Molecular Abnormality of an Inactive Aldehyde Dehydrogenase Variant Commonly Found in Orientals

• Published in: Proceedings of the National Academy of Sciences - PNAS 1984-01, Vol.81 (1), p.258-261
• Main Authors: Yoshida, Akira, I-Yih Huang, Ikawa, Michiharu
• Format: Article
• Language: English
• Subjects: Alcoholic beverages; Aldehyde Dehydrogenase; Aldehyde Oxidoreductases - genetics; Amino Acid Sequence; Amino acids; Amino Acids - analysis; Asian Continental Ancestry Group; Chromatography; Dehydrogenases; Electrophoresis; Enzymes; Genetic Variation; Humans; Isoenzymes - genetics; Japan - ethnology; Liver; Liver - enzymology; Medical sciences; Paper chromatography; Peptide Fragments - analysis; Trypsin; White people
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.81.1.258

Usual human livers contain two major aldehyde dehydrogenase [(ALDH) aldehyde: NAD+oxidoreductase] isozymes--i.e., a cytosolic ALDH1component and a mitochondrial ALDH2component--whereas ≈ 50% of Orientals are ``atypical'' and have only the ALDH1isozyme and are missing the ALDH2isozyme. We previously demonstrated that atypical livers contain an enzymatically inactive but immunologically crossreactive material (CRM) corresponding to the ALDH2component. The enzymatically active ALDH2obtained from a usual liver and the CRM obtained from an atypical liver were reduced, S-carboxymethylated, and digested by trypsin. Separation of their digests by high-performance reverse-phase chromatography and by two-dimensional paper chromatography and electrophoresis revealed that ALDH2contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-Gly-Leu-Gln-Ala-Asn-Val-Gln-Val-Lys- and that the glutamine adjacent to lysine was substituted by lysine in CRM. All other tryptic peptides, including eight peptides containing S-carboxymethylcysteine, were common in ALDH2and CRM. It is concluded that a point mutation in the human ALDH2locus produced the glutamine → lysine substitution and enzyme inactivation.