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We perform a comprehensive genome analysis on two spirochetes, T. pallidum and B. burgdorferi. First, we focus on the occurrence of protein structures in these organisms. We find that there are only a few spirochete-specific folds, relative to those in other types of bacteria. The most common fold, by far, in the spirochetes is the P-loop NTP hydrolase, followed by the TIM barrel. These folds also happen to be amongst the most multifunctional of the known folds. We also survey the membrane-protein structures in T. pallidum and find a notable large family with twelve transmembrane (TM) helices, reflecting the prevalence of 12-TM transporters in bacteria. Then we move to analysis of the metabolic pathways and overall metabolism in the spirochetes, using the metabolic-flux-balancing method. We find that the lipid biosynthesis pathway is absent from the spirochetes. This strongly limits the degree to which these organisms can metabolize NADPH. In turn, we find that the spirochetes distribute flux disproportionately through the glycolytic pathway instead of the NADPH-providing pentose phosphate pathway. Further information is available at http://bioinfo.mbb.yale.edu
J Mol Microbiol Biotechnol 2000 Oct
PMID:Genome analyses of spirochetes: a study of the protein structures, functions and metabolic pathways in Treponema pallidum and Borrelia burgdorferi. 1107 10

Insulin or agents that can mimic its action (insulin-mimetics) are necessary to promote the entry of glucose into tissues where the glucose can either be converted into energy or stored for later use. In recent years, selenium has been shown to mediate a number of insulin-like actions both in vivo and in vitro. These insulin-like actions include stimulating glucose uptake and regulating metabolic processes such as glycolysis, gluconeogenesis, fatty acid synthesis and the pentose phosphate pathway. The mechanism by which selenium is capable of mimicking insulin is not clear; however, reports indicate that selenium does activate key proteins involved in the insulin-signal cascade. Various proteins in the insulin-signal cascade have been shown to be necessary for different insulin-regulated events, and presumably data will be forthcoming soon that illustrate this similarly for selenium. This review compares the action of selenium to that of insulin and discusses the available evidence in support of selenium as an insulin-mimetic.
Cell Mol Life Sci 2000 Dec
PMID:Selenium: an insulin-mimetic. 1121 14

The structure and function of the pseudobranch has long interested scientists, but its overall role has remained a mystery. Previous studies have attributed respiratory, endocrine, osmoregulatory and sensory roles to the pseudobranch, and the present review concentrates on new findings. Perfusion experiments on the pseudobranch of the rainbow trout (Oncorhynchus mykiss) using both erythrocyte suspensions and Ringer solution have shown that this organ is able to generate values for the respiratory quotient (RQ) greater than 1.0. The release of carbon dioxide into the perfusate was found to be largely independent of flow between perfusion rates of 120-190 microl/min and could be inhibited by acetazolamide (10(-5) M), indicating a role for carbonic anhydrase. Noradrenaline (10(-5) M) had no effect on oxygen consumption or carbon dioxide release of the pseudobranch. The rate of carbon dioxide release was also dependent on the pH of the pre-pseudobranch perfusate, carbon dioxide release being reduced at lower perfusate pH values. Based on the glucose balance of the isolated saline-perfused rainbow trout pseudobranch and on the enzyme profiles for the rainbow trout, cod, swordfish and deep-water grenadier pseudobranch, it is suggested that the pentose phosphate shunt might be a source of carbon dioxide, yielding the high RQ values found for this organ. Most evidence now available indicates that the pseudobranch is integrally linked with the choroid rete and the supply of oxygen to the retina of the fish eye.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Physiology and biochemistry of the pseudobranch: an unanswered question? 1125 20

Bacterial cytidine monophosphate (CMP) kinases are characterised by an insert enlarging their CMP binding domain, and by their particular substrate specificity. Thus, both CMP and 2'-deoxy-CMP (dCMP) are good phosphate acceptors for the CMP kinase from Escherichia coli (E. coli CMPK), whereas eukaryotic UMP/CMP kinases phosphorylate the deoxynucleotides with very low efficiency. Four crystal structures of E. coli CMPK complexed with nucleoside monophosphates differing in their sugar moiety were solved. Both structures with CMP or dCMP show interactions with the pentose that were not described so far. These interactions are lost with the poorer substrates AraCMP and 2',3'-dideoxy-CMP. Comparison of all four structures shows that the pentose hydroxyls are involved in ligand-induced movements of enzyme domains. It also gives a structural basis of the mechanism by which either ribose or deoxyribose can be accommodated. In parallel, for the four nucleotides the kinetic results of the wild-type enzyme and of three structure-based variants are presented. The phosphorylation rate is significantly decreased when either of the two pentose interacting residues is mutated. One of these is an arginine that is highly conserved in all known nucleoside monophosphate kinases. In contrast, the other residue, Asp185, is typical of bacterial CMP kinases. It interacts with Ser101, the only residue conserved in all CMP binding domain inserts. Mutating Ser101 reduces CMP phosphorylation only moderately, but dramatically reduces dCMP phosphorylation. This is the first experimental evidence of a catalytic role involving the characteristic insert of bacterial CMP kinases. Furthermore, this role concerns only dCMP phosphorylation, a feature of this family of enzymes.
J Mol Biol 2002 Feb 01
PMID:Sugar specificity of bacterial CMP kinases as revealed by crystal structures and mutagenesis of Escherichia coli enzyme. 1182 79

