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 (H(2)S) was historically recognized as a toxic gas generated by natural resources. However, its enzymatic production from L-cysteine has recently been demonstrated in mammals. Cystathionine beta-synthase and cystathionine gamma-lyase, both of which can produce H(2)S, were expressed in mouse pancreatic islet cells and the beta-cell line, MIN6. L-cysteine and the H(2)S donor NaHS inhibited glucose-induced insulin release from islets and MIN6 cells. These inhibitory effects were reproduced when insulin release was stimulated by alpha-ketoisocaproate, tolbutamide, or high K+. L-cysteine and NaHS inhibited glucose-potentiated insulin release in the copresence of diazoxide and high K+. Real-time imaging of intracellular Ca2+ concentration ([Ca2+](i)) demonstrated that both L-cysteine and NaHS reversibly suppressed glucose-induced [Ca2+](i) oscillation in a single beta-cell without obvious changes in the mean value. These substances inhibited Ca2+ - or guanosine 5'-0-3-thiotriphosphate-induced insulin release from islets permeabilized with streptolysin-O. L-cysteine and NaHS reduced ATP production and attenuated glucose-induced hyperpolarization of the mitochondrial membrane potential. Finally, L-cysteine increased H(2)S content in MIN6 cells. We suggest here that L-cysteine inhibits insulin release via multiple actions on the insulin secretory process through H(2)S production. Because the activities of H(2)S-producing enzymes and the tissue H(2)S contents are known to increase under diabetic conditions, the inhibition may participate in the deterioration of insulin release in this disease.
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PMID:L-cysteine inhibits insulin release from the pancreatic beta-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. 1664 96

Mutations in ClC-5 (chloride channel 5), a member of the ClC family of chloride ion channels and antiporters, have been linked to Dent's disease, a renal disease associated with proteinuria. Several of the disease-causing mutations are premature stop mutations which lead to truncation of the C-terminus, pointing to the functional significance of this region. The C-terminus of ClC-5, like that of other eukaryotic ClC proteins, is cytoplasmic and contains a pair of CBS (cystathionine beta-synthase) domains connected by an intervening sequence. The presence of CBS domains implies a regulatory role for nucleotide interaction based on studies of other unrelated proteins bearing these domains [Ignoul and Eggermont (2005) Am. J. Physiol. Cell Physiol. 289, C1369-C1378; Scott, Hawley, Green, Anis, Stewart, Scullion, Norman and Hardie (2004) J. Clin. Invest. 113, 274-284]. However, to date, there has been no direct biochemical or biophysical evidence to support nucleotide interaction with ClC-5. In the present study, we have expressed and purified milligram quantities of the isolated C-terminus of ClC-5 (CIC-5 Ct). CD studies show that the protein is compact, with predominantly alpha-helical structure. We determined, using radiolabelled ATP, that this nucleotide binds the folded protein with low affinity, in the millimolar range, and that this interaction can be competed with 1 muM AMP. CD studies show that binding of these nucleotides causes no significant change in secondary structure, consistent with a model wherein these nucleotides bind to a preformed site. However, both nucleotides induce an increase in thermal stability of ClC-5 Ct, supporting the suggestion that both nucleotides interact with and modify the biophysical properties of this protein.
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PMID:Nucleotides bind to the C-terminus of ClC-5. 1668 97

Synechococcus elongatus PCC 7942 was able to grow with several S sources. The sulphur metabolizing enzymes viz. ATP sulphurylase, cysteine synthase, thiosulphate reductase and L- and D-cysteine desulphydrases were regulated by sulphur sources, particularly by sulphur amino acids and organic sulphate esters. Sulphur starvation reduced ATP sulphurylase and cysteine synthase whereas reduced glutathione appreciated Cys degradation activity. With partially purified enzymes apparent Km values for sulphate, ATP, D- and L-Cys, thiosulphate, sulphide and O-acetyl serine were in a range of 12-50 microM. p-Nitrophenyl sulphate inhibited ATP sulphurylase competitively. Met was a feedback inhibitor of several key enzymes.
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PMID:Catalytic and regulatory properties of sulphur metabolizing enzymes in cyanobacterium Synechococcus elongatus PCC 7942. 1699 35

Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
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PMID:Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. 1737 2

AMP-activated kinase (AMPK) is central to sensing energy status in eukaryotic cells via binding of AMP and ATP to CBS (cystathionine beta-synthase) domains in the regulatory gamma subunit. The structure of a CBS-domain pair from human AMPK gamma1 in complex with the physiological activator AMP and the pharmacological activator ZMP (AICAR) is presented.
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PMID:Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. 1745 84

