The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with computational methods that include electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The calculations will probe the roles of electrostatics, hydrogen bonding, hydrogen tunneling, and protein motion in enzyme reactions. The four enzyme reactions that will be studied have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The first specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme maintains tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The second specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DMA synthesis. DHOD is medically relevant in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically to treat diseases such as rheumatoid arthritis. The third specific aim centers on the enzyme lipoxygenase. This enzyme aids in the production of leukotrienes and lipoxins, which regulate responses in inflammation and immunity. In mammals, lipoxygenases are medically relevant in that inhibitors have been used as drug agents to treat diseases such as asthma, atherosclerosis, psoriasis, and cancer. The fourth specific aim centers on the enzyme ketosteroid isomerase (KSI), which catalyzes the isomerization of steroids. In mammals, this enzyme is medically relevant in that it controls the synthesis of steroid hormones. Deficiencies of KSI and related enzymes in humans lead to a wide range of diseases and health problems. All of these studies are relevant to public health because the elucidation of the mechanisms will facilitate the development of more effective drugs for a broad range of diseases, including cancer, asthma, malaria, and rheumatoid arthritis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056207-11
Application #
7194904
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Preusch, Peter C
Project Start
1998-05-01
Project End
2011-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
11
Fiscal Year
2007
Total Cost
$270,379
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Li, Pengfei; Soudackov, Alexander V; Hammes-Schiffer, Sharon (2018) Fundamental Insights into Proton-Coupled Electron Transfer in Soybean Lipoxygenase from Quantum Mechanical/Molecular Mechanical Free Energy Simulations. J Am Chem Soc 140:3068-3076
Hammes-Schiffer, Sharon (2017) Catalysts by Design: The Power of Theory. Acc Chem Res 50:561-566
Bingaman, Jamie L; Zhang, Sixue; Stevens, David R et al. (2017) The GlcN6P cofactor plays multiple catalytic roles in the glmS ribozyme. Nat Chem Biol 13:439-445
Horitani, Masaki; Offenbacher, Adam R; Carr, Cody A Marcus et al. (2017) 13C ENDOR Spectroscopy of Lipoxygenase-Substrate Complexes Reveals the Structural Basis for C-H Activation by Tunneling. J Am Chem Soc 139:1984-1997
Hu, Shenshen; Soudackov, Alexander V; Hammes-Schiffer, Sharon et al. (2017) Enhanced Rigidification within a Double Mutant of Soybean Lipoxygenase Provides Experimental Support for Vibronically Nonadiabatic Proton-Coupled Electron Transfer Models. ACS Catal 7:3569-3574
Ucisik, Melek N; Hammes-Schiffer, Sharon (2017) Effects of Active Site Mutations on Specificity of Nucleobase Binding in Human DNA Polymerase ?. J Phys Chem B 121:3667-3675
Zhang, Sixue; Stevens, David R; Goyal, Puja et al. (2016) Assessing the Potential Effects of Active Site Mg2+ Ions in the glmS Ribozyme-Cofactor Complex. J Phys Chem Lett 7:3984-3988
Ucisik, Melek N; Bevilacqua, Philip C; Hammes-Schiffer, Sharon (2016) Molecular Dynamics Study of Twister Ribozyme: Role of Mg(2+) Ions and the Hydrogen-Bonding Network in the Active Site. Biochemistry 55:3834-46
Soudackov, Alexander V; Hammes-Schiffer, Sharon (2016) Proton-coupled electron transfer reactions: analytical rate constants and case study of kinetic isotope effects in lipoxygenase. Faraday Discuss 195:171-189
Yu, Tao; Soudackov, Alexander V; Hammes-Schiffer, Sharon (2016) Computational Insights into Five- versus Six-Coordinate Iron Center in Ferrous Soybean Lipoxygenase. J Phys Chem Lett 7:3429-33

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