β-Cyanoalanine, an inhibitor of rat liver cystathionase

Pfeffer, Morris; Ressler, Charlotte

doi:10.1016/0006-2952(67)90217-1

Cited by 69 publications

(41 citation statements)

References 24 publications

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“…11 In our studies, inhibition of L-cysteine-induced relaxations were affected to a different extent by PAG and BCA, with the former exhibiting a greater inhibitory effect. Although both inhibit CSE, PAG is a noncompetitive/"suicide" inhibitor, whereas BCA is a competitive inhibitor 14,15 ; thus combining PAG and BCA would not be expected to yield an additional effect. Similarly to what was observed with L-cysteine, endotheliumdependent relaxations triggered by Ach were attenuated by A B C Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Bucci

Papapetropoulos

Vellecco

et al. 2010

ATVB

315

238

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Objective-Recent studies have demonstrated that hydrogen sulfide (H 2 S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H 2 S generated from cystathione ␥-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H 2 S are still under investigation. Methods and Results-Using isolated aortic rings, we observed that addition of L-cysteine led to a concentrationdependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PAG) and ␤-cyano-L-alanine (BCA). Moreover, incubation with PAG or BCA resulted in a rightward shift in sodium nitroprusside-and isoproterenol-induced relaxation. Aortic tissues exposed to PAG or BCA contained lower levels of cGMP, exposure of cells to exogenous H 2 S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H 2 S on cGMP accumulation. The ability of H 2 S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H 2 S to a cell-free system inhibited both cGMP and cAMP breakdown. Conclusion-These findings provide direct evidence that H 2 S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited. Key Words: endothelium Ⅲ hypertension Ⅲ signal transduction Ⅲ vascular muscle Ⅲ vasodilation Ⅲ cystathione ␥-lyase Ⅲ hydrogen sulfide Ⅲ cAMP Ⅲ cGMP Ⅲ phosphodiesterase N itric oxide (NO) is believed to account for most of the endothelium-derived relaxing factor activity released within the vessel wall, at least in some vessels. 1 On muscarinic stimulation, NO is produced following the conversion of L-arginine to NO by endothelial nitric oxide synthase (eNOS). 2 NO diffuses from the endothelium to the underlying smooth muscle cell layer, where it stimulates soluble guanylate cyclase to produce cGMP. cGMP in turn activates protein kinase G (PKG), which initiates a cascade of events leading to relaxation. 2,3 Hydrogen sulfide (H 2 S) is emerging as a new gaseous signaling molecule in the cardiovascular system. 4,5 Vascular endothelial cells express cystathionine ␥-lyase (CSE) and produce measurable amounts of this gasotransmitter. 6 Recent evidence suggests that H 2 S exhibits endothelium-derived relaxing factor activity. 6 In addition, it has been shown that muscarinic stimulation leads to CSE activation in the endothelium, triggering the conversion of L-cysteine to H 2 S and that CSE, like eNOS, is a calcium/calmodulindependent enzyme. Therefore, within the vascular wall, these 2 pathways coexist and serve a similar function. The relative amounts of NO versus H 2 S likely depend on the vascular bed studied 7 or on the state of the tissue, eg, healthy versus diseased. 5,8 Mice with targeted disruption of the CSE locus (CSE null mice) exhibit hypertension, similarly to what is observe...

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Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Bucci

Papapetropoulos

Vellecco

et al. 2010

ATVB

315

238

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“…2). In contrast, D,L-propargylglycine, an irreversible inhibitor of CSE (IC,, = 10m4 M) that has no effect on CBS (Uren et al, 1978;Stipanuk and Beck, 1982), and p-cyano-L-alanine, a competitive inhibitor of CSE (IC,, = 10e5 M), which also does not block CBS (Rfeffer and Ressler, 1967;Uren et al, 1978), only weakly suppressed the H,S production (13 and 19%, respectively).…”

Section: Hs Production In the Brainmentioning

confidence: 93%

The possible role of hydrogen sulfide as an endogenous neuromodulator

1996

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Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously from L-cysteine in mammalian tissues. H2S is present at relatively high levels in the brain, suggesting that it has a physiological function. Two other gases, nitric oxide and carbon monoxide, are also endogenously produced and have been proposed as neuronal messengers in the brain. In this work we show the following: (1) an H2S-producing enzyme, cystathionine beta-synthase (CBS), is highly expressed in the hippocampus; (2) CBS inhibitors hydroxylamine and amino-oxyacetate suppress the production of brain H2S; and (3) a CBS activator, S-adenosyl-L-methionine, enhances H2S production, indicating that CBS contributes to the production of endogenous H2S. We also show that physiological concentrations of H2S selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation. These observations suggest that endogenous H2S functions as a neuromodulator in the brain.

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“…Some of the commonly used pharmacological inhibitors of CSE are DL-propargylglycine (PAG) (Marcotte and Walsh 1975) which irreversibly inhibits CSE by physically obstructing the access of the substrate to the active site of the enzyme (Sun et al 2009) and the reversible inhibitor β-cyanoalanine (BCA) which has also been proposed as a competitive inhibitor of this enzyme (Pfeffer and Ressler 1967). However, these compounds have frequently been claimed to exhibit poor selectivity, require high concentrations and have limited ability to permeate the cell membrane (Szab o 2007).…”

Section: Frequently Used Inhibitors and Mouse Knockout Models Of H 2 mentioning

confidence: 99%

H2S Synthesizing Enzymes: Biochemistry and Molecular Aspects

Huang

Moore

2015

Handbook of Experimental Pharmacology

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Hydrogen sulfide (H2S) is a biologically active gas that is synthesized naturally by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthetase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are constitutively present in a wide array of biological cells and tissues and their expression can be induced by a number of disease states. It is becoming increasingly clear that H2S is an important mediator of a wide range of cell functions in health and in disease. This review therefore provides an overview of the biochemical and molecular regulation of H2S synthesizing enzymes both in physiological conditions and their modulation in disease states with particular focus on their regulation in asthma, atherosclerosis and diabetes. The importance of small molecule inhibitors in the study of molecular pathways, the current use of common H2S synthesizing enzyme inhibitors and the relevant characteristics of mice in which these enzymes have been genetically deleted will also be summarized. With a greater understanding of the molecular regulation of these enzymes in disease states, as well as the availability of novel small molecules with high specificity targeted towards H2S producing enzymes, the potential to regulate the biological functions of this intriguing gas H2S for therapeutic effect can perhaps be brought one step closer.

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β-Cyanoalanine, an inhibitor of rat liver cystathionase

Cited by 69 publications

References 24 publications

Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

The possible role of hydrogen sulfide as an endogenous neuromodulator

H2S Synthesizing Enzymes: Biochemistry and Molecular Aspects

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