Gene/Protein Disease Symptom Drug Enzyme Compound
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The third enzyme of the pentose phosphate pathway (PPP), 6-phosphogluconate dehydrogenase (6PGDH), is present in the four major stages of Trypanosoma cruzi, CL Brener clone. The enzyme was too unstable to be purified from epimastigote cell-free extracts. Two genes encoding 6PGDH were cloned and sequenced; the predicted amino acid sequences differ only in five non-essential residues. Since Southern blots suggested the presence of a single copy per haploid genome, the two genes found are probably alleles. One of these genes, encoding a protein with 78.6% identity with the Trypanosoma brucei 6PGDH, was expressed in Escherichia coli as an active recombinant enzyme, which was as unstable as the native 6PGDH. Modeling of the T. cruzi enzyme using the three-dimensional structure of the T. brucei 6PGDH as template suggested the lack of two out of five salt bridges proposed to strengthen subunit interactions in the active dimer. Restoring of these bridges by site-directed mutagenesis resulted in a more stable recombinant T. cruzi 6PGDH, which was used to determine the kinetic parameters. The K(m) value for 6-phosphogluconate (22.2+/-0.4 microM) was identical to the values reported for 6PGDHs from mammals, but the K(m) for NADP (5.9+/-0.2 microM) was significantly lower than the value reported for the human enzyme, and closer to that for the T. brucei enzyme. This suggests the possibility that inhibitors of the T. brucei 6PGDH, under development as potential drugs against African Trypanosomiasis, might also be successful for the chemotherapy of Chagas disease.
Mol Biochem Parasitol 2004 Feb
PMID:The 6-phosphogluconate dehydrogenase from Trypanosoma cruzi: the absence of two inter-subunit salt bridges as a reason for enzyme instability. 1469 32

Chromobacterium violaceum presents a distinctive phenotypic characteristic, the production of a deep violet pigment named violacein. Although the physiological function of this pigment is not well understood, the sequencing of the genome of this bacterium has given some insight into the mechanisms and control of violacein production. It was found that erythrose-4-phosphate (E4P), a precursor to aromatic amino acid biosynthesis, is produced by the non-oxidative portion of the hexose monophosphate pathway, since it lacks 6-phosphogluconate dehydrogenase. All genes leading from E4P plus phosphoenolpyruvate to tryptophan are present in the genome. Nevertheless, these genes are not organized in an operon, as in E. coli, indicating that other mechanisms are involved in expression. The sequencing data also indicated the presence and organization of an operon for violacein biosynthesis. Three of the four gene products of this operon presented similarity with nucleotide-dependent monooxygenases and one with a limiting enzyme polyketide synthase. As previously suggested, genes encoding proteins involved in quorum sensing control by N-hexanoyl-homoserine-lactone, an autoinducer signal molecule, are present in the bacterial genome. These data should help guide strategies to increase violacein biosynthesis, a potentially useful molecule.
Genet Mol Res 2004 Mar 31
PMID:Genetic analysis of violacein biosynthesis by Chromobacterium violaceum. 1510 Sep 90

It is well established that different allozyme proteins vary in heterozygosity in averages made over large numbers of species. For example, the enzyme 6-phosphogluconate dehydrogenase has a much higher average heterozygosity than glutamate dehydrogenase. Allozyme data alone provide insufficient power to determine the evolutionary cause of such a difference. Many studies have now been carried out on the DNA sequences coding for allozymes. These have identified diverse selective and nonselective causes of polymorphisms at individual loci. However the studies are mainly in a small number of model species; thus, it is difficult to identify from these DNA studies specific causes of global average heterozygosity differences among allozyme proteins. Here we demonstrate that estimates of average heterozygosity for 37 allozyme proteins in vertebrates correlate positively with Ka and Ka/Ks but not with Ks, measured in the human-mouse lineage. The values of Ka/Ks are less than 0.25, and Ka/Ks is negatively correlated with subunit number (quaternary structure), a measure of structural constraint. Proteins with lower levels of constraint have higher values of both Ka/Ks and heterozygosity. These results better support the hypothesis that differences in average allozyme diversity between proteins are more closely related to differences in the level of purifying selection than to differences in the underlying mutation rate or level of positive selection.
Mol Biol Evol 2004 Sep
PMID:Average allozyme heterozygosity in vertebrates correlates with Ka/Ks measured in the human-mouse lineage. 1520 99

