Martha Stipanuk
Professor
2009
HENutrSci

Web Bio Page

Current Activities

Current Professional Activities

Cornell University Graduate Field Membership: Nutrition

Member of American Society for Nutrition

Member of the American Society for Biochemistry and Molecular Biology



Current Research Activities
Mechanisms of molecular regulation of key enzymes of cysteine metabolism in vivo in response to dietary changes; cellular signaling pathways involved in regulation of cysteine metabolism; reciprocal regulation of cysteine dioxygenase and glutamate-cysteine ligase and their roles in regulation of cellular cysteine and glutathione concentrations; cysteine-responsive regulation of cysteine dioxygenase via the ubiquitin-proteasome pathway; cysteine-responsive regulation of glutamate-cysteine ligase at the levels of transcription and mRNA turnover; comparison of isolated cell and intact animal models for studies of amino acid metabolism; development and characterization of tissue-specific cysteine dioxygenase "knockout" mice;structure-function studies of thiol dioxygenases (cysteine dioxygenase, cysteamine dioxygenase); tissue-specific expression and function of enzymes in taurine biosynthetic pathways, especially in liver, mammary gland, and adipose tissue; amino acid deprivation and response to stress; role of amino acids in sensing of nutrient deprivation and activation of stress response pathways.



Biography

Biographical Statement
Martha Stipanuk is the James Jamison Professor in Nutrition in the Division of Nutritional Sciences at Cornell University, where she has been a faculty member since 1977. She received her B.S. from the University of Kentucky, her M.S. from Cornell University, and her Ph.D. from the University of Wisconsin-Madison in nutritional biochemistry.

Dr. Stipanuk's professional career has focused on the study of amino acid metabolism, particularly the metabolism of the sulfur-containing amino acid cysteine. Her work has contributed to an understanding of the intermediary pathways of cysteine metabolism in mammalian cells and of the role of various tissues in cysteine metabolism within the whole body. The Stipanuk laboratory is currently investigating the molecular mechanisms involved in regulation of levels of two key regulatory enzymes of cysteine metabolism, cysteine dioxygenase and glutamate-cysteine ligase in response to dietary protein or amino acid levels. These enzymes play a crucial role not only in regulating cysteine levels but in regulating the synthesis of taurine, sulfate and glutathione-compounds that are necessary for health. A genetic lack of adequate levels of functional cysteine dioxygenase has been shown to be an important factor in the development of many cases of rheumatoid arthritis. Because the regulation of these two enzymes occurs specifically in response to cysteine levels, the Stipanuk laboratory is also interested in elucidating the mechanism(s) by which the concentrations of cysteine and other amino acids are sensed by cells.

Dr. Stipanuk has a long-standing interest in teaching and course development in the area of nutrient metabolism. She has developed a multi-authored advanced textbook entitled “Biochemical, Physiological and Molecular Aspects of Human Nutrition” published by Saunders/Elsevier with the 3rd edition currently in development. Most recently, she has led efforts to develop and teach a graduate course on “Regulation of Macronutrient Metabolism.” She also teaches a specialized graduate course on “Nutritional Regulation of Mammalian Protein Synthesis and Degradation.”



Education
  • PhD 1977 - University of Wisconsin, Madison; Nutrition and Biochemistry
  • MS 1972 - Cornell University, Nutrition and Biochemistry
  • BS 1970 - University of Kentucky, Home Economics/Education


  • Keywords
    cysteine, sulfur amino acids, taurine, sulfate, sulfide, glutathione, amino acid deprivation, integrated stress response

    Courses, Websites, Pubs

    Courses Taught

    NS 6100 - Proteins and Amino Acids - Nutritional Regulation of Mammalian Protein Synthesis and Degradation

    NS 6320 - Regulation of Macronutrient Metabolism




    Related Websites

    DNS Home Page

    Stipanuk Lab



    Selected Publications

    Stipanuk, M. H. (2009) Macroautophagy and its role in nutrient homeostasis. Nutr. Rev. 67:677-689. 

