Roles of Hemoglobin Allostery in Hypoxia-induced Metabolic Alterations in Erythrocytes

Kinoshita, Ayako; Tsukada, Kosuke; Soga, Tomoyoshi; Hishiki, Takako; Ueno, Yuki; Nakayama, Yoichi; Tomita, Masaru; Suematsu, Makoto

doi:10.1074/jbc.m610717200

Cited by 86 publications

(103 citation statements)

References 49 publications

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“…CO has been believed to share varied physiological effects on biological systems with NO. However, through extrapolation of studies in vitro indicating biochemical actions of CO to trigger structural changes in gas-responsive heme proteins (such as sGC, hemoglobin) distinct from those elicited by NO, 7,19,21,22,38 evidence that CO is a unique gaseous regulator distinct from NO has been emerging. In fact, CO itself modestly activates sGC, by which hepatic sinusoids are constitutively dilated.…”

Section: Discussionmentioning

confidence: 99%

“…We performed metabolome analyses of tissue lysates collected from snap-frozen livers of mice using contrast-enhanced time of flight/mass spectrometry according to our previous methods. 18,19 Measurements of hepatic H 2 S contents were based on gas chromatography described in our previous method. 14 Biliary flux of bilirubin-IX␣ (BR-IX␣) in bile samples were determined by enzyme-linked immunosorbent assay using the anti-BR-IX␣ monoclonal antibody as described previously.…”

Section: Methodsmentioning

confidence: 99%

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Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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“…After centrifugation at 20,000 g at 4 C for 15 minutes, the supernatants were filtered through 5 kDa cut-off filter (Millipore). Metabolites including those that had at least one 13 C atom in the filtrate were analyzed by using an Agilent CE Capillary Electrophoresis System equipped with an Agilent 1100 series MSD mass spectrometer, as described previously (24). Labeled metabolites containing at least one 13 C atom in a molecule were collectively indicated as 13 …”

Section: Cell Synchronization and Ce/esi/ms Analysismentioning

confidence: 99%

“…Application of metabolomic analyses using capillary electrophoresis/electrospray ionization/mass spectrometry (CE/ESI/MS; refs. 21,22) allows us to determine fluxes of multiple metabolic pathways during cell-cycle progression in vitro (20,23,24). MALDI-IMS analyses of metastatic tumors have shown that the cancer cells in G 1 phase were more active in glycolysis than those in the other phases.…”

Section: Introductionmentioning

confidence: 99%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

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“…Kinoshita et al (2007) showed the hypoxia-induced consumption of upstream glycolytic substrates, such as glucose 6-phosphate, and increased downstream products, such as phosphoenolpyruvate, in human erythrocytes. Ishii et al (2007) reported on the response of Escherichia coli cells to genetic and environmental perturbations.…”

Section: Anionic Metabolite Analysismentioning

confidence: 99%

Profiling of primary metabolite by means of capillary electrophoresis-mass spectrometry and its application for plant science

Harada

Fukusaki

2009

Plant Biotechnology

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Metabolites in primary metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, the Calvin cycle and amino acid biosynthetic pathways, are ionic compounds. It is difficult to analyze these metabolites simultaneously by established methods for metabolite profiling of biological samples such as gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry. Capillary electrophoresis-mass spectrometry (CE-MS) is a promising method for the comprehensive and quantitative analysis of ionic metabolites. This technique enables the simultaneous determination of over 1000 charged compounds. This review discusses the principles and practical procedures for conducting CE-MS, describes specific applications of CE-MS for primary metabolite profiling, and enumerates some of the technical problems associated with CE-MS at present.

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Roles of Hemoglobin Allostery in Hypoxia-induced Metabolic Alterations in Erythrocytes

Cited by 86 publications

References 49 publications

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Profiling of primary metabolite by means of capillary electrophoresis-mass spectrometry and its application for plant science

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