Emerging Chemical Biology of Protein Persulfidation

Abstract

Significance: Protein persulfidation (the formation of RSSH), an evolutionarily conserved oxidative posttranslational modification in which thiol groups in cysteine residues are converted into persulfides, has emerged as one of the main mechanisms through which hydrogen sulfide (H 2 S) conveys its signaling. Recent Advances: New methodological advances in persulfide labeling started unraveling the chemical biology of this modification and its role in (patho)physiology. Some of the key metabolic enzymes are regulated by persulfidation. RSSH levels are important for the cellular defense against oxidative injury, and they decrease with aging, leaving proteins vulnerable to oxidative damage. Persulfidation is dysregulated in many diseases. Critical Issues: A relatively new field of signaling by protein persulfidation still has many unanswered questions: the mechanism(s) of persulfide formation and transpersulfidation and the identification of “protein persulfidases,” the improvement of methods to monitor RSSH changes and identify protein targets, and understanding the mechanisms through which this modification controls important (patho)physiological functions. Future Directions: Deep mechanistic studies using more selective and sensitive RSSH labeling techniques will provide high-resolution structural, functional, quantitative, and spatiotemporal information on RSSH dynamics and help with better understanding how H 2 S-derived protein persulfidation affects protein structure and function in health and disease. This knowledge could pave the way for targeted drug design for a wide variety of pathologies. Antioxid. Redox Signal. 39, 19–39.

Sulfite oxidase deficiency causes persulfidation loss and H2S release

“…Protein persulfidation protects the respective proteins from sulfonylation (R-SO 3 H) of cysteine residues and a subsequent loss of protein functions. Currently, the effect of reduced protein persulfidation had been mainly studied in the context of aging (Zivanovic et al, 2019), its impacts on the specific proteins remained sparse with only a handful of examples such as the persulfidation on human GAPDH (Cys152), human CSE (Cys252, 255, 307, and 310), and human eNOS (Cys443), which increase the respective enzymes’ activities, while the persulfidation on human PTP1B (Cys215) suppresses its activity (Luo et al, 2023; Vignane & Filipovic, 2023). Therefore, our study identified a large pool of proteins with sulfite-sensitive persulfides that may collectively or individually have contributed to the disease pathology in SOXD.…”

Persulfidome of Sweet Pepper Fruits during Ripening: The Case Study of Leucine Aminopeptidase That Is Positively Modulated by H2S

“…One of the mechanisms by which H 2 S regulates protein functions is by an oxiPTM named persulfidation [ 64 , 65 , 66 ], and the bulk of the proteins that undergo persulfidation are designated as the persulfidome. Research on the persulfidome is more advanced in animal cells [ 67 , 68 , 69 , 70 , 71 , 72 ], while in plants, as mentioned previously, most studies have focused on Arabidopsis, and to our knowledge, the persulfidome of any fruit is still unknown, as are the ways in which it could be modulated by ripening events since most studies have focused thus far on the Arabidopsis model plant under physiological and stress conditions [ 8 , 17 , 32 , 73 , 74 , 75 ].…”

Chemoselective Proteomics, Zinc Fingers, and a Zinc(II) Model for H2S Mediated Persulfidation

“…Persulfidation of cysteine residues (RSH→RSSH) is emerging as an important modification for posttranslational regulation of protein function [1,7c] . In addition to the enzyme activation and inactivation, persulfidation also has a protective role, serving as the evolutionarily conserved protective loop for protection of thiols from overoxidation [14a] .…”