Sulfur Metabolism Under Stress

Abstract

Significance: In humans, imbalances in the reduction-oxidation (redox) status of cells are associated with many pathological states. In addition, many therapeutics and prophylactics used as interventions for diverse pathologies either directly modulate oxidant levels or otherwise influence endogenous cellular redox systems. Recent Advances: The cellular machineries that maintain redox homeostasis or that function within antioxidant defense systems rely heavily on the regulated reactivities of sulfur atoms either within or derived from the amino acids cysteine and methionine. Recent advances have substantially advanced our understanding of the complex and essential chemistry of biological sulfur-containing molecules. Critical Issues: The redox machineries that maintain cellular homeostasis under diverse stresses can consume large amounts of energy to generate reducing power and/or large amounts of sulfur-containing nutrients to replenish or sustain intracellular stores. By understanding the metabolic pathways underlying these responses, one can better predict how to protect cells from specific stresses. Future Directions: Here, we summarize the current state of knowledge about the impacts of different stresses on cellular metabolism of sulfur-containing molecules. This analysis suggests that there remains more to be learned about how cells use sulfur chemistry to respond to stresses, which could in turn lead to advances in therapeutic interventions for some exposures or conditions.

Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption

“…Rather than pathology via oxidative damage, we suspect that pathology results from a more general disruption to homeostasis. In the current study, the TrxR1/Gsr-null livers are already deficient in disulfide reducing power; the disulfide reducing power they obtain through catabolism of methionine is associated with re-prioritization of sulfur-, amino acid-, and energy-metabolism [9,23,64,65]. Ascorbate supplementation, even though measurably decreasing oxidative stress markers in these livers, collaterally consumes critical GSH, further stressing these metabolic pathways.…”

“…Ascorbate supplementation, even though measurably decreasing oxidative stress markers in these livers, collaterally consumes critical GSH, further stressing these metabolic pathways. The cause of necrosis or liver failure in these mice, therefore, might be hepatic amino acid or energy imbalances that disrupt translation, transcription, or other basal processes [65]. Ongoing studies are examining such mechanisms in the context of these genetically modified mouse liver models.…”

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

“…There is close metabolic interdependence (Fig. 7B) of the specific metabolic flow through the re-methylation and trans-sulfuration pathways (190,275,398). The remethylation cycle is sensitivitive to availability of co-factors such as folate, B12, riboflavin, vitamin A, copper, zinc and the methyl-donors choline and serine.…”

“…Amongst the wealth of possible processes of importance, perhaps the one that has received least attention is the stoichiometry and quantitative availability of amino acid precursors for the generation of H 2 S (methionine, choline, glycine, serine, cysteine) (190,275,398,399), NO (arginine, glutamine) (247,276,277,288) and glutathione (glutamine, cysteine, glycine) (183,248,266). Except methionine, all other amino acids involved are considered to be dispensable from the diet (180,266).…”

“…The remethylation cycle is sensitivitive to availability of co-factors such as folate, B12, riboflavin, vitamin A, copper, zinc and the methyl-donors choline and serine. Trans-sulfuration, and H 2 S generation, requires adequate pyridoxal with methionine as -SH donor and serine as the 3-carbon source for cysteine formation, and endogenous H 2 S formation is necessary and sufficient to confer stress resistance in experimental models in vivo (160,275,399). The vulnerability of older people to poor B-vitamin status and the associated increased mortality is of particular concern for pyridoxal, vitamin B6 (167); because pyridoxal is implicated in immune competence and thought to ameliorate inflammation and oxidative stress it was hypothesized to also reduce COVID-19 severity (217).…”