The plastids of red algae, green plants, and glaucophytes may have originated directly from a cyanobacterium-like prokaryote via primary endosymbiosis. In contrast, the plastids of other lineages of eukaryotic phototrophs appear to be the result of secondary or tertiary endosymbiotic events involving a phototrophic eukaryote and a eukaryotic host cell. Although phylogenetic analyses of multiple plastid genes from a wide range of eukaryotic lineages have been carried out, the phylogenetic positions of the secondary plastids of the Chromista (Heterokontophyta, Haptophyta and Cryptophyta) are ambiguous in a range of different analyses. This ambiguity may be the result of unusual substitutions or bias in the plastid genes established by the secondary endosymbiosis. In this study, we carried out phylogenetic analyses of five nuclear genes of cyanobacterial origin (6-phosphogluconate dehydrogenase [gnd], oxygen-evolving-enhancer [psbO], phosphoglycerate kinase [pgk], delta-aminolevulinic acid dehydratase [aladh], and ATP synthase gamma [atpC] genes), using the genome sequence data from the primitive red alga Cyanidioschyzon merolae 10D. The sequence data robustly resolved the origin of the cyanobacterial genes in the nuclei of the Chromista (Heterokontophyta and Haptophyta) and Dinophyta, before the divergence of the extant red algae (including Porphyra [Rhodophyceae] and Cyanidioschyzon [Cyadidiophyceae]). Although it is likely that gnd genes in the Chromista were transmitted from the cyanobacterium-like ancestor of plastids in the primary endosymbiosis, other genes might have been transferred from nuclei of a red algal ancestor in the secondary endosymbiosis. Therefore, the results indicate that the Chromista might have originated from the ancient secondary endosymbiosis before the divergence of extant red algae.
J Mol Evol 2004 Jul
PMID:Cyanobacterial genes transmitted to the nucleus before divergence of red algae in the Chromista. 1538 13

The pathophysiological mechanism of Salmonella enterica subsp. enterica serovar Typhimurium (Salmonella typhimurium) induced gastroenteritis is controlled by interplay of various cell signaling events. Adherence of this organism through type-1 fimbriae is known to be a vital prerequisite for the establishment of infection. In the present investigation male albino Wistar rats were immunized with purified type-1 fimbriae and challenged intragastrically with S. typhimurium. Electrolyte transport and level of different second messengers were studied in four different groups of animals. Transepithelial fluxes of Na+ and Cl- revealed absorption in immunized-challenged group as observed in case of control and immunized group while secretion was observed in infected group. Ca2+ and 3-0-methyl-D-glucose fluxes did not show any change. Significant increase in the level of intracellular Ca2+, cAMP, membrane form of protein kinase C, prostaglandins, NADPH oxidase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, total oxygen free radicals, reactive nitrogen intermediates, citrulline and lipid peroxidation was found in the infected group. However, in the immunized-challenged group, the values of all the parameters were found to be same as that of control as well as immunized groups. Na+, K(+)-ATPase and calmodulin levels were found to be unaltered in all the groups of animals. Thus, the immunization with type-1 fimbriae has been found to be quite effective leading to the prevention of multiple physiologic derangements in isolated ileal cells suggesting the protective role of the fimbriae.
Mol Cell Biochem 2005 May
PMID:The effect of type-1 fimbrial immunization on gut pathophysiological response in rats infected with Salmonella enterica subsp. enterica serovar Typhimurium. 1601 47

