Breaking down the structure of the enzyme ALDH2: 1 tequila, 2 tequila…..ASIAN FLUSH!

Human Mitochondrial Aldehyde Dehydrogenase (ALDH2) ALDH2 catalyzes the conversion of acetaldehyde, an intermediate product of ethanol, into acetic acid. * *

ASIAN FLUSH Demographics Approximately 40% of East Asians have a reduced ALDH2 function, due to the mutation of Glu to Lys at amino acid 487. Results in high levels of acetaldehyde in the blood Symptoms include facial flushing, light headedness, palpitations, nausea, and general “hangover” symptoms occur.

Genetics Homozygotes of the Glu487Lys mutation have zero ALDH2 activity Heterozygotes of same mutation have reduced ALDH2 activity The mutation is a partial dominant Drugs to treat alcohol abusers mimic the Asian Flush phenotype

E487 NAD+ ALDH2 dimer with key connections at E487

NAD+ Binding Site Superimposed wild type and Flushing isoform ALDH2 (A chain only) Glu487Lys

Conclusions Homozygotes of the Glu487Lys mutation have zero ALDH2 activity Heterozygotes of same mutation have reduced ALDH2 activity Active site sequence is evolutionarily conserved The position of the mutation (E487K) could disrupt interactions between protein monomers The mutation causes structural changes within the protein that could disrupt interactions with NAD+ as well.