My research program is focused on cellular detoxification pathways. Glutathione, an abundant low molecular weight thiol, is largely responsible for the tightly controlled maintenance of intracellular reduction-oxidation status essential for normal cellular function. Despite its ubiquitous distribution and critical functions in mammalian systems, numerous aspects of glutathione homeostasis remain unresolved. My laboratory uses a variety of biophysical techniques, including protein crystallography, enzymology, and protein chemistry, to examine the mechanisms of the enzymes responsible for maintaining reduced glutathione reservoirs. We have also recently developed eukaryotic model systems to validate our results in relevant contexts. Our work has provided a structural framework to examine regulation of glutathione metabolism at a molecular level, with the ultimate goal of controlling flux through the glutathione pathway.
A major focus of the lab is examining how small molecule metabolites involved in cellular detoxification pathways, are directed to a given metabolic fate. In collaboration with the Simpson laboratory, we have been studying human UDP-glucose dehydrogenase. The product of this enzyme, UDP-glucuronate, has similar detoxification functions as glutathione. We are attempting to determine the regulatory mechanisms that dictate partitioning of UDP-glucuronate to one of three fates: hyaluronan production, proteoglycan biosynthesis, and detoxification by UDP-glucuronosyltransferases.
Undergraduate Researcher (co-advised w/Dr. Joe Barycki)
Started January, 2014
Structural Studies of Human UGDH
Structural Studies of Glutathione Homeostasis Enzymes
Graduate Student (co-advised w/Dr. Joe Barycki)
B.S. 2013 Biochemistry, Marietta University
Allosteric control of UDP-glucose Dehydrogenase
Graduate Student (co-advised w/Dr. Melanie Simpson)
Probing metabolite partitioning to identify rate limiting factors in alternative pathway use
Brenna M. Zimmer, Michelle E. Howell, Qin Wei, Linlin Ma, Trevor Romsdahl, Eileen G. Loughman, Jonathan E. Markham, Javier Seravalli, Joseph J. Barycki, and Melanie A. Simpson. 2016. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential. Hormones and Cancer. 2016 Jun 15. [Epub ahead of print] PMID: 27307252
George Grady, Ashley Thelen, Jaleen Albers, Ju T, Jiantao Guo, Joseph J. Barycki+, Melanie A. Simpson+. 2016. Inhibiting hexamer disassembly of human UDP-glucose dehydrogenase by photoactivated amino acid cross-linking. Biochemistry. Jun 7, 2016. 55(22), 3157-64. PMID: 27198584. +co-corresponding authors
Xiaobin Wu, Heejeong Kim, Javier Seravalli, Joseph J. Barycki, P. John Hart, David Gohara, Enrico Di Cera, Won Hee Jung, Daniel J. Kosman, and Jaekwon Lee. 2016. Potassium and the K+/H+ exchanger Kha1p promote binding of copper to ApoFet3p multi-copper ferroxidase. Journal of Biological Chemistry Apr 29, 2015. 291(18), 9796-806. PMID 26966178
Hatice K. Ozer, Adrienne C. Dlouhy, Jeremy D. Thornton, Jingjing Hu, Yilin Liu, Joseph J. Barycki, Janneke Balk, and Caryn E. Outten. 2015. Cytosolic Fe-S cluster protein maturation and iron regulation are independent of the mitochondrial Erv1/Mia40 import system. Journal of Biological Chemistry Sep 22, 2015. 290(46), 27829-40. PMID 26396185
McAtee CO, Berkebile AR, Elowsky C, Fangman T, Barycki JJ, Wahl JK 3rd, Khalimonchuk O, Naslavsky N, Caplan S, Simpson MA. (2015) Hyaluronidase Hyal1 increases tumor cell proliferation and motility through accelerated vesicle trafficking. J Biol Chem. 2015 Apr 8. pii: jbc.M115.647446. [Epub ahead of print] PMID: 25855794
Hyde AS*, Thelen AM*, Barycki JJ+, Simpson MA+. (2013) UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces. J Biol Chem 288(49): 35049-35057. *Co-first authors, +Co-coressponding authors.
Hyde AS, Farmer EL, Easley KE, van Lammeren K, Christoffels VM, Barycki JJ, Bakkers J, and Simpson MA. (2012) UDP-glucose dehydrogenase polymorphisms from patients with congenital heart valve defects disrupt enzyme stability and quaternary assembly. J Biol Chem 287(39): 32708-16.
Joseph J. Barycki. 2012. Glutathione. In Encyclopedia of Biophysics. Ed. Victor Davidson. Publisher: Springer Publishing, Inc. (Publication date Ã¢ÂÂ March 29, 2012).
Melanie Willis, Yilin Liu, Ekaterina I. Biterova, Heejeong Kim, Melanie A. Simpson, Jaekwon Lee, and Joseph J. Barycki. 2011. Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. Biochemistry. 50(29), 6508-17. PMID: 21657237
Ekaterina I. Biterova and Joseph J. Barycki. 2010. Structural basis for feedback and pharmacological inhibition of Saccharomyces cerevisiae glutamate cysteine ligase. Journal of Biological Chemistry. 285(19), 14459-14466.
Ekaterina I. Biterova and Joseph J. Barycki. 2009. Mechanistic details of glutathione biosynthesis revealed by crystal structures of S. cerevisiae glutamate cysteine ligase. Journal of Biological Chemistry. 284(47), 32700-32708.
