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Structures of human alcohol and aldehyde dehydrogenases
Enzyme
|January 1, 1987
Summary
Human alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes have distinct structures and genetic variations. Studies reveal amino acid differences and allelic variants, explaining functional diversity and isozyme evolution in ADH, and functional importance of cysteine in ALDH.
Area of Science:
- Biochemistry
- Enzymology
- Molecular Biology
Background:
- Human alcohol dehydrogenase (ADH) exists in three classes (I, II, III) with distinct subunit interactions and primary structures.
- Class I ADH comprises alpha, beta, and gamma subunits, with known primary structures, cDNA, genetic organization, and gene structures.
- Human aldehyde dehydrogenase (ALDH) has two forms (mitochondrial and cytosolic), which are tetrameric, lack functional metals, and do not form inter-type hybrids.
Purpose of the Study:
- To elucidate the structural and functional characteristics of human alcohol and aldehyde dehydrogenases.
- To investigate the genetic basis and evolutionary implications of ADH isozymes.
- To understand the role of specific residues, like cysteine, in ALDH function and its interaction with disulfiram.
Main Methods:
- Primary structure determination of ADH and ALDH subunits.
- Analysis of cDNA structures, genetic organization, and gene structures for ADH.
- Characterization of allelic variants and associated amino acid substitutions in ADH.
- Comparative analysis of mitochondrial and cytosolic ALDH primary structures.
Main Results:
- Identified 35 residue differences among alpha, beta, and gamma ADH subunits, explaining functional variations.
- Established genetic organization and allelic variants for ADH, illustrating isozyme evolution.
- Determined 68% positional identity between mitochondrial and cytosolic ALDH forms.
- Identified a conserved reactive cysteine at position 302 in ALDH, crucial for enzyme activity and disulfiram interaction.
- Characterized a functionally impaired mitochondrial ALDH variant in Oriental populations.
Conclusions:
- Human ADH and ALDH exhibit significant structural diversity and genetic variability, contributing to their distinct functions.
- Amino acid substitutions and allelic variants are key drivers of functional differences and isozyme evolution in ADH.
- A specific cysteine residue in ALDH is critical for its catalytic activity and interaction with drugs like disulfiram.
- Genetic variations in ALDH can lead to impaired enzyme function, with implications for specific populations.