3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen sulfide is also produced through cystathionine beta-synthase and cystathionine gamma-lyase, along with 3-MST, and is known to alleviate a variety of illnesses such as cancer, heart disease, and neurological conditions. The importance of cystathionine beta-synthase and cystathionine gamma-lyase in hydrogen sulfide biogenesis is well-described, but documentation of the 3-MST pathway is limited. This account compiles the current state of knowledge about the role of 3-MST in physiology and pathology. Attempts at targeting the 3-MST pathway for therapeutic benefit are discussed, highlighting the potential of 3-MST as a therapeutic target.

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.

Background: The oxidative stress evident in the Alzheimer’s disease (AD) brain leads to compromised 3‐mercaptopyruvate sulfurtransferase (3MST) function, one of the endogenous hydrogen sulfide (H₂S) producing enzymes.^1,2 Impaired 3MST function is expected to contribute toward potentiation of oxidative stress by depleting cellular glutathione (GSH) stores, and exacerbation of AD pathology by enhancing Aβ aggregation resulting in neurodegeneration. Preclinical studies with H₂S donors such as NaSH have been promising,^3,4 however further clinical translation efforts are thwarted due to their poor chemical stability, bioavailability, and dose‐limiting toxicities. We have developed a stable, bioavailable prodrug of 3MST substrate 3‐mercaptopyruvate, named sulfanegen, which can supplement the enzymatic reaction releasing H₂S.² Thus provision of sulfanegen could prove beneficial in mitigating AD‐related neurodegenerative consequences.Method: Aged, symptomatic cohorts APP/PS1 mice (7 and 12 month old) were treated with saline (N = 8) or sulfanegen (75 mg/kg, i.p., N = 8) for 12 weeks. Cognitive behavioral assessments (T‐maze) were conducted 10‐11 weeks after treatment initiation. Equal numbers of both sexes of mice were used as much as possible. The harvested brain tissues were analyzed biochemically for cortical/hippocampal Aβ1‐42 burden, oxidative stress and inflammatory markers (protein carbonyls, lipid peroxidation, glutathione assay, TNF‐α and IL6. Quantitative stereological analysis of Aβ pathology, neuroinflammation and progressive neurodegeneration were also conducted.Result: Treatment of symptomatic Alzheimer’s mice with sulfanegen prevented cognitive impairment resulting from AD pathology (Figure 1).² This was corroborated by reduced brain amyloid load as well as the reversal of oxidative stress and neuroinflammation. Neuropathological analysis also displayed modest, but significant effect of sulfanegen on Aβ levels, reactive astrogliosis and microglial reactivity. More importantly, sulfanegen caused attenuation of progressive degeneration of noradrenergic system in the LC. Additionally, administration of sulfanegen supplemented brain 3MP levels, resulting in restoration of brain 3MST function.Conclusion: Collectively, our results show that the provision of a 3MST substrate, sulfanegen, exhibits neuroprotective effects, along with restoration of cognitive function in an AD mouse model. This study suggests an important role of 3MST in AD pathophysiology and potential therapeutic utility of sulfanegen as a disease‐modifying treatment.