UT Chem/Biochem Dept

The 2008-2009 Beckman Scholars: Lynne Chantranupong

Faculty Mentor: Professor George Georgiou Length of term: Summer 08, Fall 08, Spring 09, Summer 09 Honors & Awards:University Honors (Spring 06, Fall 08, Spring 09); Brock University Entrance scholarship (2005); Arts and Sciences Scholarship (2005); Alumni scholarship (2006); College of Natural Sciences Scholarship (2008); University of Michigan Program in Biomedical Sciences Excellence in Research Award (2008): UT Undergraduate Research Fellowship (2009); Barry M. Goldwater Scholarship (2009); Dean's Honored Graduate (2010); NSF Graduate Research Fellowship (2010-2012). Publications: Thoreen CC, Chantranupong L, Keys HR, Wang T, Grey NS, Sabatini DM. Nature. (2012) 485(7396): 109-13. Chantranupong L, Heineman RH. BMC Evol Biol. (2012) 12(1):37. Romero PA, et al, ACS Synth. Bio. (accepted March 30, 2012). Stone EM, Chantranupong L, Gonzalez C, O'Neal J, Rani M, Vandenberg C, Georgiou G. J Control Release. (2012) 1:171-9. Stone EM, Chantranupong L, Georgiou G Biochemistry 2010: 49(49): 10582-8. Stone, E.M. Glazer, E.S., Chantranupong, L., Cherukuri, P., Breece, R.M. Tierney, D.L., Curley, S.A., Iverson, B.L. and Georgiou, G. ACS Chem. Biol., 2010, 5 (3), pp 333-342. Glazer ES, Stone EM, Kaluarachchi WD, Chantranupong L, Massey KL, Georgiou G, Curley SA. J Surg Res. 2010 Feb; 158(2):338-9. Cantor, J.R., Stone, E.M. Chantranupong, L. and Georgiou, G. Biochemistry 2009, 48, 11026-11031. Where is she now? Graduated with Bachelor of Science in Biology with Special Departmental Honors in Biology, May 2010. Lynne is currently in graduate school at MIT. How can I contact her? lchantran at gmail.com

Beckman research project in the Georgiou group:

Download a copy of Lynne's Research report, entitled Development of human Arginase I as a Novel Chemotherapeutic Agent

According to the American Cancer Society, over 36,000 Americans will die of melanoma, kidney, and liver cancers this year while 130,000 more will be diagnosed.¹ Undoubtedly, there is a pressing need to develop treatments that will alleviate the death and suffering resulting from these cancers.

Although arginine is not considered to be an essential amino acid, it has been found to be in high demand by malignant cells. While normal cells synthesize arginine in two steps via the urea-cycle enzymes arginosuccinate synthase (ASS) and arginosuccinate lyase, melanomas, hepatocellular and renal cell carcinomas are auxotrophic for arginine due to lack of ASS expression.² These results highlight arginine depletion as an attractive avenue towards both a novel and effective therapy of the aforementioned cancers since such a treatment would selectively starve malignant cells yet avoid the introduction of xenobiotic toxins into the body. In bacteria, arginine deaminase (ADI) catalyzes the conversion of arginine to citrulline and ammonia; however, the strong antigenicity arising from using an exogenous enzyme is anticipated to be a significant disadvantage for extended treatment regimes. One promising approach to address this drawback is utilizing related human proteins as a scaffold to construct ÒhumanizedÓ ADI with few or no epitopes. One human enzyme with the greatest potential to serve this purpose is peptidyl arginine deiminase (PAD) - a Ca²⁺-dependent enzyme which catalyzes the conversion of arginine residues to citrulline.³

Specifically, site-directed mutagenesis and error-prone mutagenesis of human PAD4 active site residues will be used to produce a library of mutated proteins. Among these mutants, those with the desired arginine catabolizing activity will be detected through their ability to rescue mutants of E. coli incompetent in catabolizing L-arginine as the sole nitrogen source and further analyzed through kinetics. E. coli-containing plasmids conferring ADI activity will then be sequenced and mutations mapped to the structure of the parent enzyme to better understand the changes leading to the desired activity. Ultimately, the research proposed here will lead towards the development of novel proteins with arginine degrading activity and minimal immunogenicity. More importantly, it will bring us closer towards a successful treatment to ease the pain and distress of those afflicted with cancer.