Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations.
The 500-residue amino acid sequence of the subunit of mitochondrial human liver aldehyde dehydrogenase is reported. It is the first structure determined for this enzyme type from any species, and is based on peptides from treatments with trypsin, CNBr, staphylococcal Glu-specific protease, and hydroxylamine. The chain is not blocked (in contrast to that of the acetylated cytosolic enzyme form), but shows N-terminal processing heterogeneity over the first seven positions. Otherwise, no evidence for subunit microheterogeneities was obtained. The structure displays 68% positional identity with that of the corresponding cytosolic enzyme, and comparisons allow functional interpretations for several segments. A region with segments suggested to participate in coenzyme binding is the most highly conserved long segment of the entire structure (positions 194-274). Cys-302, identified in the cytosolic enzyme in relation to the disulfiram reaction, is also present in the mitochondrial enzyme. A new model of the active site appears possible and involves a hydrophobic cleft. Near-total lack of conservation of the N-terminal segments may reflect a role of the N-terminal region in signaling the transport of the mitochondrial protein chains. Non-conservation of interior regions may reflect the differences between the two enzyme forms in subunit interactions, explaining the lack of heterotetrameric molecules. The presence of some internal repeat structures is also noted as well as apparently general features of differences between cytosolic and mitochondrial enzymes.
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D001665:Binding Sites; D001692:Biological Transport; D055598:Chemical Phenomena; D002621:Chemistry; D003067:Coenzymes / Q000378:metabolism; D003545:Cysteine / Q000032:analysis; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D006868:Hydrolysis; D008930:Mitochondria, Liver / Q000201:enzymology*; D011485:Protein Binding; D009626:Terminology as Topic
D000596:Amino Acids; D003067:Coenzymes; D000444:Aldehyde Dehydrogenase; D003545:Cysteine