Congratulations to MBD Fellows Lu Huo and Co-Author Ian Davis for Recent Publication

Posted On December 19, 2014
Categories Featured News

Luho and IanCrystallographic 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 which 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 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 prior to an sp3-to-sp2 transition during enzyme-mediated oxidation.