Perturbations of redox homeostasis incurred by oxidative stress appear to be a common thread connecting the etiologies of various complex and multifactorial diseases, such as cardiovascular diseases, Parkinson's disease, Alzheimer's disease, arthritis and some cancers. Glutathione is a key component of the intracellular arsenal of antioxidants in eukaryotes, and the limiting reagent in its synthesis is believed to cysteine. The transsulfuration pathway which converts homocysteine to cysteine is a quantitatively significant contributor to the intracellular cysteine pool in the liver and -50 percent of the cysteine in glutathione is derived via this pathway. Homocysteine is a sulfur containing amino acid whose elevated levels are correlated with a number of multifactorial diseases such as cardiovascular diseases, neural tube defects and Alzheimer's disease. However, intracellular regulation of this amino acid and of the metabolic link to the major cellular redox buffer pool of glutathione are poorly understood. This proposal focuses on three key loci important in regulation of homocysteine concentrations: methionine synthase, methionine synthase reductase and cystathionine beta-synthase. Mutations in each of these enzymes is correlated with hereditary hyperhomocystenemia which is inherited as an autosomal recessive disorder. Using a combination of biophysical, cell biological and mouse model studies for cystathionine beta-synthase deficiency, we will; (i) characterize how polymorphic variations and hereditary mutations in methionine synthase reductase influence redox activation of methionine synthase-dependent transmethyiation of homocysteine, (ii) elucidate the mechanism of translational regulation of methionine synthase and (iii) elucidate the mechanism of redox regulation of homocysteine metabolism and its influence on glutathione homeostasis. These studies will provide important insights into multiple levels of regulation of homocysteine metabolism and will assess the effects of modulating the transsulfuration pathway on glutathione-dependent antioxidant defense in cell culture and in mice.
| Mor-Vaknin, Nirit; Legendre, Maureen; Yu, Yue et al. (2013) Murine colitis is mediated by vimentin. Sci Rep 3:1045 |
| Vitvitsky, Victor M; Garg, Sanjay K; Keep, Richard F et al. (2012) Na+ and K+ ion imbalances in Alzheimer's disease. Biochim Biophys Acta 1822:1671-81 |
| Kigerl, Kristina A; Ankeny, Daniel P; Garg, Sanjay K et al. (2012) System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233:333-41 |
| Vitvitsky, Victor; Kabil, Omer; Banerjee, Ruma (2012) High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid Redox Signal 17:22-31 |
| Banerjee, Ruma (2012) Redox outside the box: linking extracellular redox remodeling with intracellular redox metabolism. J Biol Chem 287:4397-402 |
| Garg, Sanjay K; Vitvitsky, Victor; Albin, Roger et al. (2011) Astrocytic redox remodeling by amyloid beta peptide. Antioxid Redox Signal 14:2385-97 |
| Garg, Sanjay K; Yan, Zhonghua; Vitvitsky, Victor et al. (2011) Differential dependence on cysteine from transsulfuration versus transport during T cell activation. Antioxid Redox Signal 15:39-47 |
| Vitvitsky, Victor; Garg, Sanjay K; Banerjee, Ruma (2011) Taurine biosynthesis by neurons and astrocytes. J Biol Chem 286:32002-10 |
| Banerjee, Ruma (2011) Hydrogen sulfide: redox metabolism and signaling. Antioxid Redox Signal 15:339-41 |
| Yan, Zhonghua; Garg, Sanjay K; Banerjee, Ruma (2010) Regulatory T cells interfere with glutathione metabolism in dendritic cells and T cells. J Biol Chem 285:41525-32 |
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