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

Shintani, Tsunehiro; Iwabuchi, Takuya; Soga, Tomoyoshi; Kato, Yuichiro; Yamamoto, Takehiro; Takano, Naoharu; Hishiki, Takako; Ueno, Yuki; Ikeda, Satsuki; Sakuragawa, Tadayuki; Ishikawa, Kazuo; Goda, Nobuhito; Kitagawa, Yuko; Kajimura, Mayumi; Matsumoto, Kenji; Suematsu, Makoto

doi:10.1002/hep.22604

Cited by 96 publications

(109 citation statements)

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“…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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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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“…A recent metabolomic study in murine liver using capillary electrophoresis-mass spectrometry (CE-MS) identified CBS as a CO sensor regulating bicarbonate-dependent biliary choleresis (27). CBS is a hemethiolate enzyme (28) that catalyzes multiple H 2 S-generating reactions (29,30).…”

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confidence: 99%

“…The prosthetic heme of this enzyme (31)(32)(33) allows the reversible coordinate bonding of gaseous ligands, such as CO and NO (34). Interestingly, CO, but not NO, inhibits the activity of CBS in vitro (31,32) and in vivo (27), making CBS a CO-specific sensor.…”

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confidence: 99%

“…HO-2 uses O 2 to generate CO, which tonically inhibits the ability of astrocytic CBS, a CO-specific sensor (27,31,32), to generate vasodilatory H 2 S (17-21). During hypoxia, inhibition of HO-2-mediated CO production occurs, with a corresponding release of the tonic inhibition of CBS, allowing it to generate H 2 S, which in turn elicits arteriolar vasodilation.…”

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confidence: 99%

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Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H 2 S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H 2 S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.gas biology | neurovascular unit | energy metabolism | gasotransmitter T he cerebral circulation is maintained by autoregulation, which prevents marked alterations in response to changes in blood pressure, whereas functional hyperemia links blood flow to neural activity (1). Blood flow regulation in the brain is modulated by O 2 (2), with increased cerebral blood flow in response to hypoxia critical for protecting the brain against diverse insults. Such regulation also participates in functional hyperemia, as demonstrated by functional MRI investigations indicating a transient decrease in O 2 levels preceding activation of blood flow in response to neuronal firing (3).Alterations in cerebral blood flow in response to hypoxia and neural activity are mediated via several neurotransmitter systems, with prominent involvement of the gaseous mediator nitric oxide (NO) (1, 2). In response to glutamate acting on NMDA receptors, neuronal NO synthase (nNOS) is activated by increases in intracellular calcium, with the generated NO stimulating soluble guanylyl cyclase, thereby increasing cGMP levels to dilate blood vessels (4). Functional hyperemia is decreased by ∼50% in rats in response to inhibition of nNOS (5). Another gaseous mediator, CO (6-8), is also vasoactive. In some blood vessel systems (e.g., liver sinusoids), CO causes vasodilation, and inhibition of its biosynthetic enzyme HO-2 leads to vasoconstriction (9-13). However, in the cerebral circulation, CO elicits vasoconstriction. Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6-12, 15) or potassium channels (13, 16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17-21). H 2 S can be physiologically ...

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“…They discovered that CO binds to the heme moiety of cystathionine β-synthase (CBS), an enzyme that generates H 2 S, and that CO inhibits CBS catalytic activity [9]. More recently, an elegant series of experiments have revealed that in the brain, CO is generated by HO2, binds to CBS, and inhibits its activity; however, under hypoxic conditions, CO production falls, CBS is no longer inhibited, resulting in the production of H 2 S, which functions as a vasodilator [10].…”

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confidence: 99%

Gas biology: small molecular medicine

Semenza

Prabhakar

2012

J Mol Med

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In this special issue of the Journal of Molecular Medicine, we present five review articles concerning small molecules that play big roles in physiology and medicine: the gases oxygen (O 2 ), nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S). Of these, the essential requirement for O 2 is well known to physicians, scientists, and laymen alike. However, it is only within the last two decades that we have begun to understand the molecular mechanisms by which every cell in our body senses the local O 2 concentration and responds to reduced O 2 availability (i.e., hypoxia) with changes in gene expression that are mediated by the hypoxia-inducible factors HIF-1 and HIF-2 [1]. Recent evidence suggest that NO, CO, and H 2 S function as signaling molecules that also play critical roles in regulating O 2 homeostasis.Philip Marsden and colleagues (University of Toronto) describe the fascinating crosstalk between O 2 sensing and NO signaling that occurs to regulate red blood cell levels and blood vessel tone, which together play critical roles in O 2 delivery [2]. In particular, they discuss exciting data from their lab demonstrating that the physiological responses to anemic hypoxia (reduced O 2 carrying capacity) and hypoxic hypoxia (reduced O 2 ) are mechanistically distinct. This difference is dramatically illustrated by their finding that subjecting mice that lack neuronal NO synthase (also known as nNOS or NOS1) to anemic hypoxia resulted in an increased mortality rate, compared to wild-type mice, whereas these NOS1-deficient mice were protected against mortality during hypoxic hypoxia [3]. Their delineation of the molecular and cellular basis for these effects is truly elegant physiology. The crosstalk between O 2 sensing and NO signaling is extensive and includes increased expression of inducible NOS (also known as iNOS or NOS2) under hypoxic conditions that is mediated by HIF-1 [4,5] and the regulation of HIF-1 activity by S-nitrosylation of a cysteine residue in the HIF-1α subunit [6].Puneet Anand and Jonathan Stamler (Case Western Reserve University) provide a global view of protein Snitrosylation and its effects on protein function [7]. They describe several different molecular mechanisms by which proteins are nitrosylated and counteracting mechanisms by which they are denitrosylated, which is analogous to the phosphorylation and dephosphorylation of proteins by kinases and phosphatases. The balance between nitrosylation and denitrosylation is dependent on the redox state of the cell, thus establishing inherent crosstalk between NO and reactive oxygen species. The authors discuss several examples of diseases associated with dysregulated S-nitrosylation, which may therefore represent a novel therapeutic target.Makoto Suetmatsu and colleagues (Keio University) discuss the biological role of CO, which is generated by heme oxygenases (HO1 and HO2) using heme and O 2 as

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

Cited by 96 publications

References 42 publications

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

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

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Gas biology: small molecular medicine

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