InterPro domain: IPR016161

This entry represents a structural domain found in aldehyde dehydrogenases [ 1 ] and histidinol dehydrogenases [ 2 ]. These proteins contain two similar domains, each with a 3-layer alpha/beta/alpha structure, which probably arose from a duplication. These enzymes bind NAD differently from other NAD(P)-dependent oxidoreductases.

Aldehyde dehydrogenases ( 1.2.1.3 and 1.2.1.5 ) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [ 3 ]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase.

Histidinol dehydrogenase ( 1.1.1.23 ) (HDH) catalyses the terminal step in the biosynthesis of histidine in bacteria, fungi, and plants, the four-electron oxidation of L-histidinol to histidine. In 4-electron dehydrogenases, a single active site catalyses 2 separate oxidation steps: oxidation of the substrate alcohol to an intermediate aldehyde; and oxidation of the aldehyde to the product acid, in this case His [ 4 ]. The reaction proceeds via a tightly- or covalently-bound inter-mediate, and requires the presence of 2 NAD molecules [ 5 ]. By contrast with most dehydrogenases, the substrate is bound before the NAD coenzyme [ 5 ]. A Cys residue has been implicated in the catalytic mechanism of the second oxidative step [ 5 ]. In bacteria HDH is a single chain polypeptide; in fungi it is the C-terminal domain of a multifunctional enzyme which catalyzes three different steps of histidine biosynthesis; and in plants it is expressed as nuclear encoded protein precursor which is exported to the chloroplast [ 5 ].

1. Coenzyme isomerization is integral to catalysis in aldehyde dehydrogenase. Biochemistry 42, 7100-9
2. Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 99, 1859-64
3. Inducible (class 3) aldehyde dehydrogenase from rat hepatocellular carcinoma and 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated liver: distant relationship to the class 1 and 2 enzymes from mammalian liver cytosol/mitochondria. Biochemistry 28, 1160-7
4. A cysteine residue (cysteine-116) in the histidinol binding site of histidinol dehydrogenase. Biochemistry 25, 4778-84
5. Structural and functional conservation of histidinol dehydrogenase between plants and microbes. Proc. Natl. Acad. Sci. U.S.A. 88, 4133-7