Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.2.1.22 (cystathionine beta-synthase)
965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen sulfide (H2S) is a naturally occurring gas that may act as an endogenous signaling molecule. In the brain, H2S is mainly produced by cystathionine beta-synthase (CBS) and its cellular effects have been attributed to interactions with N-methyl-D-aspartate (NMDA) receptors and cyclic adenosine 3',5'-monophosphate (cAMP). In contrast, direct vasodilator actions of H2S are most probably mediated by opening smooth muscle ATP-sensitive K+ (K(ATP)) channels. In the hypothalamus, K(ATP) channel-dependent mechanisms are involved in CNS-mediated regulation of blood pressure. In this report, we investigated the hypothesis that H2S may act via K(ATP) channels in the hypothalamus to regulate blood pressure. Mean arterial blood pressure (MAP) and heart rate were monitored in freely moving rats via a pressure transducer placed in the femoral artery. Drugs were infused via a cannula placed in the posterior hypothalamus. Infusion of 200 microM sodium hydrogen sulfide (NaHS), an H2S donor, into the hypothalamus of freely moving rats reduced MAP and heart rate. Infusion of 300 nM to 3 microM gliclazide dose-dependently blocked the effect of 200 microM NaHS. Infusion of the CBS activator, s-adenosyl-L-methionine (0.1 mM and 1 mM), likewise decreased MAP. Infusion of the CBS inhibitors aminooxyacetic acid (10 mM) and hydroxylamine (20 mM) increased MAP but did not block the effects of infusion of 200 microM NaHS. These data indicate that actions of H2S in the hypothalamus decrease blood pressure and heart rate in freely moving rats. This effect appears to be mediated by a K(ATP) channel-dependent mechanism and mimicked by endogenous H2S.
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PMID:Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats. 1820 37

O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine beta-synthase and cystathionine gamma-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a PO2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar approximately 10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to PO2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues.
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PMID:Hydrogen sulfide as an oxygen sensor in trout gill chemoreceptors. 1856 35

In the present study, we investigated the pharmacological action of hydrogen sulfide (H2S, using sodium hydrosulfide, NaHS, and/or sodium sulfide, Na2S as donors) on sympathetic neurotransmission from isolated, superfused porcine iris-ciliary bodies. We also examined the effect of H2S on norepinephrine (NE), dopamine and epinephrine concentrations in isolated porcine anterior uvea. Release of [3H]NE was triggered by electrical field stimulation and basal catecholamine concentrations was measured by high performance liquid chromatography (HPLC). Both NaHS and Na2S caused a concentration-dependent inhibition of electrically evoked [3H]NE release from porcine iris-ciliary body without affecting basal [3H]NE efflux. The inhibitory action of H2S donors on NE release was attenuated by aminooxyacetic acid (AOA) and propargyglycine (PAG), inhibitors of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), respectively. With the exception of dopamine, NaHS caused a concentration-dependent reduction in endogenous NE and epinephrine concentrations in isolated iris-ciliary bodies. We conclude that H2S can inhibit sympathetic neurotransmission from isolated porcine anterior uvea, an effect that is dependent, at least in part, on intramural biosynthesis of this gas. Furthermore, the observed action of H2S donors on sympathetic transmission may be due to a direct action of this gas on neurotransmitter pools.
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PMID:Effect of hydrogen sulfide on sympathetic neurotransmission and catecholamine levels in isolated porcine iris-ciliary body. 1862 36