Studies of nectar sugar composition in the Proteaceae, an ancient southern hemisphere plant family, have demonstrated that xylose comprises up to 39% of nectar sugar in two genera, Protea and Faurea, and may therefore represent a substantial fraction of the energy available to pollinators of these plants. Although insect and bird pollinators of Protea species are averse to xylose, mice (Aethomys namaquensis) will drink pure xylose, which is metabolized either by gut bacteria or by the mouse tissues. In the form of xylan polymers, the pentose sugar D-xylose is a structural component of plant cell walls, and there is considerable biotechnological interest in xylose fermentation. Bacteria and yeasts convert D-xylose to D-xylulose and thence via the pentose phosphate pathway to fructose-6-phosphate, which is either oxidized or fermented to ethanol. Gut symbionts of rodent pollinators may be analogous to ruminal xylose-metabolizing bacteria. The presence of xylose in Protea and Faurea nectar remains puzzling in view of pollinator aversions: even for rodent pollinators, it is the least preferred nectar sugar. In the generalized pollination systems of the Proteaceae, a coevolutionary explanation for nectar xylose as an attractant for mammalian pollinators is probably less likely than one involving plant physiology, with xylose in phloem sap being secreted passively into the nectar.
Comp Biochem Physiol B Biochem Mol Biol 2002 Apr
PMID:Xylose as a nectar sugar: from biochemistry to ecology. 1192 77

The dehydroepiandrosterone metabolite epiandrosterone (EPI) inhibits the pentose phosphate pathway (PPP) and dilates isolated blood vessels pre-contracted by partial depolarization. We found that EPI (10-100 microM) also dose-dependently decreases left-ventricular developed pressure (LVDP), the rate of myocardial contraction (+d p /d t), and the pressure rate product (PRP); at 100 microM EPI, LVDP (131+/-9 vs 34+/-7 mmHg), +d p /dt (1515+/-94 vs 542+/-185 mmHg/s), and PRP (37870+/-2471 vs 9498+/-2375 HR x mmHg/min) were all significantly (P<0.05) reduced. EPI also elevated CPP in isolated hearts, decreased levels of myocardial NADPH and nitrite, and dose-dependently relaxed rat aortic rings pre-contracted with KCl. Electrophysiological analysis of single ventricular myocytes using whole cell clamp showed EPI to dose-dependently (100 n M-100 microM) and reversibly inhibit L-type channel currents carried by Ba2+ (IBa) (IC50=42+/-6 microM) by as much as 50%. At 30 microM, EPI shifted the steady-state inactivation curve to more negative potentials (V50=-26.6 mV vs -38.0 mV), thereby accelerating the decay of IBa during depolarization. These results suggest that EPI may act as a L-type Ca2+ channel antagonist with properties similar to those of 1,4-dihydropyridine (DHP) Ca2+ channel blockers.
J Mol Cell Cardiol 2002 Jun
PMID:Epiandrosterone, a metabolite of testosterone precursor, blocks L-type calcium channels of ventricular myocytes and inhibits myocardial contractility. 1205 55

Strains of Enterobacter cloacae show promise as biocontrol agents for Pythium ultimum-induced damping-off on cucumber and other crops. E. cloacae A145 is a mini-Tn5 Km transposon mutant of strain 501R3 that was significantly reduced in suppression of damping-off on cucumber caused by P. ultimum. Strain A145 was deficient in colonization of cucumber, sunflower, and wheat seeds and significantly reduced in colonization of corn and cowpea seeds relative to strain 501R3. Populations of strain A145 were also significantly lower than those of strain 501R3 at all sampling times in cucumber, wheat, and sunflower rhizosphere. Populations of strain A145 were not detectable in any rhizosphere after 42 days, while populations of strain 501R3 remained at substantial levels throughout all experiments. Molecular characterization of strain A145 indicated mini-Tn5 Km was inserted in a region of the E. cloacae genome with a high degree of DNA and amino acid sequence similarity to rpiA, which encodes ribose-5-phosphate isomerase. In Escherichia coli, RpiA catalyzes the interconversion of ribose-5-phosphate and ribulose-5-phosphate and is a key enzyme in the pentose phosphate pathway. Ribose-5-phosphate isomerase activity in cell lysates from strain A145 was approximately 3.5% of that from strain 501R3. In addition, strain A145 was a ribose auxotroph, as expected for an rpiA mutant. Introduction of a 1.0-kb DNA fragment containing only the rpiA homologue into strain A145 restored ribose phosphate isomerase activity, prototrophy, seedling colonization, and disease suppression to levels similar to those associated with strain 501R3. Experiments reported here indicate a key role for rpiA and possibly the pentose phosphate pathway in suppression of damping-off and colonization of subterranean portions of plants by E. cloacae.
Mol Plant Microbe Interact 2002 Aug
PMID:Mutation of rpiA in Enterobacter cloacae decreases seed and root colonization and biocontrol of damping-off caused by Pythium ultimum on cucumber. 1218 39

