Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.1.22 (cystathionine beta-synthase)
 965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gram-positive human pathogen Staphylococcus aureus is often isolated with media containing potassium tellurite, to which it has a higher level of resistance than Escherichia coli. The S. aureus cysM gene was isolated in a screen for genes that would increase the level of tellurite resistance of E. coli DH5alpha. The protein encoded by S. aureus cysM is sequentially and functionally homologous to the O-acetylserine (thiol)-lyase B family of cysteine synthase proteins. An S. aureus cysM knockout mutant grows poorly in cysteine-limiting conditions, and analysis of the thiol content in cell extracts showed that the cysM mutant produced significantly less cysteine than wild-type S. aureus SH1000. S. aureus SH1000 cannot use sulfate, sulfite, or sulfonates as the source of sulfur in cysteine biosynthesis, which is explained by the absence of genes required for the uptake and reduction of these compounds in the S. aureus genome. S. aureus SH1000, however, can utilize thiosulfate, sulfide, or glutathione as the sole source of sulfur. Mutation of cysM caused increased sensitivity of S. aureus to tellurite, hydrogen peroxide, acid, and diamide and also significantly reduced the ability of S. aureus to recover from starvation in amino acid- or phosphate-limiting conditions, indicating a role for cysteine in the S. aureus stress response and survival mechanisms.
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PMID:Role of a cysteine synthase in Staphylococcus aureus. 1499 87

The enzymes of the transsulfuration pathway also have the capacity to catalyze the desulfhydration of cysteine. Recent studies demonstrate a role of the transsulfuration enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, in catalyzing the desulfhydration of cysteine in brain and smooth muscle. The H2S produced from cysteine functions as a neuromodulator and smooth muscle relaxant. In glutamatergic neurons, the production of H2S by cystathionine beta-synthase enhances N-methyl-D-aspartate (NMDA) receptor-mediated currents. In smooth muscle cells, H2S produced by cystathionine gamma-lyase enhances the outward flux of potassium by opening potassium channels, leading to hyperpolarization of membrane potential and smooth muscle relaxation.
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PMID:New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant. 1549 68

The ATPase subunit of the osmoregulatory ATP-binding cassette transporter OpuA from Lactococcus lactis has a C-terminal extension, the tandem cystathionine beta-synthase (CBS) domain, which constitutes the sensor that allows the transporter to sense and respond to osmotic stress (Biemans-Oldehinkel, E., Mahmood, N. A. B. N., and Poolman, B. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 10624-10629). C-terminal of the tandem CBS domain is an 18-residue anionic tail (DIPDEDEVEEIEKEEENK). To investigate the ion specificity of the full transporter, we probed the activity of inside-out reconstituted wild-type OpuA and the anionic tail deletion mutant OpuADelta12; these molecules have the tandem CBS domains facing the external medium. At a mole fraction of 40% of anionic lipids in the membrane, the threshold ionic strength for activation of OpuA was approximately 0.15, irrespective of the electrolyte composition of the medium. At equivalent concentrations, bivalent cations (Mg(2+) and Ba(2+)) were more effective in activating OpuA than NH(4)(+), K(+), Na(+), or Li(+), consistent with an ionic strength-based sensing mechanism. Surprisingly, Rb(+) and Cs(+) were potent inhibitors of wild-type OpuA, and 0.1 mM RbCl was sufficient to completely inhibit the transporter even in the presence of 0.2 M KCl. Rb(+) and Cs(+) were no longer inhibitory in OpuADelta12, indicating that the anionic C-terminal tail participates in the formation of a binding site for large alkali metal ions. Compared with OpuADelta12, wild-type OpuA required substantially less potassium ions (the dominant ion under physiological conditions) for activation. Our data lend new support for the contention that the CBS module in OpuA constitutes the ionic strength sensor whose activity is modulated by the C-terminal anionic tail.
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PMID:Ion specificity and ionic strength dependence of the osmoregulatory ABC transporter OpuA. 1684 87

