The aldo-keto reductase family of NADPH-dependent oxidoreductases is widely distributed in man and in animals (Wirth and Wermuth, 1985; Wermuth, 1985; Grimshaw and Mathur, 1989). Aldose reductase (EC 1.1.1.21; ALR2) and aldehyde reductase (EC 1.1.1.2; ALR1), monomeric members of the aldo-keto reductase family, exhibit broad, overlapping specificities, consistent with a role in detoxification of aldehydes (Grimshaw, 1992). ALR2 has received special attention due to its putative role in the etiology of diabetic complications (Gabbay, 1975; Kador and Kinoshita, 1985). Most crystallographic and mechanistic studies have focused on ALR2. ALR2 is comprised of an α/β-barrel without a classic Rossman fold at the dinucleotide binding site (Rondeau et al., 1992; Wilson et al., 1992); ALR2 utilizes an ordered mechanism with NADPH binding preceeding aldehyde binding, followed by hydride transfer, alcohol release and rate-determining isomerization of the ALR2-NADP binary complex prior to NADP release (Grimshaw et al., 1990; Kubisecki et al., 1992). ALR1 is similar structurally to ALR2 (El-Kabbani et al., 1995) and utilizes a similar ordered mechanism (Davidson and Flynn, 1979; Daly and Mantle, 1982). However, the rate determining reaction for ALR1 appears to involve earlier steps in the reaction sequence including hydride transfer from the reduced nicotinamide ring to the aldehyde as well as proton transfer (Barski et al., 1995). Thus, k_cat values for ALR1 are more sensitive to variations in substrate than is observed with ALR2.