Carbon flux analysis during a pseudo-stationary phase of metabolite accumulation in a genetically engineered strain of Corynebacterium glutamicum, containing plasmids leading to over-expression of the ilvBNCD and panBC operons, has identified the basic metabolic constraints governing the potential of this bacterium to produce pantothenate. Carbon flux converging on pyruvate (75% of glucose uptake) is controlled by anabolic precursor requirements and NADPH demand provoking high carbon loss as CO2 via the pentose pathway. Virtually all the flux of pyruvate is directed into the branched pathway leading to both valine and pantothenate production, but flux towards valine is tenfold higher than that transformed to pantothenate, indicating that significant improvements will only be obtained if carbon flux at the ketoisovalerate branchpoint can be modulated.
Mol Biol Rep 2002
PMID:Carbon flux analysis in a pantothenate overproducing Corynebacterium glutamicum strain. 1224 Oct 42

Preterm infants lack adequate surfactant production and often require oxygen support for adequate oxygenation. Prolonged oxygen treatment leads to the development of bronchopulmonary dysplasia (BPD), a disease process characterized by the blunting of alveolarization and proliferation of myofibroblasts. In the present study, we investigated metabolic adaptive changes in cultured fibroblasts isolated from immature (d18) and near-term (d21), fetal rat lungs in response to normoxic (21%) and hyperoxic (95%) exposures. We used the [1,2-13C2]D-glucose tracer and gas chromatography/mass spectrometry to characterize glucose carbon redistribution between the nucleic acid ribose, lactate, and palmitate synthetic pathways, and reverse transcriptase-polymerase chain reaction to assess adipose differentiation related protein (ADRP) mRNA expression in response to hyperoxic exposure. Exposure to hyperoxia at each passage caused decrease (*, p<0.05 vs. 21% O2) in ADRP mRNA expression in the d18 fibroblasts. This passage-dependent transdifferentiation is accompanied by a moderate (9-20%) increase in the synthesis of nucleic acid ribose from glucose through the non-oxidative steps of the pentose cycle. In contrast, d18 fibroblasts showed over an 85% decrease in the de novo synthesis of palmitate from glucose, while d21 fibroblasts showed a less pronounced 32-38% decrease in de novo lipid synthesis in hyperoxia-exposed cultures. It can be concluded from these studies that: (1) there is a maturation dependent sensitivity to hyperoxia; (2) transdifferentiation of flbroblast as demonstrated by changes in ADRP expression is accompanied by metabolic enzymes changes affecting ribose acid synthesis from glucose, and (3) hyperoxia specifically inhibits lipogenesis from glucose. Hyperoxia-induced metabolic changes thus play a key role in the transdifferentiation of lung fibroblasts to myofibroblasts and the pathogenesis of BPD.
Mol Genet Metab 2002 Nov
PMID:Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat lung lipofibroblasts. 1240 71

We recently described the ABC transporter Ngc (encoded by the ncgEFG operon) from Streptomyces olivaceoviridis, the first of its kind to be shown to transport N-acetylglucosamine and N,N'-diacetylchitobiose (chitobiose). A chromosomal mutant carrying a disruption of the ngcE gene, which encodes the sugar binding protein, was still able to transport N-acetylglucosamine. This phenotype can now be attributed to a functional phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS). Two adjacent homologous genes, ptsC1 and ptsC2, were identified, and deduced to encode proteins which are 56% identical and can be predicted to contain eight transmembrane regions. PtsC1 (432 amino acids) and PtsC2 (403 residues) each correspond to a single EIIC domain; such domains are otherwise known only in several bacterial multidomain permeases for glucose/mannose or N-acetylglucosamine. The C-terminal sequences of PtsC1 and PtsC2 correspond to the motifs LKTPGREP and LPTRGRES, respectively. The ptsB gene located upstream of ptsC1 is predicted to encode a homologue of the EIIB domains usually found in bacterial multidomain permeases. Physiological and biochemical analyses of ngcE mutants carrying disruptive insertions in ptsC1 or ptsC2 or both revealed that, when grown on N-acetylglucosamine, the membrane component PtsC2, unlike PtsC1, mediates PEP-dependent, specific (K(m)=5 micro M) transport of N-acetylglucosamine, but not of other hexoses. Cross-complementation of membrane and cytoplasmic fractions from the various mutants led to the conclusion that S. olivaceoviridis also expresses the functional soluble components HPr, EI and EIIA of the PTS system. During growth on xylose, uptake of this pentose occurred if ptsC1 or ptsC2 was intact, but not in a mutant containing disrupted forms of both genes.
Mol Genet Genomics 2002 Nov
PMID:Streptomyces olivaceoviridis possesses a phosphotransferase system that mediates specific, phosphoenolpyruvate-dependent uptake of N-acetylglucosamine. 1243 56


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