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Why acetaldehyde kills the DERA aldolase
Crotonaldehyde, the acetaldehyde aldol product, covalently bridges catalytic K167 to nearby C47; a C47M mutant survives 300 mM acetaldehyde.
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What product is the mechanism-based inhibitor of DERA?
Crotonaldehyde from aldol condensation of two acetaldehydes.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
How does crotonaldehyde covalently inactivate DERA?
It links catalytic lysine to a nearby cysteine.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
What happens at 200–300 mM acetaldehyde?
Irreversible inactivation that washing cannot restore.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
Which residues form the covalent link after 300 mM acetaldehyde?
The ligand orients to bond the sulfur of C47 while still on K167.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
How much more potent is crotonaldehyde than acetaldehyde?
More than 100-fold; 1 mM nearly fully inactivates in under an hour.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
What does C47M do in 300 mM acetaldehyde?
It loses no activity even after 16 h.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
How much activity does C47M retain?
60 ± 5% of wild type, with Tm 65.1 °C vs 66.6 °C.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
How conserved is C47?
In 91% of 3700 orthologues with ≥20% identity.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
What is K167’s normal catalytic role?
It forms a Schiff base with the donor; K201 and D102 run a proton relay.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
What protective strategy do the authors highlight?
Replace the single reactive cysteine to make an acetaldehyde-resistant enzyme.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified
Why might cells use this suicide chemistry?
High acetaldehyde is harmful; shutting DERA could limit further acetaldehyde production.
Source: Mechanism-based inhibition of an aldolase at high concentrations of its natural substrate acetaldehyde: structural insights and protective strategies · DOI · quote verified