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Mechanism Jonathan Nguyen access channel enzyme dihydroorotate dehydrogenase DHODH teri occupies site flunamide active of DHODH Greenernee1 teriflunanideis Normally DHODH catalyzes the oxidation of DHO into orotate by transferring electrons to ubiquinone through the redox cofactor FMN This process is disturbed when teri unomide enters dihydroorotate dehydrogenase through a narrow region in the access channel and binds to the active site The carbonyl of teri unomide hydrogen bonds with water which in turn is bound to Arg136 Meanwhile the OH that is part of the enol hydrogen bonds to Tyr356 The triu uoromethyl group which contains aromatic rings has many hydrophobic interactions with the residues in the tunnel In addition the amide side chain of teri unomide undergoes a 180 degree rotation which leads to a direct interaction with the arginine residue Arg265 All of these bonds and interactions combined e ectively block the substrate dihydroorotate from attaching to the DHODH enzyme This prevents the conversion of dihydroorotate to orotate The tunnel where ubiquininone accepts electrons from DHO the same tunnel where teri unomide occupies to block the active site is distal to the surface of DHODH The redox site where DHO and FMN bind is proximal to the surface of DHODH References E 2 D0x 0 2 2 E O I H O Oxidation Z 2H 2 2H reduction 3 3 2 10x 3 2 3 E 3 3 2 3 E 1 3 0 H 1 0 E 1 1 1 E 4 mediator 2e 2H Oxidation reduction 2 2H 4 6 I A Ox 3 0 2 2 E 3 2 1 3 E 3 E 1 2 2 E 6 terriftunomide Oxidation States of Ligand Reactions Mendotaipeergatorse FMN FMNH2 Fang J Uchiumi T Yagi M Matsumoto S Amamoto R Takazaki S Yamaza H Nonaka K Kang D 2013 Dihydro orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction Bioscience reports 33 2 e00021 https doi org 10 1042 BSR20120097 Liu S Neidhardt E A Grossman T H Ocain T Clardy J 2000 Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents Structure 8 1 25 33 https doi org 10 1016 s0969 2126 00 00077 0 Munier Lehmann H Vidalain P O Tangy F Janin Y L 2013 On dihydroorotate dehydrogenases and their inhibitors and uses Journal of Medicinal Chemistry 56 8 3148 3167 https doi org 10 1021 jm301848w

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UIUC CHEM 332 - Mechanism Unit 1

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