Hydrogen sulfide (H2S) is a recently identified gasotransmitter that may mediate hypoxic responses in vascular smooth muscle. H2S also appears to be a signaling molecule in mammalian non-vascular smooth muscle, but its existence and function in non-mammalian non-vascular smooth muscle have not been examined. In the present study we examined H2S production and its physiological effects in urinary bladder from steelhead and rainbow trout (Oncorhynchus mykiss) and evaluated the relationship between H2S and hypoxia. H2S was produced by trout bladders, and its production was sensitive to inhibitors of cystathionine beta-synthase and cystathionine gamma-lyase. H2S produced a dose-dependent relaxation in unstimulated and carbachol pre-contracted bladders and inhibited spontaneous contractions. Bladders pre-contracted with 80 mmol l(-1) KCl were less sensitive to H2S than bladders contracted with either 80 mmol l(-1) KC2H3O2 (KAc) or carbachol, suggesting that some of the H2S effects are mediated through an ion channel. However, H2S relaxation of bladders was not affected by the potassium channel inhibitors, apamin, charybdotoxin, 4-aminopyridine, and glybenclamide, or by chloride channel/exchange inhibitors 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt, tamoxifen and glybenclamide, or by the presence or absence of extracellular HCO3-. Inhibitors of neuronal mechanisms, tetrodotoxin, strychnine and N-vanillylnonanamide were likewise ineffective. Hypoxia (aeration with N2) also relaxed bladders, was competitive with H2S for relaxation, and it was equally sensitive to KCl, and unaffected by neuronal blockade or the presence of extracellular HCO3-. Inhibitors of H2S synthesis also inhibited hypoxic relaxation. These experiments suggest that H2S is a phylogenetically ancient gasotransmitter in non-mammalian non-vascular smooth muscle and that it serves as an oxygen sensor/transducer, mediating the effects of hypoxia.
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PMID:Hydrogen sulfide mediates hypoxia-induced relaxation of trout urinary bladder smooth muscle. 1688 71

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

We have previously shown that the C-terminal cystathionine beta-synthase (CBS) domains of the nucleotide-binding domains of the ABC transporter OpuA, in conjunction with an anionic membrane surface function, act as sensor of internal ionic strength (I(in)). Here, we show that a surface-exposed cationic region in the CBS module domain is critical for ion sensing. The consecutive substitution of up to five cationic residues led to a gradual decrease of the ionic strength dependence of transport. In fact, a 5-fold mutant was essentially independent of salt in the range from 0 to 250 mm KCl (or NaCl), supplemented to medium of 30 mm potassium phosphate. Importantly, the threshold temperature for transport was lowered by 5-7 degrees C and the temperature coefficient Q(10) was lowered from 8 to approximately 1.5 in the 5-fold mutant, indicating that large conformational changes are accompanying the CBS-mediated regulation of transport. Furthermore, by replacing the anionic C-terminal tail residues that extend the CBS module with histidines, the transport of OpuA became pH-dependent, presumably by additional charge interactions of the histidine residues with the membrane. The pH dependence was not observed at high ionic strength. Altogether the analyses of the CBS mutants support the notion that the osmotic regulation of OpuA involves a simple biophysical switching mechanism, in which nonspecific electrostatic interactions of a protein module with the membrane are sufficient to lock the transporter in the inactive state.
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PMID:Engineering of ion sensing by the cystathionine beta-synthase module of the ABC transporter OpuA. 1932 26

Environmental toxicants influence development, behavior, and ultimately survival. The nematode Caenorhabditis elegans has proven to be an exceptionally powerful model for toxicological studies. Here, we develop novel technologies to describe the effects of cyanide toxicity with high spatiotemporal resolution. Importantly, we use these methods to examine the genetic underpinnings of cyanide resistance. Caenorhabditis elegans that lack the EGL-9 oxygen sensing enzyme have been shown to be resistant to hydrogen cyanide (HCN) gas produced by the pathogen Pseudomonas aeruginosa PAO1. We demonstrate that the cyanide resistance exhibited by egl-9 mutants is completely dependent on the HIF-1 hypoxia-inducible factor and is mediated by the cysl-2 cysteine synthase, which likely functions in metabolic pathways that inactivate cyanide. Further, the expression of cysl-2 correlates with the degree of cyanide resistance exhibited in each genetic background. We find that each mutant exhibits similar relative resistance to HCN gas on plates or to aqueous potassium cyanide in microfluidic chambers. The design of the microfluidic devices, in combination with real-time imaging, addresses a series of challenges presented by mutant phenotypes and by the chemical nature of the toxicant. The microfluidic assay produces a set of behavioral parameters with increased resolution that describe cyanide toxicity and resistance in C. elegans, and this is particularly useful in analyzing subtle phenotypes. These multiparameter analyses of C. elegans behavior hold great potential as a means to monitor the effects of toxicants or chemical interventions in real time and to study the biological networks that underpin toxicant resistance.
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PMID:Multiparameter behavioral analyses provide insights to mechanisms of cyanide resistance in Caenorhabditis elegans. 2380