Regulation of Homocysteine-dependent Redox Homeostasis

Summary

Principal Investigator: RUMA V BANERJEE
Affiliation: University of Michigan
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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. pmc Murine colitis is mediated by vimentin
    Nirit Mor-Vaknin
    Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, MI 48109 5640, USA
    Sci Rep 3:1045. 2013
  2. pmc Regulatory T cells interfere with glutathione metabolism in dendritic cells and T cells
    Zhonghua Yan
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109 5606, USA
    J Biol Chem 285:41525-32. 2010
  3. pmc Na+ and K+ ion imbalances in Alzheimer's disease
    Victor M Vitvitsky
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109 0600, USA
    Biochim Biophys Acta 1822:1671-81. 2012
  4. pmc High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations
    Victor Vitvitsky
    Biological Chemistry Department, University of Michigan Medical Center, Ann Arbor, Michigan 48109 0600, USA
    Antioxid Redox Signal 17:22-31. 2012
  5. doi One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders
    Sergiu P Paşca
    Department of Medical Biochemistry, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
    J Cell Mol Med 13:4229-38. 2009
  6. pmc The logic of the hepatic methionine metabolic cycle
    M V Martinov
    National Research Center for Hematology, RAMS, Moscow, Russia
    Biochim Biophys Acta 1804:89-96. 2010
  7. pmc The redox status of cystinotic fibroblasts
    Victor Vitvitsky
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109 5606, USA
    Mol Genet Metab 99:384-8. 2010
  8. pmc Redox remodeling as an immunoregulatory strategy
    Zhonghua Yan
    Department of Biological Chemistry, University of Michigan Medical Center, University of Michigan, Ann Arbor, Michigan 48109 5606, USA
    Biochemistry 49:1059-66. 2010
  9. pmc Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation
    Bermans J Iskandar
    Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    J Clin Invest 120:1603-16. 2010
  10. pmc Differential dependence on cysteine from transsulfuration versus transport during T cell activation
    Sanjay K Garg
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, 48109, USA
    Antioxid Redox Signal 15:39-47. 2011

Scientific Experts

  • RUMA V BANERJEE
  • Bermans Iskandar
  • HOWARD GENDELMAN
  • Victor Vitvitsky
  • Sanjay K Garg
  • Zhonghua Yan
  • Anna Prudova
  • Victor M Vitvitsky
  • Zachary Bauman
  • Sebastian Oltean
  • Nirit Mor-Vaknin
  • Kristina A Kigerl
  • M V Martinov
  • Jonathan Kipnis
  • Sergiu P Paşca
  • 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
  • Carlos H C Serezani
  • Michael D Swanson
  • Antonello Punturieri
  • Maureen Legendre
  • Marta J Gonzalez-Hernandez
  • Marc Peters-Golden
  • Seagal Teitz-Tennenbaum
  • Yue Yu
  • N Cary Engleberg
  • John Y Kao
  • Anna Jatzek
  • David M Markovitz
  • Ping Wei
  • Wenmin Lai
  • Richard F Keep
  • Phillip G Popovich
  • Zhen Guan
  • Daniel P Ankeny
  • Dana M McTigue
  • Roger L Albin
  • Omer Kabil
  • Roger Albin
  • Marc Witcher
  • Jess Thoene
  • V M Vitvitsky
  • F I Ataullakhanov
  • Eleonora Dronca
  • Ileana Benga
  • Stephen K Fisher
  • Felicia Iftene
  • Anne M Heacock
  • Beatrix K Ferencz
  • Maria Dronca
  • Tamás Kaucsár
  • Emoke Endreffy
  • Elena C Craciun
  • Rodica Cornean
  • 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