    Ueki, I. and Stipanuk, M.H. (2009) 3T3-L1 adipocytes and rat adipose tissue have a high capacity for taurine synthesis by the cysteine dioxygenase/cysteinesulfinate decarboxylase and cysteamine dioxygenase pathways. J. Nutr. 139:207-214..

    Stipanuk, M.H., Ueki, I., Dominy, J.E. Jr., Simmons, C.R., and Hirschberger, L.L. (2009) Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Amino Acids 37:55-63. 

    Stipanuk, M.H., Dominy, J.E., Jr., Ueki, I., and Hirschberger, L.L. (2008) Measurement of cysteine dioxygenase activity and protein abundance. Curr. Prot. Toxicol. 6.15.1-6.15.25.

    Simmons, C.R., Krishnamoorthy, K., Granett, S.L., Schuller, D.J., Dominy, J.E. Jr., Begley, T.P., Stipanuk, M.H., and Karplus, P.A. (2008) A putative Fe2+-bound persulfenate intermediate in cysteine dioxygenase. Biochemistry 47:11390-11392.

    Dominy, J.E. Jr., Hwang, J., Guo, S., Hirschberger, L.L., Zhang, S., and Stipanuk, M.H. (2008) Synthesis of amino acid cofactor in cysteine dioxygenase is regulated by substrate and represents a novel post-translational regulation of activity. J. Biol. Chem. 283:12188-12201.

    Lee, J-I., Dominy, J.E., Jr., Sikalidis, A. K., Hirschberger, L.L., Wang,W., and Stipanuk, M.H. (2008) HepG2/C3A cells respond to cysteine-deprivation by induction of the amino acid deprivation/integrated stress response pathway. Physiol. Genomics 33:218-229.

    Dominy,J. E. Jr., Simmons, C.R., Hirschberger, L.L., Hwang, J., Coloso, R.M., Stipanuk, M.H. (2007) Discovery and characterization of a second mammalian thiol dioxygenase: Cysteamine dioxygenase. J. Biol. Chem. 282:25189-25198.

    Ueki, I., and Stipanuk, M.H. (2007) Enzymes of the taurine biosynthetic pathway are expressed in rat mammary gland. J. Nutr. 137:1887-1894.

    Dominy, J.E., Jr., Hwang, J., and Stipanuk, M.H. (2007) Overexpression of cysteine dioxygenase reduces intracellular cysteine and glutathione pools in HepG2/C3A cells. Am. J. Physiol. Endocrinol. Metab. 293:E62-E69.

    Stipanuk, M.H., Dominy, J.E. Jr., Lee, J-I., and Coloso, R.M. (2006) Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J. Nutr. 136:1652S-1659S.

    Dominy, J.E. Jr., Simmons, C.R., Karplus, P.A., Gehring, A.M., and Stipanuk, M.H. (2006) Identification and characterization of bacterial cysteine dioxygenases: a new route of cysteine degradation for eubacteria. J. Bacteriol. 188:5561-5569.

    Simmons,C.R., Liu, Q., Huang, Q., Hao, Q., Begley, T.P., Karplus, P.A., and Stipanuk, M.H. (2006) Crystal structure of mammalian cysteine dioxygenase: A novel mononuclear iron center for cysteine thiol oxidation. J. Biol. Chem. 281:18723-18733. [Issue cover is CDO structure]

    Stipanuk, M.H. and Dominy, J.E. Jr. (2006) Surprising insights that aren't so surprising in the modeling of sulfur amino acid metabolism. Amino Acids 30:251-256.

    Dominy, J.E., Hirschberger, L.L., Coloso, R. M., and Stipanuk, M.H. (2006) Regulation of cysteine dioxygenase degradation is mediated by intracellular cysteine levels and the ubiquitin-26S proteasome system in the living rat. Biochem. J. 394:267-273.

