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Title: Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [3] ;  [3] ;  [2] ;  [1]
  1. Georgia State Univ., Atlanta, GA (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Kansai Univ., Osaka (Japan)
Publication Date:
OSTI Identifier:
1168512
Grant/Contract Number:
SC00112704; AC02-98CH10886; W-31-109-ENG-38; AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States); Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES chemical sciences; biochemistry; chemical biology; physical chemistry