Kristin Williams, Sierra Cullati, Aaron Sand, Ekaterina I. Biterova and Joseph J. Barycki. 2009. Crystal structure of acivicin-inhibited gamma-glutamyltranspeptidase reveals a critical role for the C-terminus in autoprocessing and catalysis. Biochemistry. 48(11), 2459-2467.
Ling Zhang, Alamelu G. Bharadwaj, Andrew Casper, Joel Barkley, Joseph J. Barycki and Melanie A. Simpson. 2009. Hyaluronidase activity of human Hyal1 requires active site acidic and tyrosine residues. Journal of Biological Chemistry. 282(14), 9433-9442.
Amy Morrow, Kristin Williams, Aaron Sand, Gina Boanca, and Joseph J. Barycki. 2007. Characterization of H. pylori gamma-glutamyltranspeptidase reveals the molecular basis for substrate specificity and a critical role for the tyrosine 433-containing loop in catalysis. Biochemistry, 46 (46), 13407-13414.
Katherine E. Easley, Brandi J. Sommer, Gina Boanca, Joseph J. Barycki, and Melanie A. Simpson. 2007. Characterization of human UDP-glucose dehydrogenase reveals critical catalytic roles for lysine 220 and aspartate 280. Biochemistry, 46(2), 369-78.
Gina Boanca, Aaron Sand, Toshihiro Okada, Hideyuki Suzuki, Hidehiko Kumagai, Keiichi Fukuyama, and Joseph J. Barycki. 2007. Autoprocessing of H. pylori gamma-glutamyltranspeptidase leads to the formation of a threonine-threonine catalytic dyad. Journal of Biological Chemistry, 282 (1), 534-541.
Gina Boanca, Aaron Sand, and Joseph J. Barycki. 2006. Uncoupling enzymatic and autoprocessing activities of H. pylori gamma-glutamyltranspeptidase. Journal of Biological Chemistry 281 (28), 19029-19037.
Ekaterina I. Biterova, Anton A. Turanov, Vadim N. Gladyshev and Joseph J. Barycki. 2005. Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism. Proceedings of the National Academies of Sciences 102(42), 15018-15023.
Patricia L. Herman, Mark Behrens, Sarbani Chakraborty, Brenda M. Chrastil, Joseph Barycki and Donald P. Weeks. 2005. A three component dicamba O-demethylase from Pseudomonas maltophilia, strain DI-6: Gene isolation, characterization, and heterologous expression. Journal of Biological Chemistry 280, 24759-24767.
Peter J Hanley, Stefan DrÃÂ¶se, Ulrich Brandt, Rachel A Lareau, Abir L Banerjee, D. K. Srivastava, Leonard J Banaszak, Joseph J Barycki, Paul P Van Veldhoven, and Jurgen Daut. 2005. 5-hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for beta-oxidation of fatty acids. The Journal of Physiology 562(Pt 2), 307-318.
Brandi J. Sommer, Joseph J. Barycki, and Melanie A. Simpson. 2004. Characterization of human UDP-glucose dehydrogenase: Cys 276 is required for the second of two successive oxidations. Journal of Biological Chemistry 279, 23590-235906.
Joseph J. Barycki, Laurie K. O'Brien, Arnold W. Strauss, and Leonard J. Banaszak. 2001. Glutamate 170 of human L-3-hydroxyacyl-CoA dehydrogenase is required for proper orientation of the catalytic histidine and structural integrity of the enzyme. Journal of Biological Chemistry 276, 36718-36726.
Joseph J. Barycki, Laurie K. O'Brien, Arnold W. Strauss, and Leonard J. Banaszak. 2000. Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase. Journal of Biological Chemistry 275, 27186-27196.
Joseph J. Barycki, Laurie K. O'Brien, Jens J. Birktoft, Arnold W. Strauss, and Leonard J. Banaszak. 1999. Pig heart short chain L-3-hydroxyacyl-CoA dehydrogenase revisited: Sequence analysis and crystal structure determination. Protein Science 8(10), 2010-2018.
Joseph J. Barycki, Laurie K. O'Brien, Judy M. Bratt, Rongguang Zhang, Ruslan Sanishvili, Arnold W. Strauss, and Leonard J. Banaszak. 1999. Biochemical characterization and crystal structure determination of human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into catalytic mechanism. Biochemistry 38(18), 5786-5798.
Joseph J. Barycki and Roberta F. Colman. 1997. Identification of the non-substrate binding site of rat liver glutathione S-transferase, isozyme 1-1, by the steroid affinity label, 3beta-(iodoacetoxy)dehydroisoandrosterone. Archives of Biochemistry and Biophysics 345, 16-31.
Jibo Wang, Joseph J. Barycki and Roberta F. Colman. 1996. Tyrosine 8 contributes to catalysis but is not required for activity of rat liver glutathione S-transferase, 1-1. Protein Science 5, 1032-1042.
Joseph J. Barycki and Roberta F. Colman. 1993. Affinity labeling of glutathione S-transferase, isozyme 4-4, by 4-(fluorosulfonyl)benzoic acid reveals Tyr 115 to be an important determinant of xenobiotic substrate specificity. Biochemistry 32, 13002-13011.
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