    Simmons, C.R. Hirschberger, L.L., Machi, M.S., and Stipanuk, M.H. (2006) Expression, purification, and kinetic characterization of recombinant rat cysteine dioxygenase, a non-heme metalloenzyme necessary for regulation of cellular cysteine levels. Protein Expr. Purif. 47:74-81.

    Dominy, J.E., Jr., Hirschberger, L.L., Coloso, R.M., and Stipanuk, M.H. (2006) In vivo regulation of cysteine dioxygenase via the ubiquitin-26S proteasome system. Adv. Exp. Biol. Med. 583:37-47.

    Coloso, R.M., Hirschberger, L.L. Dominy, J.E. Jr., Lee, J-I., and Stipanuk, M.H. (2006) Cysteamine dioxygenase: evidence for the physiological conversion of cysteamine to hypotaurine in rat and mouse tissues. Adv. Exp. Biol. 583:25-36.

    Lee J.-I., Kang, J., Stipanuk, M.H. (2006) Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation. Biochem. J. 393:181-190.

    Stipanuk MH, JE Dominy Jr, J-I Lee, and RM Coloso (2006) Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J. Nutr. 136:1652S-1659S.

    Stipanuk MH, M and Watford (2006) Amino acid metabolism. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 320-418.

    Stipanuk MH (2006) Nutrients: History and definitions. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 3-12.

    Lewis BA, and MH Stipanuk (2006) Structure, nomenclature, and properties of carbohydrates. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 67-89.

    Stipanuk MH (2006) Protein and amino acid requirements. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 419-448.

    Stipanuk MH (2006) Regulation of fuel utilization in response to exercise. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 566-589.
    Stipanuk MH (2006) Disturbances of energy balance. In: Biochemical, Physiological & Molecular Aspects of Human Nutrition (M.H. Stipanuk, ed.), Saunders/Elsevier, St. Louis, pp. 640-660.

    Stipanuk MH (2006) Transamination. In: McGraw Hill Encyclopedia of Science & Technology, 10th edition, McGraw Hill, pp. 540-543.

    Simmons, C.R., Hao, Q., Stipanuk, M.H. (2005) Crystallization and preliminary x-ray analysis of purified recombinant cysteine dioxygenase, a non-heme metalloenzyme necessary for regulation of cellular cysteine levels. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. 61:1013-1016.

    Stipanuk MH (2005) Homocysteine, Cysteine and Taurine. In: Modern Nutrition in Health and Disease, 10th edition, ME Shils, M. Shike, AC Ros, B Caballero, RJ Cousins, eds., pp. 545-562.

    Stipanuk, M. H., Hirschberger, L. L., Londono, M. P., Cresenzi, C. L., and Yu, A. F. (2004) The ubiquitin-proteasome system is responsible for cysteine-responsive regulation of cysteine dioxygenase concentration in liver. Am. J. Physiol. Endocrinol. Metab. 286: E439-E448.

    Lee, J.-I., Londono, M. P., Hirschberger, L. L., and Stipanuk, M. H. (2004) Regulation of cysteine dioxygenase and gamma-glutamylcysteine synthetase is associated with hepatic cysteine level. J. Nutr. Biochem. 15: 112-122.

    Stipanuk, M. H. Londono, M., Hirschberger, L. L., Wang, L.,and Hickey, C. (2004) Evidence for expression of a single distinct form of mammalian cysteine dioxygenase. Amino Acids 26: 99-106.

    Dominy JE and MH Stipanuk (2004) New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant. Nutr Rev Sep;62(9):348-353.

    Stipanuk MH (2004) Role of the liver in regulation of body cysteine and taurine levels: a brief review. Neurochem. Res. 29:105-110.

    Stipanuk MH (2004) Sulfur Amino Acid Metabolism -- Pathways for Production and Removal of Homocysteine and Cystine. Annu. Rev. Nutr. 24:539-577. 