Publications34

  1. pmc Murine colitis is mediated by vimentin
    Nirit Mor-Vaknin
    Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, MI 48109 5640, USA
    Sci Rep 3:1045. 2013
    ..Our results suggest that vimentin impedes bacterial killing and production of ROS, thereby contributing to the pathogenesis of acute colitis...
  2. pmc Regulatory T cells interfere with glutathione metabolism in dendritic cells and T cells
    Zhonghua Yan
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109 5606, USA
    J Biol Chem 285:41525-32. 2010
    ..Together, these data provide novel insights into modulation of sulfur-based redox metabolism by Tregs, leading to suppression of T cell activation and proliferation...
  3. pmc Na+ and K+ ion imbalances in Alzheimer's disease
    Victor M Vitvitsky
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109 0600, USA
    Biochim Biophys Acta 1822:1671-81. 2012
    ....
  4. pmc High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations
    Victor Vitvitsky
    Biological Chemistry Department, University of Michigan Medical Center, Ann Arbor, Michigan 48109 0600, USA
    Antioxid Redox Signal 17:22-31. 2012
    ..4, 37°C, and at physiologically relevant cysteine concentrations. We have also studied the kinetics of H(2)S clearance by liver, kidney, and brain homogenates under aerobic and anaerobic conditions...
  5. doi One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders
    Sergiu P Paşca
    Department of Medical Biochemistry, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
    J Cell Mol Med 13:4229-38. 2009
    ....
  6. pmc The logic of the hepatic methionine metabolic cycle
    M V Martinov
    National Research Center for Hematology, RAMS, Moscow, Russia
    Biochim Biophys Acta 1804:89-96. 2010
    ....
  7. pmc The redox status of cystinotic fibroblasts
    Victor Vitvitsky
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109 5606, USA
    Mol Genet Metab 99:384-8. 2010
    ..Hence, mechanisms other than cytosolic redox perturbations are involved in the etiology of nephropathic cystinosis...
  8. pmc Redox remodeling as an immunoregulatory strategy
    Zhonghua Yan
    Department of Biological Chemistry, University of Michigan Medical Center, University of Michigan, Ann Arbor, Michigan 48109 5606, USA
    Biochemistry 49:1059-66. 2010
    ..The role of regulatory T cells in perturbing redox remodeling by dendritic cells and its implications as a general regulatory T cell suppression mechanism are discussed...
  9. pmc Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation
    Bermans J Iskandar
    Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA
    J Clin Invest 120:1603-16. 2010
    ..If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries...
  10. pmc Differential dependence on cysteine from transsulfuration versus transport during T cell activation
    Sanjay K Garg
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, 48109, USA
    Antioxid Redox Signal 15:39-47. 2011
    ..Inhibition of the transsulfuration pathway in both primary and transformed T cells decreases cell viability under oxidative-stress conditions...
  11. pmc Astrocytic redox remodeling by amyloid beta peptide
    Sanjay K Garg
    Department of Biochemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Antioxid Redox Signal 14:2385-97. 2011
    ..Our study suggests that the alterations in astrocytic redox status could compromise the neuroprotective potential of astrocytes and may be a potential new target for therapeutic intervention in Alzheimer's disease...
  12. pmc Hydrogen sulfide: redox metabolism and signaling
    Ruma Banerjee
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan
    Antioxid Redox Signal 15:339-41. 2011
    ..Some of these issues are the subject of the current Forum on H(2)S. Antioxid. Redox Signal. 15, 339-341...
  13. pmc Taurine biosynthesis by neurons and astrocytes
    Victor Vitvitsky
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109 0600, USA
    J Biol Chem 286:32002-10. 2011
    ..Consistent with its role as an organic osmolyte, taurine synthesis was stimulated under hypertonic conditions in neurons...
  14. pmc System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo
    Kristina A Kigerl
    Center for Brain and Spinal Cord Repair, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
    Exp Neurol 233:333-41. 2012
    ..Together, these data indicate that modulation of redox balance in CNS macrophages, perhaps through regulating system x(c)(-), could be a novel approach for attenuating injurious neuroinflammatory cascades...
  15. pmc Redox outside the box: linking extracellular redox remodeling with intracellular redox metabolism
    Ruma Banerjee
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    J Biol Chem 287:4397-402. 2012
    ..In this minireview, the mechanism of extracellular redox remodeling due to intracellular sulfur metabolism is discussed in the context of various cell-cell communication paradigms...
  16. pmc 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...
  17. doi 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
    ....
  18. pmc 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...
  19. 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...
  20. 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...
  21. 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...
  22. pmc 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...
  23. 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...
  24. 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
    ....
  25. 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...
  26. 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...
  27. 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...
  28. pmc 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...
  29. 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...
  30. pmc 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...
  31. pmc 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...
  32. 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
    ....
  33. pmc 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
    ....
  34. 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
    ....