Substrate Binding Pocket Structure of Human Aldehyde Dehydrogenases

Abstract

Human aldehyde dehydrogenases (AIDH), catalyzing irreversible oxidation of various aliphatic and aromatic aldehydes to the corresponding carboxylic acids, constitute a complex enzyme family (Pietruszko, 1983; Hempel and Jornvall, 1989; Hempel and Lindahl, 1989; Yoshida et al., 1991). There are at least five AlDHs that have been purified and characterized from human liver or stomach: AlDH1 and A1DH2 (E1 and E2; Greenfield and Pietruszko, 1977), A1DH3 (Wang et al., 1990), A1DH4 (E4, glutamic g-semialdehyde dehydrogenase; Forte-McRobbie and Pietruszko, 1986), and g-aminobutyraldehyde dehydrogenase (E3, Kurys et al., 1989). Kinetically, the AlDHs can be classified into two groups according to their Km values for acetaldehyde. The low Km (mM range) forms comprise AlDH1, A1DH2, and g-aminobutyraldehyde dehydrogenase (Greenfield and Pietruszko, 1977; Kurys et al., 1989). A1DH3 and A1DH4 belong to the high Km (mM range) forms (Yin et al., 1989; Forte-McRobbie and Pietruszko, 1986). Structurally, AlDHl and A1DH2 show highest sequence homology (68%) among the above AlDHs (Hempel et al., 1984, 1985; Hsu et al., 1985). The degree of positional identity between AIDH1/2, A1DH3, and g-aminobutyraldehyde dehydrogenase is 30–40% (Hsu et al., 1985, 1992; Yin et al., 1991; Kurys et al., 1993), suggesting a distant relationship. A1DH4 has a larger subunit which shows no significant sequence homologies to all the known AlDHs (Forte-McRobbie and Pietruszko, 1986; Hempel et al., 1992), thus excluding it from the AlDH family. Recently, genes, i.e. AIDH5 through AIDH8, encoding four additional human AlDHs have been cloned and characterized (Hsu et al., 1991, 1994). The kinetic properties of these new AlDH forms remain to be elucidated.