Regulation of Homocysteine-dependent Redox Homeostasis

Summary

Principal Investigator: RUMA V BANERJEE
Affiliation: University of Michigan
Country: USA
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

Top Publications

  1. ncbi Expression profiling of homocysteine junction enzymes in the NCI60 panel of human cancer cell lines
    Wen Zhang
    Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
    Cancer Res 65:1554-60. 2005
  2. ncbi IFN-gamma and IL-4 differentially shape metabolic responses and neuroprotective phenotype of astrocytes
    Sanjay K Garg
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, 48109 0606, USA
    J Neurochem 108:1155-66. 2009
  3. ncbi Muscarinic receptor regulation of osmosensitive taurine transport in human SH-SY5Y neuroblastoma cells
    Daniel J Foster
    Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109 2200, USA
    J Neurochem 108:437-49. 2009
  4. ncbi Impeded electron transfer from a pathogenic FMN domain mutant of methionine synthase reductase and its responsiveness to flavin supplementation
    Carmen G Gherasim
    Biochemistry Department, University of Nebraska, Lincoln, Nebraska 68588 0664, USA
    Biochemistry 47:12515-22. 2008
  5. ncbi The undertow of sulfur metabolism on glutamatergic neurotransmission
    Ruma Banerjee
    Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 0606, USA
    Trends Biochem Sci 33:413-9. 2008
  6. ncbi An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism
    Tatyana K Korendyaseva
    National Research Center for Hematology, RAMS, Moscow, Russia
    PLoS Comput Biol 4:e1000076. 2008
  7. ncbi Nitrated alpha-synuclein and microglial neuroregulatory activities
    Ashley D Reynolds
    Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA
    J Neuroimmune Pharmacol 3:59-74. 2008
  8. ncbi Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cells
    Anna Prudova
    Redox Biology Center and the Biochemistry Department, University of Nebraska, Lincoln, Nebraska, USA
    Antioxid Redox Signal 9:1875-81. 2007
  9. ncbi Translational regulation of human methionine synthase by upstream open reading frames
    Bekir Col
    Redox Biology Center, Biochemistry Department, University of Nebraska, Lincoln, NE 68588 0664, USA
    Biochim Biophys Acta 1769:532-40. 2007
  10. ncbi Polymorphic background of methionine synthase reductase modulates the phenotype of a disease-causing mutation
    Carmen Gherasim
    Redox Biology Center and Biochemistry Department, University of Nebraska Lincoln, Lincoln, Nebraska 68588 0664, USA
    Hum Mutat 28:1028-33. 2007

Scientific Experts

  • HOWARD GENDELMAN
  • Ruma Banerjee
  • Victor Vitvitsky
  • Anna Prudova
  • Sanjay K Garg
  • Victor M Vitvitsky
  • Zachary Bauman
  • Sebastian Oltean
  • Jonathan Kipnis
  • Zhonghua Yan
  • Daniel J Foster
  • Tatyana K Korendyaseva
  • Carmen G Gherasim
  • Ashley D Reynolds
  • Carmen Gherasim
  • Bekir Col
  • Mark P Thomas
  • Fazoil I Ataullakhanov
  • Sanjay Garg
  • Aaron Braun
  • Cheng-Gang Zou
  • Wen Zhang
  • Stephen K Fisher
  • Anne M Heacock
  • Jason G Glanzer
  • Ashraf Raza
  • Pawel Ciborowski
  • Uzma Zaman
  • Vladimir A Volkov
  • Tara Nordgren
  • Michael V Martinov
  • Denis N Kuvatov
  • Irena Kadiu
  • Matthias Albin
  • Kathryn Chartrand
  • Ashley Reynolds
  • Alexander Lin
  • Sanjana Dayal
  • Steven R Lentz
  • Sally Stabler
  • David S Rosenblatt
  • Anuja Ghorpade
  • Shelly C Lu
  • Mark Thomas
  • Mikhail V Martinov
  • Horatiu Olteanu
  • Peter Madzelan

Detail Information

Publications19

  1. ncbi Expression profiling of homocysteine junction enzymes in the NCI60 panel of human cancer cell lines
    Wen Zhang
    Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
    Cancer Res 65:1554-60. 2005
    ....
  2. ncbi IFN-gamma and IL-4 differentially shape metabolic responses and neuroprotective phenotype of astrocytes
    Sanjay K Garg
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, 48109 0606, USA
    J Neurochem 108:1155-66. 2009
    ....
  3. ncbi Muscarinic receptor regulation of osmosensitive taurine transport in human SH-SY5Y neuroblastoma cells
    Daniel 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...
  4. ncbi Impeded electron transfer from a pathogenic FMN domain mutant of methionine synthase reductase and its responsiveness to flavin supplementation
    Carmen G Gherasim
    Biochemistry Department, University of Nebraska, Lincoln, Nebraska 68588 0664, USA
    Biochemistry 47:12515-22. 2008
    ....
  5. ncbi The undertow of sulfur metabolism on glutamatergic neurotransmission
    Ruma Banerjee
    Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 0606, USA
    Trends Biochem Sci 33:413-9. 2008
    ....
  6. ncbi An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism
    Tatyana 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...
  7. ncbi Nitrated alpha-synuclein and microglial neuroregulatory activities
    Ashley 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...
  8. ncbi Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cells
    Anna 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...
  9. ncbi Translational regulation of human methionine synthase by upstream open reading frames
    Bekir 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...
  10. ncbi Polymorphic background of methionine synthase reductase modulates the phenotype of a disease-causing mutation
    Carmen 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...
  11. ncbi Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels
    Victor 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...
  12. ncbi Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's disease
    Mark 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...
  13. ncbi Monocyte differentiation, activation, and mycobacterial killing are linked to transsulfuration-dependent redox metabolism
    Sanjay Garg
    Redox Biology Center and the Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0664, USA
    J Biol Chem 281:38712-20. 2006
    ....
  14. ncbi A functional transsulfuration pathway in the brain links to glutathione homeostasis
    Victor 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...
  15. ncbi S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity
    Anna 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...
  16. ncbi A B12-responsive internal ribosome entry site (IRES) element in human methionine synthase
    Sebastian 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...
  17. ncbi Analysis of pathological defects in methionine metabolism using a simple mathematical model
    Anna 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...
  18. ncbi Homocysteine and redox signaling
    Cheng-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...
  19. ncbi Extracellular redox modulation by regulatory T cells
    Zhonghua 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...