Abnormal nitration and S-sulfhydration modification of Sp1-CSE-H2S pathway trap the progress of hyperhomocysteinemia into a vicious cycle

Luo, Cheng-Hua; Ji, Dengyu; Yan, Li; Cao, Yan; Zhang, Shangyue; Yan, Wenjing; Xue, Ke; Chai, Jiayin; Wu, Ye; Liu, Huirong; Wang, Wen

doi:10.1016/j.freeradbiomed.2020.12.440

Cited by 11 publications

(10 citation statements)

References 50 publications

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“…The remaining displayed enzymatic activities similar to the WT enzyme ( Figure 5 ). These results only partially overlap with those reported by Luo et al for the corresponding Cys-to-Ala substitutions [ 23 ]. In that study, C84A, C109A, and C307A CSE had statistically significant lower activity than the WT enzyme, whereas the C70A variant had 50% higher activity.…”

Section: Discussionsupporting

confidence: 78%

“…In vitro SUMOylation of CSE has been reported [ 22 ], although the functional implications remain to be determined. Recently, CSE has been shown to be impaired by nitration of tyrosine residues promoted by excess homocysteine as a result of high dietary methionine in mice [ 23 ]. Notably, in the same report, Luo et al demonstrated that seven cysteine residues (Cys84, Cys109, Cys172, Cys229, Cys252, Cys307, and Cys310) in human CSE expressed in HEK293 cells can be targeted by persulfidation.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, in the same report, Luo et al demonstrated that seven cysteine residues (Cys84, Cys109, Cys172, Cys229, Cys252, Cys307, and Cys310) in human CSE expressed in HEK293 cells can be targeted by persulfidation. Furthermore, except for Cys172 and Cys310, this cysteine modification appears to be important for the CSE H 2 S-synthesizing activity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Asimakopoulou and co-workers reported on CSE inhibition by the NO donor diethylamine NONOate and hypothesized the possibility of cysteine s -nitrosation [ 39 ]. Moreover, as described above, CSE nitration modulated by excess homocysteine negatively impacts CSE activity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Human Cystathionine γ-Lyase Is Inhibited by s-Nitrosation: A New Crosstalk Mechanism between NO and H2S

et al. 2021

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The ‘gasotransmitters’ hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO) act as second messengers in human physiology, mediating signal transduction via interaction with or chemical modification of protein targets, thereby regulating processes such as neurotransmission, blood flow, immunomodulation, or energy metabolism. Due to their broad reactivity and potential toxicity, the biosynthesis and breakdown of H2S, NO, and CO are tightly regulated. Growing evidence highlights the active role of gasotransmitters in their mutual cross-regulation. In human physiology, the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are prominent H2S enzymatic sources. While CBS is known to be inhibited by NO and CO, little is known about CSE regulation by gasotransmitters. Herein, we investigated the effect of s-nitrosation on CSE catalytic activity. H2S production by recombinant human CSE was found to be inhibited by the physiological nitrosating agent s-nitrosoglutathione (GSNO), while reduced glutathione had no effect. GSNO-induced inhibition was partially reverted by ascorbate and accompanied by the disappearance of one solvent accessible protein thiol. By combining differential derivatization procedures and mass spectrometry-based analysis with functional assays, seven out of the ten protein cysteine residues, namely Cys84, Cys109, Cys137, Cys172, Cys229, Cys307, and Cys310, were identified as targets of s-nitrosation. By generating conservative Cys-to-Ser variants of the identified s-nitrosated cysteines, Cys137 was identified as most significantly contributing to the GSNO-mediated CSE inhibition. These results highlight a new mechanism of crosstalk between gasotransmitters.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Human Cystathionine γ-Lyase Is Inhibited by s-Nitrosation: A New Crosstalk Mechanism between NO and H2S

et al. 2021

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“…Importantly, all of them seemed to bear significant selectivities for urease since they did not substantially inhibit other gas‐producing enzymes, that is, cystathionine beta‐synthase (CBS) and cystathionine γ‐lyase (CSE), two H 2 S‐generating enzymes (Figure 1F). Noticeably, EBS at high concentrations could interfere with the activity of CSE (Table 1), suggesting that the modification of Cys could interfere with the activity of CSE, a phenomenon that has been observed previously 40 . Moreover, the potent inhibitory effects of these inhibitors were likely due to on‐target inhibition of JBU rather than the nonspecific reaction with NH 3 or forming an aggregation since they did not react with NH 3 and their inhibition was not attenuated by the detergent (Figure S2A,B).…”

Section: Resultssupporting

confidence: 71%

High‐throughput tandem‐microwell assay for ammonia repositions FDA‐Approved drugs to inhibit Helicobacter pylori urease

Liu

Zhang

et al. 2021

The FASEB Journal

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To date, little attempt has been made to develop new treatments for Helicobacter pylori (H. pylori), although the community is aware of the shortage of treatments for H. pylori. In this study, we developed a 192-tandem-microwell-based highthroughput assay for ammonia that is a known virulence factor of H. pylori and a product of urease. We could identify few drugs, that is, panobinostat, dacinostat, ebselen, captan, and disulfiram, to potently inhibit the activity of ureases from bacterial or plant species. These inhibitors suppress the activity of urease via substrate-competitive or covalent-allosteric mechanism, but all except captan prevent the antibiotic-resistant H. pylori strain from killing human gastric cells, with a more pronounced effect than acetohydroxamic acid, a well-known urease inhibitor and clinically used drug for the treatment of bacterial infection.This study offers several bases for the development of new treatments for ureasecontaining pathogens and to study the mechanism responsible for the regulation of urease activity.

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Overview of cysteine metabolism

Carballal

Banerjee

2022

Redox Chemistry and Biology of Thiols

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Abnormal nitration and S-sulfhydration modification of Sp1-CSE-H2S pathway trap the progress of hyperhomocysteinemia into a vicious cycle

Cited by 11 publications

References 50 publications

Human Cystathionine γ-Lyase Is Inhibited by s-Nitrosation: A New Crosstalk Mechanism between NO and H2S

Human Cystathionine γ-Lyase Is Inhibited by s-Nitrosation: A New Crosstalk Mechanism between NO and H2S

High‐throughput tandem‐microwell assay for ammonia repositions FDA‐Approved drugs to inhibit Helicobacter pylori urease

Overview of cysteine metabolism

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