Premium
Extending the Kynurenine Pathway to an Aldehyde Disarming Enzyme: Mechanistic Study of Bacterial AMSDH and Identification of the Correct Human Enzyme
Author(s) -
Davis Ian,
Huo Lu,
Liu Fange,
Andi Babak,
Esaki Shingo,
Iwaki Hiroaki,
Hasegawa Yoshie,
Orville Allen,
Liu Aimin
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.573.3
Subject(s) - kynurenine pathway , enzyme , metabolic pathway , chemistry , catabolism , kynurenine , biochemistry , acetaldehyde , dehydrogenase , stereochemistry , aldehyde dehydrogenase , tryptophan , amino acid , ethanol
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 which can decay into neuroactive compounds that have been associated with numerous neurological diseases, such as quinolinic acid (QUIN).An enzyme of this pathway, 2‐aminomuconate‐6‐semialdehyde dehydrogenase, which is responsible for ‘disarming’ the final aldehydic intermediate, has yet to be studied at the molecular level. Its activity steers the vast majority of metabolic flux to further catabolism and prevents overproduction of a metabolic dead‐end, picolinic acid. In this presentation we will show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms, two of which are covalently‐bound, substrate‐enzyme adducts. The crystal‐ and solution‐state spectroscopic data along with the crystal structures also reveal that the substrate must undergo an isomerization reaction prior to oxidation. This study provides an in‐depth mechanistic understanding of an anticipated dehydrogenase in the kynurenine pathway.