THE MUTATION IN THE MITOCHONDRIAL ALDEHYDE DEHYDROGENASE (ALDH2) GENERESPONSIBLE FOR ALCOHOL-INDUCED FLUSHING INCREASES TURNOVER OF THE ENZYME TETRAMERS IN A DOMINANT FASHION

Deficiency in mitochondrial aldehyde dehydrogenase (ALDHZ), a tetramer ic enzyme, results from inheriting one or two ALDH22 alleles, This al lele encodes a protein subunit with a lysine for glutamate substitutio n at position 487 and is dominant over the wild-type allele, ALDH21. The ALDH22-encoded subunit (ALDH2K) reduces the activity of ALDH2 enz yme in cell lines expressing the wild-type subunit (ALDH2E). In additi on to this effect on the enzyme activity, we now report that ALDH22 h eterozygotes had lower levels of ALDH2 immunoreactive protein in autop sy liver samples. The half-lives of ALDH2 protein in HeLa cell lines e xpressing ALDH21, ALDH2*2, or both were determined by the rate of los s of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments, By either measure, ALDH2E e nzyme was very stable, with a half-life of at least 22 h, ALDH2K enzym e had an enzyme half-life of only 14 h, In cells expressing both subun its, most of the subunits assemble as heterotetramers, and these enzym es had a half-life of 13 h, Thus, the effect of ALDH2K on enzyme turno ver is dominant. These studies indicate that the ALDH22 allele exerts its dominant effect both by interfering with the catalytic activity o f the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochond rial enzyme's turnover.