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Title: Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

Abstract

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 sp 3-to-sp 2 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:
Research Org.:
Argonne National Lab. (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)
OSTI Identifier:
1168512
Alternate Identifier(s):
OSTI ID: 1201330
Report Number(s):
BNL-107771-2015-JA
Journal ID: ISSN 2041-1723; ncomms6935
Grant/Contract Number:  
SC00112704; AC02-98CH10886; W-31-109-ENG-38; AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; chemical sciences; biochemistry; chemical biology; physical chemistry

Citation Formats

Huo, Lu, Davis, Ian, Liu, Fange, Andi, Babak, Esaki, Shingo, Iwaki, Hiroaki, Hasegawa, Yoshie, Orville, Allen M., and Liu, Aimin. Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action. United States: N. p., 2015. Web. doi:10.1038/ncomms6935.
Huo, Lu, Davis, Ian, Liu, Fange, Andi, Babak, Esaki, Shingo, Iwaki, Hiroaki, Hasegawa, Yoshie, Orville, Allen M., & Liu, Aimin. Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action. United States. doi:10.1038/ncomms6935.
Huo, Lu, Davis, Ian, Liu, Fange, Andi, Babak, Esaki, Shingo, Iwaki, Hiroaki, Hasegawa, Yoshie, Orville, Allen M., and Liu, Aimin. Wed . "Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action". United States. doi:10.1038/ncomms6935. https://www.osti.gov/servlets/purl/1168512.
@article{osti_1168512,
title = {Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action},
author = {Huo, Lu and Davis, Ian and Liu, Fange and Andi, Babak and Esaki, Shingo and Iwaki, Hiroaki and Hasegawa, Yoshie and Orville, Allen M. and Liu, Aimin},
abstractNote = {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.},
doi = {10.1038/ncomms6935},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {Wed Jan 07 00:00:00 EST 2015},
month = {Wed Jan 07 00:00:00 EST 2015}
}

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