Genomes and Genes
Regulation of Homocysteine-dependent Redox Homeostasis
Principal Investigator: RUMA V BANERJEE
Affiliation: University of Michigan
Abstract: 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.
Funding Period: 2003-08-11 - 2007-08-31
more information: NIH RePORT
- Expression profiling of homocysteine junction enzymes in the NCI60 panel of human cancer cell linesWen Zhang
Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
Cancer Res 65:1554-60. 2005....
- IFN-gamma and IL-4 differentially shape metabolic responses and neuroprotective phenotype of astrocytesSanjay K Garg
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, 48109 0606, USA
J Neurochem 108:1155-66. 2009....
- Muscarinic receptor regulation of osmosensitive taurine transport in human SH-SY5Y neuroblastoma cellsDaniel J Foster
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 2200, USA
J Neurochem 108:437-49. 2009..The results suggest that muscarinic receptor activation can regulate both the volume-dependent efflux and uptake of taurine and that these events may be functionally coupled...
- Impeded electron transfer from a pathogenic FMN domain mutant of methionine synthase reductase and its responsiveness to flavin supplementationCarmen G Gherasim
Biochemistry Department, University of Nebraska, Lincoln, Nebraska 68588 0664, USA
Biochemistry 47:12515-22. 2008....
- The undertow of sulfur metabolism on glutamatergic neurotransmissionRuma Banerjee
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 0606, USA
Trends Biochem Sci 33:413-9. 2008....
- An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolismTatyana K Korendyaseva
National Research Center for Hematology, RAMS, Moscow, Russia
PLoS Comput Biol 4:e1000076. 2008..This regulatory switch is triggered by [Met] and provides a mechanism for stabilization of methionine levels in blood over wide variations in dietary methionine intake...
- Nitrated alpha-synuclein and microglial neuroregulatory activitiesAshley D Reynolds
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA
J Neuroimmune Pharmacol 3:59-74. 2008..Inhibition of cathepsin B attenuated, in part, N-alpha-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration...
- Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cellsAnna Prudova
Redox Biology Center and the Biochemistry Department, University of Nebraska, Lincoln, Nebraska, USA
Antioxid Redox Signal 9:1875-81. 2007..These results demonstrate regulation of the homocysteine-clearing enzyme, CBS, by testosterone and suggest the potential utility of targeting this enzyme as a chemotherapeutic strategy...
- Translational regulation of human methionine synthase by upstream open reading framesBekir Col
Redox Biology Center, Biochemistry Department, University of Nebraska, Lincoln, NE 68588 0664, USA
Biochim Biophys Acta 1769:532-40. 2007..This study reveals complex regulation of the essential housekeeping gene, methionine synthase, by the uORFs in its leader sequence...
- Polymorphic background of methionine synthase reductase modulates the phenotype of a disease-causing mutationCarmen Gherasim
Redox Biology Center and Biochemistry Department, University of Nebraska Lincoln, Lincoln, Nebraska 68588 0664, USA
Hum Mutat 28:1028-33. 2007..Val56Met mutation and the p.Ile22Met variation, which was confirmed by sequence analysis. This study reveals how a genetic variation can modulate phenotypic expression of a disease-causing mutation...
- Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levelsVictor Vitvitsky
Redox Biology Center and the Biochemistry Dept, University of Nebraska, Lincoln, NE 68588 0664, USA
Am J Physiol Renal Physiol 293:F594-600. 2007..Our data suggest that testosterone-dependent regulation of human CBS in kidney may contribute to sex-dependent differences in homocysteine transsulfuration...
- Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's diseaseMark P Thomas
Laboratory of Neuroregeneration, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198 5880, USA
J Neurochem 100:503-19. 2007..Understanding these linkages may lead to novel therapeutics for Parkinson's disease where modulation of redox-related stress may slow disease progression...
- Monocyte differentiation, activation, and mycobacterial killing are linked to transsulfuration-dependent redox metabolismSanjay Garg
Redox Biology Center and the Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 0664, USA
J Biol Chem 281:38712-20. 2006....
- A functional transsulfuration pathway in the brain links to glutathione homeostasisVictor Vitvitsky
Redox Biology Center, University of Nebraska Lincoln, Lincoln, Nebraska 68588, USA
J Biol Chem 281:35785-93. 2006..This study establishes the presence of an intact transsulfuration pathway and demonstrates its contribution to glutathione-dependent redox-buffering capacity under ex vivo conditions in brain cells and slices...
- S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacityAnna Prudova
Redox Biology Center and Biochemistry Department, University of Nebraska, Lincoln, NE 68588 0664, USA
Proc Natl Acad Sci U S A 103:6489-94. 2006..A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations...
- A B12-responsive internal ribosome entry site (IRES) element in human methionine synthaseSebastian Oltean
Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588 0664, USA
J Biol Chem 280:32662-8. 2005..Modulation of the IRES-dependent translation of an essential gene by the cofactor of the encoded enzyme represents a novel example of a gene-nutrient interaction...
- Analysis of pathological defects in methionine metabolism using a simple mathematical modelAnna Prudova
Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 0664, USA
Biochim Biophys Acta 1741:331-8. 2005..The theoretical predictions were found to be in good agreement with experimental data obtained with the human hepatoma cell line, HepG2...
- Homocysteine and redox signalingCheng Gang Zou
Biochemistry Department, University of Nebraska, Lincoln, NE 68588, USA
Antioxid Redox Signal 7:547-59. 2005..We also discuss redox regulation of the key enzymes involved in homocysteine clearance: methionine synthase, betaine-homocysteine methyltranferase, and cystathionine beta-synthase...
- Extracellular redox modulation by regulatory T cellsZhonghua Yan
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, USA
Nat Chem Biol 5:721-3. 2009..Regulatory T cells inhibit this redox metabolite signaling pathway, which represents a previously unrecognized mechanism for immunosuppression of effector T cells...