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Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms6935· OSTI ID:1168512
 [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)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States); Brookhaven National Laboratory (BNL), Upton, NY (United States); Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357; AC02-98CH10886; W-31109-ENG-38
OSTI ID:
1168512
Alternate ID(s):
OSTI ID: 1201330
OSTI ID: 1229002
Report Number(s):
BNL--107771-2015-JA; ncomms6935
Journal Information:
Nature Communications, Journal Name: Nature Communications Vol. 6; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (6)

The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus journal May 2018
NADP-Dependent Aldehyde Dehydrogenase from ArchaeonPyrobaculum sp.1860: Structural and Functional Features journal January 2016
Reassignment of the human aldehyde dehydrogenase ALDH8A1 (ALDH12) to the kynurenine pathway in tryptophan catabolism journal April 2018
Quaternary structure of α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase (ACMSD) controls its activity journal June 2019
Combining X-ray and neutron crystallography with spectroscopy journal February 2017
What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? journal May 2015

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