Chemical Biology of Reactive Sulfur Species: Hydrolysis-Driven Equilibrium of Polysulfides as a Determinant of Physiological Functions

Abstract

Significance: Polysulfide species ( i.e., R-S n -R′, n > 2; and R-S n -H, n > 1) exist in many organisms. The highly nucleophilic nature of hydropersulfides and hydropolysulfides contributes to the potent antioxidant activities of polysulfide species that protect organisms against oxidative and electrophilic stresses. Recent Advances: Accumulating evidence suggests that organic polysulfides (R-S n -R′) readily undergo alkaline hydrolysis, which results in formation of both nucleophilic hydrosulfide/polysulfide (R-S n −1 H) and electrophilic sulfenic acid (R′SOH) species. Polysulfides maintain a steady-state equilibrium that is driven by hydrolysis even in aqueous physiological milieus. This unique property makes polysulfide chemistry and biology more complex than previously believed. Critical Issues: The hydrolysis equilibrium of polysulfides shifts to the right when electrophiles are present. Strong electrophilic alkylating agents ( e.g., monobromobimane) greatly enhance polysulfide hydrolysis, which leads to increased polysulfide degradation and artifactual formation of bis-S-bimane adducts in the absence of free hydrogen sulfide. The finding that hydroxyl group-containing substances such as tyrosine efficiently protected polysulfides from hydrolysis led to development of the new alkylating agent, N -iodoacetyl l -tyrosine methyl ester (TME-IAM). TME-IAM efficiently and specifically traps and stabilizes hydropolysulfides and protects polysulfide chains from hydrolysis, and, when used with mass spectrometry, TME-IAM allows speciation of the reactive sulfur metabolome. In addition, the polyethylene glycol-conjugated maleimide-labeling gel shift assay, which relies on unique hydrolysis equilibrium of polysulfides, will be a reliable technique for proteomics of polysulfide-containing proteins. Future Directions: Using precise methodologies to achieve a better understanding of the occurrence and metabolism of polysulfide species is necessary to gain insights into the undefined biology of polysulfide species. Antioxid. Redox Signal. 36, 327–336.

Reactive sulfur species and their significance in health and disease

“…This high susceptibility of polysulfides (RSS n SR, n ≥1) to hydrolysis distinguishes them from disulfides (RSSR), which undergo a hydrolysis reaction only under strong alkaline conditions. The alkaline hydrolysis of RSSR leads to production of reduced thiol (RSH) and sulfenic acid (RSOH) [ 104 , 110 ]. At neutral pH, the equilibrium of the reaction of RSSR hydrolysis is shifted to the left, so disulfides at physiological pH rather do not undergo hydrolysis.…”

“…It has been shown that various alkylating reagents including IAA, NEM, mBrB or dimedone can enhance the hydrolysis of polysulfides [ 104 , 112 ]. During the hydrolysis, there is some equilibrium between RSS n SR and its products, i.e.…”

“…RSSH and RSSOH. Alkylating agents reacting with RSSOH or RSSH shift this equilibrium to the right leading to enhanced decomposition of RSS n R. Interestingly, it was revealed that such alkaline hydrolysis of polysulfides could be significantly prevented by hydroxyl group-containing compounds such as β-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAA), tyrosine or serine [ 104 , 112 ]. This observation suggests that moieties of naturally occurring amino acids containing hydroxyl groups (tyrosine and serine) may be involved in maintaining the polysulfide stability and in the regulation of their homeostasis.…”

“…The finding that the hydroxyl group-containing agents efficiently protect polysulfides from hydrolytic degradation led the Akaike’s research group to develop the new alkylating agent namely, N-iodoacetyl L-tyrosine methyl ester (TME-IAA) ( Figure 11 ). This compound specifically traps and stabilizes polysulfides and protects them against hydrolysis, and used with mass spectrometry allows for successful polysulfide analysis [ 103 , 104 ]. Kasamatsu et al noted a loss of nearly 40% of glutathione tetrasulfide after 1 h of incubation at physiological pH while in the presence of mBrB, the total loss reached nearly 70% of the initial amount of tetrasulfide.…”

Supramolecular Activation of S8 by Cucurbiturils in Water and Mechanism of Reduction to H2S by Thiols: Insights into Biological Sulfane Sulfur Trafficking

“…For example, small molecule RSS donors have shown high efficacy in animal models for conditions ranging from cardiovascular disease and ischemia/reperfusion injury to gastrointestinal inflammation and wound healing. [23][24][25] Similarly, contemporary investigations have led to the discovery of new fundamental chemistry of persulfides and polysulfides, [26][27][28] new approaches for responsive RSS delivery, [29][30] and new interconnectivities with other small signaling molecules. [31][32][33][34][35] An attractive approach for sulfane sulfur delivery would be to use systems with only S 0 atoms.…”