CBS (cystathionine beta-synthase) domains are found in proteins from all kingdoms of life, and point mutations in these domains are responsible for a variety of hereditary diseases in humans; however, the functions of CBS domains are not well understood. In the present study, we cloned, expressed in Escherichia coli, and characterized a family II PPase (inorganic pyrophosphatase) from Moorella thermoacetica (mtCBS-PPase) that has a pair of tandem 60-amino-acid CBS domains within its N-terminal domain. Because mtCBS-PPase is a dimer and requires transition metal ions (Co2+ or Mn2+) for activity, it resembles common family II PPases, which lack CBS domains. The mtCBS-PPase, however, has lower activity than common family II PPases, is potently inhibited by ADP and AMP, and is activated up to 1.6-fold by ATP. Inhibition by AMP is competitive, whereas inhibition by ADP and activation by ATP are both of mixed types. The nucleotides are effective at nanomolar (ADP) or micromolar concentrations (AMP and ATP) and appear to compete for the same site on the enzyme. The nucleotide-binding affinities are thus 100-10000-fold higher than for other CBS-domain-containing proteins. Interestingly, genes encoding CBS-PPase occur most frequently in bacteria that have a membrane-bound H+-translocating PPase with a comparable PP(i)-hydrolysing activity. Our results suggest that soluble nucleotide-regulated PPases act as amplifiers of metabolism in bacteria by enhancing or suppressing ATP production and biosynthetic reactions at high and low [ATP]/([AMP]+[ADP]) ratios respectively.
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PMID:A CBS domain-containing pyrophosphatase of Moorella thermoacetica is regulated by adenine nucleotides. 1771 78

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

The purpose of the present study was to verify our assumption that rhythmic respiratory activity may be regulated by endogenous hydrogen sulfide (H(2)S) in the medullary slices of neonatal rats. We found that a moderate concentration of donor of H(2)S, NaHS, mainly induced diphasic respiratory responses indicated by changes of discharge frequency (DF) of hypoglossal rootlets, an initial inhibitory stage followed by a later excitatory one. Cystathionine beta-synthase (CBS) substrate, cysteine (CYS), exerted similar effects. CBS inhibitor, NH(2)OH, could eliminate both inhibitory and excitatory effects in the two stages induced by CYS. K(ATP) channel blocker, glibenclamide (Gl), could eliminate the decrease in DF in the initial stage, but not the increase in the later one. On the other hand, adenyl cyclase (AC) inhibitor, SQ-22536 (SQ) could eliminate the increase in DF in the later stage, but not the decrease in the initial one, of the rootlets caused by NaHS. Co-application of Gl and SQ eliminated both inhibitory and excitatory effect induced by NaHS. The cAMP level was increased in the later stage but not in the initial one by NaHS, and the increase in the cAMP level could be eliminated by SQ. It can be concluded that the endogenous H(2)S could be produced through the CBS-H(2)S pathway and could be involved in the control of the central rhythmic respiration in the in vitro medullary slices of neonatal rats by opening K(ATP) channels and activating AC-cAMP pathway of the neurons.
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PMID:Endogenous hydrogen sulfide is involved in regulation of respiration in medullary slice of neonatal rats. 1879

Hydrogen sulfide (H(2)S) has been known for hundreds of years because of its poisoning effect. Once the basal bio-production became evident its pathophysiological role started to be investigated in depth. H(2)S is a gas that can be formed by the action of two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, both involved in the metabolism of cysteine. It has several features in common with the other two well known "gasotransmitters" (nitric oxide and carbon monoxide) in the biological systems. These three gasses share some biological targets; however, they also have dissimilarities. For instance, the three gases target heme-proteins and open K(ATP) channels; H(2)S as NO is an antioxidant, but in contrast to the latter molecule, H(2)S does not directly form radicals. In the last years H(2)S has been implicated in several physiological and pathophysiological processes such as long term synaptic potentiation, vasorelaxation, pro- and anti-inflammatory conditions, cardiac inotropism regulation, cardioprotection, and several other physiological mechanisms. We will focus on the biological role of H(2)S as a molecule able to trigger cell signaling. Our attention will be particularly devoted on the effects in cardiovascular system and in cardioprotection. We will also provide available information on H(2)S-donating drugs which have so far been tested in order to conjugate the beneficial effect of H(2)S with other pharmaceutical properties.
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PMID:Physiological and pharmacological features of the novel gasotransmitter: hydrogen sulfide. 1928 49

In mammals, 5'-AMP-activated protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic serine/threonine kinase subunit (alpha) and two regulatory subunits (beta and gamma). The gamma-subunit senses the intracellular energy status by competitively binding AMP and ATP and is thought to be responsible for allosteric regulation of the whole complex. We describe herein the crystal structure of protein MJ1225 from Methanocaldococcus jannaschii complexed to AMP, ADP, and ATP. Our data provide evidence of a strong conservation of the key functional features seen in the gamma-subunit of the eukaryotic AMPK, and more importantly, it reveals a novel AMP binding site, herein denoted as site E, which had not been previously described in cystathionine beta-synthase domains so far. Site E is located in a small cavity existing between the alpha-helices structurally equivalent to those disrupting the internal symmetry of each Bateman domain in gamma-AMPKs and shows striking similarities with a symmetry-related crevice of the mammalian enzyme that hosts the pathological mutation N488I.
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PMID:The crystal structure of protein MJ1225 from Methanocaldococcus jannaschii shows strong conservation of key structural features seen in the eukaryal gamma-AMPK. 2038 58


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