    Stipanuk MH (2003) Role of the liver in regulation of body cysteine and taurine levels. Neurochem. Res. 29:105-110.

    Cresenzi, C. L., Lee, J.-I., and Stipanuk, M. H. (2003) Cysteine is the metabolic signal responsible for dietary regulation of cysteine dioxygenase and glutamate cysteine ligase in vivo. J. Nutr. 133:2697-2702.

    Stipanuk, M. H. (2003) Role of the liver in regulation of body cysteine and taurine levels. Neurochem. Res. 29: 105-110.

    Stipanuk MH (2003) Nutrients; Sodium; Calorie. In: Encyclopedia of Food (SH Katz, ed.). Charles Scribner's Sons, Vol. 2, pp. 578-588; Vol. 3, pp. 294-297; Vol. 1, pp. 297-298.

    Stipanuk MH, M Londono, J-I Lee, M Hu, and AF Yu (2002) Enzymes and metabolites of cysteine metabolism in nonhepatic tissues of rats show little response to changes in dietary protein or sulfur amino acid levels. J. Nutr. 132:3369-3378.

    Bella DL, LL Hirschberger, YH Kwon, and MH Stipanuk (2002) Cysteine metabolism in periportal and perivenous hepatocytes: perivenous cells have greater capacity for glutathione production and taurine synthesis but not for cysteine catabolism. Amino Acids 23:453-458. 

    Kwon, Y.H. and Stipanuk, M.H. 2001. Cysteine regulates cysteine dioxygenase and g-glutamylcysteine synthetase in cultured rat hepatocytes. Am. J. Physiol. 280: E804-E815.

    Bella, D.L., Kwon, Y.H., Hirschberger, L.L. and Stipanuk, M. H. 2000. Evidence for the posttranscriptional regulation of cysteine dioxygenase in rat liver. In: Taurine 4: Taurine and Excitable Tissues, L. D. Corte, R. J. Huxtable, G. Sgaragli, and K. F. Tipton, eds., Plenum Press, pp. 71-85.

    Ohta, J., Kwon, Y.-H. and Stipanuk, M. H. (2000) Cysteine metabolism by primary cultures of hepatocytes responds to methionine supplementation of the culture medium. Amino Acids 19:705-728.

    Hirschberger, L. L., Daval, S., Stover, P. J., and Stipanuk, M. H. (2000) Murine cysteine dioxygenase: structural organization, tissue-specific expression and promoter identification. Gene 277: 153-161.

    Stipanuk MH and M Watford (2000) Amino acid metabolism. In: Biochemical and Physiological Bases of Human Nutrition, MH Stipanuk, ed. WB Saunders, pp. 233-286.

    Ohta J, Y-H Kwon, and MH Stipanuk (2000) Cysteine dioxygenase and gamma-glutamylcysteine synthetase activities in primary cultured hepatocytes respond to sulfur amino acid supplementation in a reciprocal manner. Amino Acids 19:705-728. 

    Baynes RD and MH Stipanuk (2000) Iron. In: Biochemical and Physiological Bases of Human Nutrition, MH Stipanuk, ed. WB Saunders, pp. 711-740.

    Bella DL, LL Hirschberger, Y Hosokawa, and MH Stipanuk (1999) Mechanisms involved in the regulation of key enzymes of cysteine metabolism in rat liver in vivo. Am. J. Physiol. 276 (Endocrinol. Metab. 39):E326-E335.

    Stipanuk MH (1999) Homocysteine, cysteine and taurine. In: Modern Nutrition in Health and Disease, 9th ed. (Shils, M. E., et al., eds.), pp. 543-558.

    Bella DL, C Hahn, and MH Stipanuk (1999) Effects of nonsulfur and sulfur amino acids on the regulation of hepatic enzymes of cysteine metabolism. Am. J. Physiol. 277 (Endocrinol. Metab. 40):E144-E153.