-dehydratase (GMD, 2 EC 4.2.1.47) is the first enzyme in the biosynthetic pathways that leads to the formation of several deoxyhexoses, such as GDP-L-fucose (1), GDP-D-rhamnose (2), GDP-6-deoxy-D-talose (3), and GDP-Dperosamine (4). Genes encoding GMDs have been identified in most prokaryotes and eukaryotes (5-8). Recently, we characterized the first GMD encoded by a virus, Paramecium bursaria chlorella virus 1 (PBCV-1) (9). PBCV-1 is the prototype of a group (family Phycodnaviridae) of large, icosahedral, plaqueforming, double-stranded DNA viruses that replicate in certain unicellular, eukaryotic chlorella-like green algae (10). In nature, the chlorella host is a hereditary endosymbiont in the ciliated protozoan P. bursaria. PBCV-1 has ϳ365 protein-encoding genes, including genes that encode several proteins that resemble enzymes involved in the metabolism and processing of sugars; these proteins include five putative glycosyltransferases believed to be involved in the glycosylation of the virus major capsid protein (11). PBCV-1 also encodes the two enzymes involved in GDP-Lfucose biosynthesis, GMD and GDP-4-keto-6-deoxy-D-mannose epimerase/reductase (GMER) (Fig. 1) (9).GMD is a member of the short-chain dehydrogenase/reductase family of proteins (12) and in general has structural features compatible with enzymes belonging to the reductase-epimerase-dehydrogenase superfamily (13). GMD sequences are well conserved among organisms; they all contain three conserved amino acids, Ser/Thr, Tyr, and Lys, involved in ca...

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Structural comparisons lead to the definition of a new superfamily of NAD(P)(H)-accepting oxidoreductases: the single-domain reductases/epimerases/dehydrogenases (the ‘RED’ family)

Cited by 73 publications

References 18 publications

Identification and Biochemical Characterization of Mutants in the Proanthocyanidin Pathway in Arabidopsis

Identification and Biochemical Characterization of Mutants in the Proanthocyanidin Pathway in Arabidopsis

MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II

Differential Role of NADP+ and NADPH in the Activity and Structure of GDP-D-mannose 4,6-Dehydratase from Two Chlorella Viruses

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