The three-dimensional structure of betaine aldehyde dehydrogenase, the most abundant aldehyde dehydrogenase (ALDH) of cod liver, has been determined at 2.1 A resolution by the X-ray crystallographic method of molecular replacement.This enzyme represents a novel structure of the highly multiple ALDH, with at least 12 distinct classes in humans. This betaine ALDH of class 9 is different from the two recently determined ALDH structures (classes 2 and 3). Like these, the betaine ALDH structure has three domains, one coenzyme binding domain, one catalytic domain. and one oligomerization domain. Crystals grown in the presence or absence of NAD' have very similar structures and no significant conformational change occurs upon coenzyme binding. This is probably due to the tight interactions between domains within the subunit and between subunits in the tetramer. The oligomerization domains link the catalytic domains together into two 20-stranded pleated sheet structures. The overall structure is similar to that of the tetrameric bovine class 2 and dimeric rat class 3 ALDH, but the coenzyme binding with the nicotinamide in anti conformation, resembles that of class 2 rather than of class 3.
A plant class III alcohol dehydrogenase (or glutathione-dependent formaldehyde dehydrogenase) has been characterized. The enzyme is a typical class III member with enzymatic parameters and substrate specificity closely related to those of already established animal forms. Km values with the pea enzyme are 6.5 ,LM for NADI), 2 ,uM for S-hydroxymethylglutathione, and 840 ,uM for octanol versus 9, 4, and 1200 ftM, respectively, with the human enzyme.Structurally, the pea/human class III enzymes are closely related, exhibiting a residue identity of 69%So and with only 3 of 23 residues differing among those often considered in substrate and coenzyme binding. In contrast, the corresponding ethanol-active enzymes, the long-known human liver and pea alcohol dehydrogenases, differ more (47% residue identities) and are also in functionally important active site segments, with 12 of the 23 positions exchanged, including no less than 7 at the usually much conserved coenzyme-binding segment. These differences affect functionally important residues that are often class-distinguishing, such as those at positions 48, 51, and 115, where the plant ethanol-active forms resemble class III (Thr, Tyr, and Arg, respectively) rather than the animal ethanol-active class I forms (typically Ser, His, and Asp, respectively). Calculations of phylogenetic trees support the conclusions from functional residues in subgrouping plant ethanol-active dehydrogenases and the animal ethanol-active enzymes (class I) as separate descendants from the class III line. It appears that the classical plant alcohol dehydrogenases (now called class P) have a duplicatory origin separate from that of the animal class I enzymes and therefore a paralogous relationship with functional convergence of their alcohol substrate specificity. Combined, the results establish the conserved nature of class III also in plants, and contribute to the molecular and functional understanding of alcohol dehydrogenases by defining two branches of plant enzymes into the system. Different sets of dimeric zinc-containing alcohol dehydrogenases of the medium-chain dehydrogenase/reductase (MDR) (1) type have been characterized in animals and plants. One set encompasses animal alcohol dehydrogenases, including the classical, ethanol-active liver enzyme of class I with about 20 characterized enzymes (2-5), the apparently parent (6, 7) class III form [or glutathione-dependent formaldehyde dehydrogenase, present also in prokaryotes (8, 9)], and a total of minimally six classes (10) and some mixed-class lines (11,12) in vertebrates. The other is the set of plant alcohol dehydrogenases, of which about 20 enzymes have been structurally characterized (3,4,13 (8, 9). In short, the animal enzyme system appears to originate from class III, which is hardly ethanol-active, and to have evolved into the other classes, including the ethanol-active class I liver enzyme, during vertebrate radiation. However, the structurally characterized plant enzymes exhibit reasonable ethanol activity, like the...
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