Hydrogen sulfide (H2S) is recognized as a neuromodulator as well as neuroprotectant in the brain. H2S can be produced from cysteine by enzymes such as cystathionine beta-synthase. However, a mechanism for releasing H2S under physiologic conditions has not been identified. Here we show that H2S is released from bound sulfur, an intracellular store of sulfur, in neurons and astrocytes of mice and rats in the presence of physiologic concentrations of endogenous reducing substances glutathione and cysteine. The highest pH to release H2S from another sulfur store, acid-labile sulfur, which is localized mainly in mitochondria, is 5.4. Because mitochondria are not in the acidic condition, acid-labile sulfur may not be a physiologic source of H2S. Free H2S is immediately absorbed and stored as bound sulfur. Our novel method, using silver particles to measure free H2S, shows that free H2S is maintained at a low level in basal conditions. Alkalinization of the cytoplasm is required for effective release of H2S from bound sulfur, and this condition is achieved in astrocytes by the high concentrations of extracellular K+ that are normally present when nearby neurons are excited. These data present a new perspective on the regulation of H2S in the brain.
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PMID:A source of hydrogen sulfide and a mechanism of its release in the brain. 1875 2

The gas hydrogen sulfide (H2S) is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow and leukocyte adhesion. In addition, it may have antiinflammatory and antiapoptotic effects. H2S has recently attracted much interest as a potent vasorelaxative substance that may establish itself alongside another gaseous signal molecule, nitric oxide (NO). In contrast to NO, the major source of H2S in blood may be production by red blood cells or by vascular smooth muscle cells. H2S is produced from cysteine, involving the enzymes cystathionine beta-synthase and cystathionine gamma-lyase (CSE). The importance of CSE was recently demonstrated in a mouse lacking CSE which showed reduced H2S levels and developed hypertension and reduced endothelium-mediated vasorelaxation. These data establish H2S as a new and important biologic signal molecule and as a new regulator of vascular blood flow and blood pressure.
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PMID:Hydrogen sulfide: a new gaseous signal molecule and blood pressure regulator. 1938 33

In mammals, the two enzymes in the trans-sulfuration pathway, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), are believed to be chiefly responsible for hydrogen sulfide (H2S) biogenesis. In this study, we report a detailed kinetic analysis of the human and yeast CBS-catalyzed reactions that result in H2S generation. CBS from both organisms shows a marked preference for H2S generation by beta-replacement of cysteine by homocysteine. The alternative H2S-generating reactions, i.e. beta-elimination of cysteine to generate serine or condensation of 2 mol of cysteine to generate lanthionine, are quantitatively less significant. The kinetic data were employed to simulate the turnover numbers of the various CBS-catalyzed reactions at physiologically relevant substrate concentrations. At equimolar concentrations of CBS and CSE, the simulations predict that H2S production by CBS would account for approximately 25-70% of the total H2S generated via the trans-sulfuration pathway depending on the extent of allosteric activation of CBS by S-adenosylmethionine. The relative contribution of CBS to H2S genesis is expected to decrease under hyperhomocysteinemic conditions. CBS is predicted to be virtually the sole source of lanthionine, and CSE, but not CBS, efficiently cleaves lanthionine. The insensitivity of the CBS-catalyzed H2S-generating reactions to the grade of hyperhomocysteinemia is in stark contrast to the responsiveness of CSE and suggests a previously unrecognized role for CSE in intracellular homocysteine management. Finally, our studies reveal that the profligacy of the trans-sulfuration pathway results not only in a multiplicity of H2S-yielding reactions but also yields novel thioether metabolites, thus increasing the complexity of the sulfur metabolome.
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PMID:Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. 1953 79

Mitochondrial mechanism of oxidative stress and matrix metalloproteinase (MMP) activation was unclear. Our recent data suggested that MMPs are localized to mitochondria and activated by peroxynitrite, which causes cardiovascular remodeling and failure. Recently, we have demonstrated that elevated levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) increase oxidative stress in the mitochondria. Although HHcy causes heart failure, interestingly, it is becoming very clear that Hcy can generate hydrogen sulfide (H2S), if the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL) are present. H2S is a strong anti-oxidant and vasorelaxing agent. Paradoxically, it is interesting that Hcy, a precursor of H2S can be cardioprotective. The CGL is ubiquitous, while the CBS is not present in the vascular tissues. Therefore, under normal condition, only half of Hcy can be converted to H2S. However, there is strong potential for gene therapy of CBS to vascular tissue that can mitigate the detrimental effects of Hcy by converting it to H2S. This scenario is possible, if the activities of both the enzymes (CBS and CGL) are increased in tissues by gene therapy.
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PMID:Homocysteine, hydrogen sulfide (H2S) and NMDA-receptor in heart failure. 2036 7