3-Hydroxyisobutyrate, a central metabolite in the valine catabolic pathway, is reversibly oxidized to methylmalonate semialdehyde by a specific dehydrogenase belonging to the 3-hydroxyacid dehydrogenase family. To gain insight into the function of this enzyme at the atomic level, we have determined the first crystal structures of the 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8: holo enzyme and sulfate ion complex. The crystal structures reveal a unique tetrameric oligomerization and a bound cofactor NADP+. This bacterial enzyme may adopt a novel cofactor-dependence on NADP, whereas NAD is preferred in eukaryotic enzymes. The protomer folds into two distinct domains with open/closed interdomain conformations. The cofactor NADP+ with syn nicotinamide and the sulfate ion are bound to distinct sites located at the interdomain cleft of the protomer through an induced-fit domain closure upon cofactor binding. From the structural comparison with the crystal structure of 6-phosphogluconate dehydrogenase, another member of the 3-hydroxyacid dehydrogenase family, it is suggested that the observed sulfate ion and the substrate 3-hydroxyisobutyrate share the same binding pocket. The observed oligomeric state might be important for the catalytic function through forming the active site involving two adjacent subunits, which seems to be conserved in the 3-hydroxyacid dehydrogenases. A kinetic study confirms that this enzyme has strict substrate specificity for 3-hydroxyisobutyrate and serine, but it cannot distinguish the chirality of the substrates. Lys165 is likely the catalytic residue of the enzyme.
J Mol Biol 2005 Sep 30
PMID:Crystal structure of novel NADP-dependent 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8. 1612 23

Previously, we have shown that the age-related changes in 6-phosphogluconate dehydrogenase (6PGDH) activity depend on sex, and that oestradiol is playing a crucial role in the regulation of 6PGDH gene expression in rat liver, but not in other tissues [Pankiewicz, A., Sledzinski, T., Nogalska, A., Swierczynski, J., 2003. Tissue specific, sex and age-related differences in the 6-phosphogluconate dehydrogenase gene expression. Int. J. Biochem. Cell Biol. 35, 235-245.]. To complete the knowledge on the influence of sex hormones on 6PGDH activity, experiments have been performed on the effect of testosterone on 6PGDH gene expression in rat white adipose tissue and liver. The results presented here disclosed that in young male rats high serum testosterone concentration was associated with high white adipose tissue 6PGDH activity. After orchidectomy, a decrease in serum testosterone concentration (both in young and old rats) was observed. In contrast, no changes in white adipose tissue and liver 6PGDH activity were found. In female rats, both young and old, serum testosterone concentration was below the limit of detection, whereas 6PGDH activity was much higher in young than in old animals. Moreover, the testosterone administration to 9-month old male rats (which displayed much lower serum testosterone concentration that young animals) resulted in no effect on 6PGDH activity either in WAT or in the liver. In conclusion, the results presented in this paper indicate that testosterone does not play any role in the age- and gender-related differences in 6PGDH gene expression in white adipose tissue.
Comp Biochem Physiol B Biochem Mol Biol 2006 May
PMID:Gender- and age-related changes in 6-phosphogluconate dehydrogenase gene expression in white adipose tissue of rats (Rattus norvegicus) are not related to serum testosterone concentration. 1649 3

