'''Crystal Structure of the Tryptamine-Derived (Indol-3-Acetamide)-TTQ Adduct of Aromatic Amine Dehydrogenase'''
===Crystal Structure of the Tryptamine-Derived (Indol-3-Acetamide)-TTQ Adduct of Aromatic Amine Dehydrogenase===
==Overview==
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Aromatic amine dehydrogenase uses a tryptophan tryptophylquinone (TTQ) cofactor to oxidatively deaminate primary aromatic amines. In the reductive half-reaction, a proton is transferred from the substrate C1 to betaAsp-128 O-2, in a reaction that proceeds by H-tunneling. Using solution studies, kinetic crystallography, and computational simulation we show that the mechanism of oxidation of aromatic carbinolamines is similar to amine oxidation, but that carbinolamine oxidation occurs at a substantially reduced rate. This has enabled us to determine for the first time the structure of the intermediate prior to the H-transfer/reduction step. The proton-betaAsp-128 O-2 distance is approximately 3.7A, in contrast to the distance of approximately 2.7A predicted for the intermediate formed with the corresponding primary amine substrate. This difference of approximately 1.0 A is due to an unexpected conformation of the substrate moiety, which is supported by molecular dynamic simulations and reflected in the approximately 10(7)-fold slower TTQ reduction rate with phenylaminoethanol compared with that with primary amines. A water molecule is observed near TTQ C-6 and is likely derived from the collapse of the preceding carbinolamine TTQ-adduct. We suggest this water molecule is involved in consecutive proton transfers following TTQ reduction, and is ultimately repositioned near the TTQ O-7 concomitant with protein rearrangement. For all carbinolamines tested, highly stable amide-TTQ adducts are formed following proton abstraction and TTQ reduction. Slow hydrolysis of the amide occurs after, rather than prior to, TTQ oxidation and leads ultimately to a carboxylic acid product.
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==About this Structure==
==About this Structure==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Tryptophan tryptophyl quinone]]
[[Category: Tryptophan tryptophyl quinone]]
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Revision as of 11:40, 28 July 2008
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Crystal Structure of the Tryptamine-Derived (Indol-3-Acetamide)-TTQ Adduct of Aromatic Amine DehydrogenaseCrystal Structure of the Tryptamine-Derived (Indol-3-Acetamide)-TTQ Adduct of Aromatic Amine Dehydrogenase
New insights into the reductive half-reaction mechanism of aromatic amine dehydrogenase revealed by reaction with carbinolamine substrates., Roujeinikova A, Hothi P, Masgrau L, Sutcliffe MJ, Scrutton NS, Leys D, J Biol Chem. 2007 Aug 17;282(33):23766-77. Epub 2007 May 1. PMID:17475620
