The discovery that endogenously produced H2S is a signaling molecule that mediates varied physiological effects in mammals ranging from neuromodulatory to cardioprotective, has spurred enormous recent interest in understanding its biology and in exploiting its pharmacological potential. Enzymes involved in sulfur metabolism catalyze the biogenesis of H2S and include: cystathionine -synthase (CBS), - cystathionase (CSE) and mercaptopyruvate sulfurtransferase (MST). However, despite the rising interest in H2S biochemistry, fundamental questions remain regarding regulation of its production, its mechanism of action and its destruction. In this study, we propose to address significant gaps in our understanding of the reaction mechanisms and regulation of H2S production by addressing the following specific aims. (i) Structure- function studies on H2S biogenesis will focus on elucidating the reaction mechanisms of CBS, CSE and MST and conducting a high throughput screen using a small molecule library as a platform for in vitro and ex vivo screening of activators and/or inhibitors of CBS and CSE. (ii) Regulation of CBS, CSE and MST by redox, androgens and sumoylation will be investigated to determine how these parameters modulate H2S production, affect transsulfuration flux and localization of glutathione pools during the cell cycle. The impact of the proposed studies is both fundamental (i.e., gaining insights into the operation and regulation of H2S-generating enzymes) and translational (i.e., informing therapeutic options for circumventing metabolic blockades, screening for activators/inhibitors of H2S production and characterizing testosterone regulation of the transsulfuration pathway in androgen-responsive prostate cancer).
Homocystinuria, cystathionuria and mercaptolactate-cysteine disulfiduria are rare/orphan diseases that result from defects in three enzymes in sulfur metabolism that also contribute to biogenesis of the signaling molecule, H2S, which mediates an array of physiological effects. We will elucidate the reaction mechanisms and regulation of these enzymes, which is essential for understanding how the process is corrupted in patients, and, for informing treatment options.
|Cremers, Claudia M; Knoefler, Daniela; Vitvitsky, Victor et al. (2014) Bile salts act as effective protein-unfolding agents and instigators of disulfide stress in vivo. Proc Natl Acad Sci U S A 111:E1610-9|
|DeRatt, Barbara N; Ralat, Maria A; Kabil, Omer et al. (2014) Vitamin B-6 restriction reduces the production of hydrogen sulfide and its biomarkers by the transsulfuration pathway in cultured human hepatoma cells. J Nutr 144:1501-8|
|Kabil, Omer; Banerjee, Ruma (2014) Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal 20:770-82|
|Banerjee, Ruma (2014) Introduction to the thematic minireview series on enzyme evolution. J Biol Chem 289:30196-7|
|Kabil, Omer; Motl, Nicole; Banerjee, Ruma (2014) H2S and its role in redox signaling. Biochim Biophys Acta 1844:1355-66|
|Gherasim, Carmen; Yadav, Pramod K; Kabil, Omer et al. (2014) Nitrite reductase activity and inhibition of H?S biogenesis by human cystathionine ß-synthase. PLoS One 9:e85544|
|Kabil, Omer; Vitvitsky, Victor; Banerjee, Ruma (2014) Sulfur as a signaling nutrient through hydrogen sulfide. Annu Rev Nutr 34:171-205|
|Garg, Sanjay K; Delaney, Colin; Toubai, Tomomi et al. (2014) Aging is associated with increased regulatory T-cell function. Aging Cell 13:441-8|
|Libiad, Marouane; Yadav, Pramod Kumar; Vitvitsky, Victor et al. (2014) Organization of the human mitochondrial hydrogen sulfide oxidation pathway. J Biol Chem 289:30901-10|
|Carballal, Sebastian; Cuevasanta, Ernesto; Marmisolle, Ines et al. (2013) Kinetics of reversible reductive carbonylation of heme in human cystathionine *-synthase. Biochemistry 52:4553-62|
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