The objectives of this study are to examine hepatic gene expression changes caused by GH transgenesis and enhanced growth. This is the first use of cDNA microarrays to study the influence of GH transgenesis on liver gene expression in a non-mammalian vertebrate, and the first such study using sexually immature animals. Three groups of coho salmon were examined: GH transgenic on full ration (T), GH transgenic on restricted ration (R), and control non-transgenic (C). Specific growth rates for weight in T were approximately eightfold higher than in C, and fourfold higher than in R. Differential gene expression in T, R, and C samples was determined using approximately 3500 and 16,000 gene microarrays, and R and C samples were compared on a different approximately 4000 gene microarray. The use of multiple microarray platforms increased the overall proportion of the hepatic transcriptome considered in these studies. Cross-platform comparisons identified genes behaving similarly between studies. For example, genes encoding a precerebellin-like protein and complement component C3 were downregulated in R relative to C (R < C) in two microarray studies, and hemoglobins alpha and beta were R > C in all three studies. Comparisons of informative gene lists within and between studies inferred causes of altered gene expression. For example, ten genes, including 78 kDa glucose-regulated protein, glycerol-3-phosphate dehydrogenase, hemoglobins alpha and beta, and a C-type lectin, were likely induced by GH transgenesis due to their presence in both T > C and R > C gene lists. Eleven genes, including hepcidin, nuclear protein p8, precerebellin-like, transketolase, and fatty acid-binding protein, were present in both T < C and R < C gene lists and were, therefore, likely suppressed by GH transgenesis. A large number of salmonid genes identified in these studies are involved in iron homeostasis, mitochondrial function, carbohydrate metabolism, cellular proliferation, and innate immunity. Pentose phosphate pathway genes phosphogluconate dehydrogenase, transaldolase, and transketolase, were dysregulated in GH transgenic samples relative to control samples. Changes in the expression of genes involved in maintaining hemoglobin levels (heme oxygenase, hemoglobins alpha and beta, Kruppel-like globin gene activator, hepcidin) in R and T fish indicate a need for additional hemoglobin in the transgenic fish, perhaps due to higher metabolic rate required for enhanced growth.
J Mol Endocrinol 2006 Oct
PMID:Multiple microarray platforms utilized for hepatic gene expression profiling of GH transgenic coho salmon with and without ration restriction. 1703 44

Enzymes from the pentose phosphate pathway (PPP) are potential drug targets for the development of new drugs against Trypanosoma brucei, the causative agent of African sleeping disease: for instance, the 6-phosphogluconate dehydrogenase is currently studied actively for such purposes. Structural and functional studies are necessary to better characterize the associated enzymes and compare them to their human homologues, in order to undertake structure-based drug design studies on such targets. In this context, the crystal structure of 6-phosphogluconolactonase (6PGL) from T. brucei, the second enzyme from PPP, was determined at 2.1 Angstroms resolution. Comparison of its sequence and structure to other related proteins in the 6PGL family with a known structure (Thermotoga maritima Tm6GPL 1PBT and Vibrio cholerae Vc6PGL (1Y89), which have not been discussed in print), or in the glucosamine-6-phosphate-deaminase family (hexameric Escherichia coli 1DEA and monomeric Bacillus subtilis 2BKV), allowed the identification of the 6PGL active site. In addition to the analysis of the crystal structure, 3D NMR interaction studies and docking experiments are reported here. Key residues involved in substrate binding or in catalysis were identified.
J Mol Biol 2007 Feb 23
PMID:Three dimensional structure and implications for the catalytic mechanism of 6-phosphogluconolactonase from Trypanosoma brucei. 1719 81

Corynebacterium glutamicum is a Gram-positive soil bacterium that prefers the simultaneous catabolism of different carbon sources rather than their sequential utilization. This type of metabolism requires an adaptation of the utilization rates to the overall metabolic capacity. Here we show how two functionally redundant GntR-type transcriptional regulators, designated GntR1 and GntR2, co-ordinately regulate gluconate catabolism and glucose uptake. GntR1 and GntR2 strongly repress the genes encoding gluconate permease (gntP), gluconate kinase (gntK), and 6-phosphogluconate dehydrogenase (gnd) and weakly the pentose phosphate pathway genes organized in the tkt-tal-zwf-opcA-devB cluster. In contrast, ptsG encoding the EII(Glc) permease of the glucose phosphotransferase system (PTS) is activated by GntR1 and GntR2. Gluconate and glucono-delta-lactone interfere with binding of GntR1 and GntR2 to their target promoters, leading to a derepression of the genes involved in gluconate catabolism and reduced ptsG expression. To our knowledge, this is the first example for gluconate-dependent transcriptional control of PTS genes. A mutant lacking both gntR1 and gntR2 shows a 60% lower glucose uptake rate and growth rate than the wild type when cultivated on glucose as sole carbon source. This growth defect can be complemented by plasmid-encoded GntR1 or GntR2.
Mol Microbiol 2008 Jan
PMID:Co-ordinated regulation of gluconate catabolism and glucose uptake in Corynebacterium glutamicum by two functionally equivalent transcriptional regulators, GntR1 and GntR2. 1804 70


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