Research in the last two decades has transformed the way hydrogen sulphide (H2S) is perceived from a noxious gas to a gaso-transmitter with a vast potential in pharmacotherapy. H2S is synthesized in various body-systems using the enzymes cystathionine beta-synthase and cystathionine gamma-lyase; either of these being the predominat enzyme in a particular system. H2S may be one of the physiological modulators of blood pressure in humans. The gas relaxes the vascular smooth muscle cells by opening up K(ATP) channels. Moreover, it suppresses the proliferation of vascular smooth muscle cells. H2S may also be contributing in the protection afforded by ischaemia-preconditioning. Testosterone is thought to be responsible for the higher central nervous system level of H2S in males. In the central nervous system, H2S is implicated in Alzheimer's disease, epilepsy, stroke and Down's syndrome. Insulin secretion is associated with a decrease in the H2S levels. Raised H2S is detrimental in acute pancreatitis as well as in septic shock. Recently, H2S-releasing derivatives of certain drugs have shown promise in protection against gastric ulcer and in inflammatory bowel disease. The beneficial effects of certain sulphur containing herbs like ginseng and garlic may be mediated via H2S. In future, development of specific drugs modulating H2S levels may prove beneficial in varied disorders.
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PMID:Gaso-transmitter hydrogen sulphide: potential new target in pharmacotherapy. 2111 45

Hydrogen sulfide (H2S), an endogenously produced small molecule, protects animals from various stresses. Recent studies demonstrate that animals exposed to H2S are long lived, resistant to hypoxia, and resistant to ischemia-reperfusion injury. We performed a forward genetic screen to gain insights into the molecular mechanisms Caenorhabditis elegans uses to appropriately respond to H2S. At least two distinct pathways appear to be important for this response, including the H2S-oxidation pathway and the hydrogen cyanide (HCN)-assimilation pathway. The H2S-oxidation pathway requires two distinct enzymes important for the oxidation of H2S: the sulfide:quinone reductase sqrd-1 and the dioxygenase ethe-1. The HCN-assimilation pathway requires the cysteine synthase homologs cysl-1 and cysl-2. A low dose of either H2S or HCN can activate hypoxia-inducible factor 1 (HIF-1), which is required for C. elegans to respond to either gas. sqrd-1 and cysl-2 represent the entry points in the H2S-oxidation and HCN-assimilation pathways, respectively, and expression of both of these enzymes is highly induced by HIF-1 in response to both H2S and HCN. In addition to their role in appropriately responding to H2S and HCN, we found that cysl-1 and cysl-2 are both essential mediators of innate immunity against fast paralytic killing by Pseudomonas. Furthermore, in agreement with these data, we showed that growing worms in the presence of H2S is sufficient to confer resistance to Pseudomonas fast paralytic killing. Our results suggest the hypoxia-independent hif-1 response in C. elegans evolved to respond to the naturally occurring small molecules H2S and HCN.
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PMID:The response of Caenorhabditis elegans to hydrogen sulfide and hydrogen cyanide. 2184 Aug 52

The aims of this study were to investigate the presence of H2S-positive (H2S+) neurons and to study their distribution of in the nuclei of the medulla oblongata and the pons which are included in the cardiovascular center. Using immunocytochemical method to detect cystathionine beta-synthase, the presence of H2S+ neurons was demonstrated in the nuclei studied of Wistar rats (n = 16). More intense the reaction was detected in the large cells of motor nuclei, whereas the small cells of sensory nuclei usually had low-to-moderate enzyme activity. The data obtained provide a considerable amount of new information regarding the organization of brain nerve centers, including those controlling the cardiovascular system.
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PMID:[H2S-positive neurons in some nuclei of cardiovascular center of rat brain]. 2272 30


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