Professor, Department of Physiology & Biophysics
Tryptophan Dioxygenase (TDO) and Indoleamine 2,3-Dioxygenase (IDO) are the only two heme-containing enzymes that catalyze the breakdown of the essential amino acid tryptophan along the kynurenine (KYN) pathway. Recently, TDO and IDO have emerged as key targets in cancer immunotherapy because of their roles in promoting cancer immune escape. The critical barrier for the development of TDO and IDO-selective inhibitors for cancer therapy lies in the poor knowledge of the molecular properties of the two enzymes. The goal of our research is to delineate the structure and function relationships of TDO and IDO with an integrated approach involving molecular biology, protein chemistry, structural biology, enzymology, biophysics and drug discovery. Specifically, we employ microscopic spectroscopy-guided x-ray crystallography, combined with site-directed mutagenesis, to investigate the three-dimensional structures of the stable derivatives, as well as transient intermediates, of TDO and IDO. In parallel, we use state-of-the art spectroscopic techniques (such as UV-Vis, Raman, FTIR, CD, fluorescence and EPR), combined with kinetic strategies (such as stopped-flow and continuous-flow), to interrogate the differential biochemical and biophysical properties of the two enzymes in free solution. The resulting mechanistic information is integrated by computational studies with Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM).
"O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1." Malachowski WP, Winters M, DuHadaway JB, Lewis-Ballester A, Badir S, Wai J, Rahman M, Sheikh E, LaLonde JM, Yeh SR, Prendergast GC, Muller AJ.
Eur J Med Chem. 108, 564-76, 2016.
“Spectroscopic and mutagenesis studies of human PGRMC1.” Kaluka D, Batabyal D, Chiang BY, Poulos TL, Yeh SR. Biochemistry. 54, 1638-47, 2015.
“Catalytic intermediates of inducible nitric oxide synthase stabilized by the W188H mutation.” Sabat J, Egawa T, Lu C, Stuehr DJ, Gerfen GJ, Rousseau DL, Yeh SR. J Biol Chem. 288, 6095-106, 2013.
“Ferryl derivatives of human indoleamine 2,3-dioxygenase” Lu C, Yeh SR. J Biol Chem. 286, 21220-30, 2011.
“Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase.” Capece L, Lewis-Ballester A, Marti MA, Estrin DA, Yeh SR., Biochemistry, 50, 10910-8, 2011.
“Spectroscopic Studies of Ligand and Substrate Binding to Human Indoleamine 2,3-Dioxygenase.” Lu C, Lin Y, Yeh SR. Biochemistry, 49, 5028-34, 2010.
"Evidence for a ferryl intermediate in a heme-based dioxygenase." Lewis-Ballester A, Batabyal D, Egawa T, Lu C, Lin Y, Marti MA, Capece L, Estrin DA, Yeh SR. Proc Natl Acad Sci U S A. 106, 17371-6, 2009.
"Inhibitory substrate binding site of human indoleamine 2,3-dioxygenase." Lu C, Lin Y, Yeh SR. J Am Chem Soc.131, 12866-7, 2009.
"Substrate-protein interaction in human tryptophan dioxygenase: the critical role of H76." Batabyal D, Yeh SR. J Am Chem Soc. 131, 3260-70, 2009.
"Design and evaluation of a passive alcove-based microfluidic mixer." Egawa T, Durand JL, Hayden EY, Rousseau DL, Yeh SR. Anal Chem. 81, 1622-7, 2009.
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 313
Bronx, NY 10461