Biography
Martha Stipanuk was the James Jamison Professor in Nutrition in the Division of Nutritional Sciences at Cornell University, where she was a faculty member since 1977 until her retirement in 2018. 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 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, including glutathione synthesis and taurine production, within the whole body. The Stipanuk laboratory played a major role in elucidating the physiological function, regulation, structure, and protein coenzyme formation of cysteine dioxygenase, an iron-dependent enzyme that catalyzes the first step in the cysteinesulfinate-dependent pathway of cysteine catabolism. Cysteine dioxygenase plays a crucial role in regulating cysteine levels, in promoting taurine biosynthesis, and in restricting the metabolism of cysteine through the intermediate hydrogen sulfide, preventing sulfide toxicity and facilitating hydrogen sulfide signaling. The regulation of cysteine dioxygenase abundance and activity state occurs specifically in response to cysteine levels. The Stipanuk laboratory was also interested in elucidating the mechanism(s) by which the concentrations of other amino acids are sensed by cells and how cells respond to changes in amino acid availability.
Dr. Stipanuk had a long-standing interest in teaching and course development in the area of nutrient metabolism. She developed a multi-authored advanced textbook entitled “Biochemical, Physiological and Molecular Aspects of Human Nutrition” published by Saunders/Elsevier with the 3rd edition released in 2012 and the 4th edition in progress. At Cornell, she taught graduate courses on “Regulation of Macronutrient Metabolism” and “Nutritional Regulation of Mammalian Protein Synthesis and Degradation.”
In 2015, she was elected a Fellow of the American Society for Nutrition in recognition of her distinguished career in nutrition science research.
In 2018 she retired and was granted Emerita status.
Mechanisms of molecular regulation of key enzymes of cysteine metabolism in response to dietary changes; 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 and hydrogen sulfide biosynthetic pathways; amino acid deprivation and response to stress; role of amino acids in sensing of nutrient deprivation and activation of stress response pathways.
Mazor KM, Stipanuk MH (2016) GCN2- and eIF2α-phosphorylation-independent, but ATF4-dependent, induction of CARE-containing genes in methionine-deficient cells. Amino Acids 48:2831-2842.
Driggers CM, Kean KM, Hirschberger LL, Cooley RB, Stipanuk MH, Karplus PA (2016) Structure-Based Insights into the Role of the Cys-Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase. J Mol Biol 428:3999-4012.
Niewiadomski J, Zhou JQ, Roman HB, Liu X, Hirschberger LL, Locasale JW, Stipanuk MH (2016) Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice. Ann N Y Acad Sci 1363:99-115.
Jurkowska H, Niewiadomski J, Hirschberger LL, Roman HB, Mazor KM, Liu X, Locasale JW, Park E, Stipanuk MH (2016) Downregulation of hepatic betaine:homocysteine methyltransferase (BHMT) expression in taurine-deficient mice is reversed by taurine supplementation in vivo. Amino Acids 48:665-676.
Jurkowska H., Roman H.B., Hirschberger L.L., Sasakura K., Nagano T., Hanaoka K., Krijt J., Stipanuk M.H. (2014) Primary hepatocytes from mice lacking cysteine dioxygenase show increased cysteine concentrations and higher rates of metabolism of cysteine to hydrogen sulfide and thiosulfate. Amino Acids 46:1353-1365.
Sikalidis A.K., Mazor K.M., Lee J.I., Roman H.B., Hirschberger L.L., Stipanuk M.H. (2014) Upregulation of capacity for glutathione synthesis in response to amino acid deprivation: regulation of glutamate-cysteine ligase subunits. Amino Acids 46:1285-1296.
Driggers C.M., Cooley R.B., Sankaran B., Hirschberger L.L., Stipanuk M.H., and Karplus P.A. (2013) Cysteine dioxygenase structures from pH4 to 9: consistent cys-persulfenate formation at intermediate pH and a Cys-bound enzyme at higher pH. J Mol Biol. 425:3121-3136.
Roman H.B., Hirschberger L.L., Krijt J., Valli A., Kožich V., and Stipanuk M.H. (2013) The cysteine dioxgenase knockout mouse: altered cysteine metabolism in nonhepatic tissues leads to excess H2S/HS- production and evidence of pancreatic and lung toxicity. Antioxid Redox Signal. 19:1321-1336.
Ueki, I., Roman, H.B., Hirschberger, L.L., Junior, C., and Stipanuk, M.H. (2012) Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase. Am J Physiol Endocrinol Metab. 302:E1292-E1299.
Ueki, I., Roman, H.B., Valli, A., Fieselmann, K., Lam, J., Peters, R., Hirschberger, L.L., and Stipanuk, M.H. (2011) Knockout of the cysteine dioxygenase gene results in severe impairment in taurine synthesis and increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 301: E688-E684.
Stipanuk M.H. and Ueki, I. (2011) Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis. 34:17-32.
Stipanuk MH, Simmons CR, Karplus PA, Dominy JE Jr. (2011) Thiol dioxygenases: unique families of cupin proteins. Amino Acids 41:91-102.
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.
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.
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].
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.
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, 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 g-glutamylcysteine synthetase is associated with hepatic cysteine level. J. Nutr. Biochem. 15: 112-122.
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.
Bella, D.L., Hirschberger, L.L., Hosokawa, Y., and Stipanuk, M.H. (1999) The mechanisms involved in the regulation of key enzymes of cysteine metabolism in rat liver in vivo. Am. J. Physiol. 276 (Endocrin. Metab. 39): E326-E335.
Garcia, R.A.G. and Stipanuk, M.H. (1992) The splanchnic organs, liver and kidney have unique roles in the metabolism of sulfur amino acids and their metabolites in rats. J. Nutr. 122: 1693-1701.
Stipanuk, M.H. and Beck, P.W. (1982) Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem. J. 206: 267-277.
Stipanuk, M.H. (2004) Sulfur Amino Acid Metabolism – Pathways for Production and Removal of Homocysteine and Cystine. Annu. Rev. Nutr. 24:539-577.
Stipanuk, M.H. (1986) Metabolism of the sulfur-containing amino acids. Annu. Rev. Nutr. 6:179-209.
Cornell University Graduate Field Membership: Nutrition
Member of American Society for Nutrition; Member of Publications Management Committee
Member of the American Society for Biochemistry and Molecular Biology
Member of the American Society for Physiology
1977, PhD, Nutrition and Biochemistry, University of Wisconsin
1972, MS, Nutrition and Biochemistry, Cornell University
1970, BS, Home Economics/Education, University of Kentucky