Inhibition of Cysteine Protease Activity by NO-donors

Ascenzi, Paolo; Salvati, Luca; Bolognesi, Martino; Colasanti, Marco; Polticelli, Fabio; Venturini, Giorgio

doi:10.2174/1389203013381170

Cited by 76 publications

(45 citation statements)

References 98 publications

(167 reference statements)

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“…Each of these enzymes possess active site cysteines that are reactive and susceptible to covalent modification (31)(32)(33). In the caspase activity assay, 10 M Aldi-1 or Aldi-2 showed no inhibitory effect on caspase-6, whereas the caspase-6 specific inhibitor, LE22, completely abolished the activity of this protease (Fig.…”

Section: Inhibition By Aldi Compounds Is Specific To Aldehydementioning

confidence: 96%

Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Khanna

Chen

Kimble-Hill

et al. 2011

Journal of Biological Chemistry

101

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Background: ALDH enzymes metabolize aldehydes in many pathways, including the inactivation of cyclophosphamide. Results: Covalent inhibitors against ALDH were discovered, and their mechanism of action was determined. Conclusion: Covalent inhibitors against ALDH potentiate cell killing in cyclophosphamide-resistant cells. Significance: These inhibitors represent novel research tools and can serve as leads toward therapeutics where increased ALDH activity is associated with disease.

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Section: Inhibition By Aldi Compounds Is Specific To Aldehydementioning

confidence: 96%

Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Khanna

Chen

Kimble-Hill

et al. 2011

Journal of Biological Chemistry

101

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“…Exogenous nitric oxide and physiologically relevant NO donors, such as S-nitrosoglutathine, SIN-1, SNP, and GEA3162 significantly enhanced neutrophil apoptosis [44][45][46][47][48]. Interestingly, high levels of ROS or reactive nitrogen species (RNS) inhibit caspase activity, indicating that an alternative caspase-independent death pathway may be involved in ROS-induced cell death [49,50]. It was reported that oxidative stress can trigger endonuclease G-mediated DNA fragmentation in the absence of caspase activity, providing a possible caspase-independent death pathway mediating ROS-induced neutrophil death [51].…”

Section: Intracellular Mediators Of Neutrophil Apoptosismentioning

confidence: 99%

Constitutive neutrophil apoptosis: Mechanisms and regulation

2007

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Neutrophil constitutive death is a critical cellular process for modulating neutrophil number and function, and it plays an essential role in neutrophil homeostasis and the resolution of inflammation. Neutrophils die due to programmed cell death or apoptosis. In this article, we review recent studies on the mechanism of neutrophil apoptosis. The involvement of caspase, calpain, reactive oxygen species, cellular survival/death signaling pathways, mitochondria, and BCL-2 family member proteins are discussed. The fate of neutrophils can be influenced within the inflammatory microenvironment. We summarize the current understanding regarding the modulation of neutrophil apoptotic death by various extracellular stimuli such as proinflammatory cytokines, cell adhesion, phagocytosis, red blood cells, and platelets. The involvement of neutrophil apoptosis in infectious and inflammatory diseases is also addressed. Am. J. Hematol. 83:288-295, 2008. V

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“…Consensus S-nitrosylation motifs have been postulated by Stamler et al (1997). These motifs have been suggested to contain hydrophilic residues adjacent to the specific cysteine either in the primary structure (Stamler et al, 1997) or brought together by three-dimensional (3D) conformations (Ascenzi et al, 2000(Ascenzi et al, , 2001. However, our previous studies, utilizing short peptide sequences, suggested that S-nitrosylation may be independent of the amino acids surrounding the cysteine residue.…”

Section: Introductionmentioning

confidence: 99%

Identification of the Cysteine Nitrosylation Sites in Human Endothelial Nitric Oxide Synthase

Tummala

Ryzhov

Ravi

et al. 2008

DNA and Cell Biology

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S-nitrosylation, or the replacement of the hydrogen atom in the thiol group of cysteine residues by a -NO moiety, is a physiologically important posttranslational modification. In our previous work we have shown that Snitrosylation is involved in the disruption of the endothelial nitric oxide synthase (eNOS) dimer and that this involves the disruption of the zinc (Zn) tetrathiolate cluster due to the S-nitrosylation of Cysteine 98. However, human eNOS contains 28 other cysteine residues whose potential to undergo S-nitrosylation has not been determined. Thus, the goal of this study was to identify the cysteine residues within eNOS that are susceptible to S-nitrosylation in vitro. To accomplish this, we utilized a modified biotin switch assay. Our modification included the tryptic digestion of the S-nitrosylated eNOS protein to allow the isolation of S-nitrosylated peptides for further identification by mass spectrometry. Our data indicate that multiple cysteine residues are capable of undergoing S-nitrosylation in the presence of an excess of a nitrosylating agent. All these cysteine residues identified were found to be located on the surface of the protein according to the available X-ray structure of the oxygenase domain of eNOS. Among those identified were Cys 93 and 98, the residues involved in the formation of the eNOS dimer through a Zn tetrathiolate cluster. In addition, cysteine residues within the reductase domain were identified as undergoing S-nitrosylation. We identified cysteines 660, 801, and 1113 as capable of undergoing S-nitrosylation. These cysteines are located within regions known to bind flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and nicotinamide adenine dinucleotide (NADPH) although from our studies their functional significance is unclear. Finally we identified cysteines 852, 975=990, and 1047=1049 as being susceptible to Snitrosylation. These cysteines are located in regions of eNOS that have not been implicated in any known biochemical functions and the significance of their S-nitrosylation is not clear from this study. Thus, our data indicate that the eNOS protein can be S-nitrosylated at multiple sites other than within the Zn tetrathiolate cluster, suggesting that S-nitrosylation may regulate eNOS function in ways other than simply by inducing dimer collapse.

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Inhibition of Cysteine Protease Activity by NO-donors

Cited by 76 publications

References 98 publications

Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Constitutive neutrophil apoptosis: Mechanisms and regulation

Identification of the Cysteine Nitrosylation Sites in Human Endothelial Nitric Oxide Synthase

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