Extended superfamily of short alcohol-polyol-sugar dehydrogenases: structural similarities between glucose and ribitol dehydrogenases (original) (raw)
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The crystal structure of glucose dehydrogenase from< i> Thermoplasma acidophilum
1994
Background: The archaea are a group of organisms distinct from bacteria and eukaryotes. Structures of proteins from archaea are of interest because they function in extreme environments and because structural studies may reveal evolutionary relationships between proteins. The enzyme glucose dehydrogenase from the thermophilic archaeon Thermoplasma acidophilum is of additional interest because it is involved in an unusual pathway of sugar metabolism. Results: We have determined the crystal structure of this glucose dehydrogenase to 2.9 A resolution. The monomer comprises a central nucleotide-binding domain, common to other nucleotide-binding dehydroge-nases, flanked by the catalytic domain. Unexpectedly, we observed significant structural homology between the catalytic domain of horse liver alcohol dehydrogenase and T acidophilum glucose dehydrogenase. Conclusions: The structural homology between glucose dehydrogenase and alcohol dehydrogenase suggests an evolutionary relationship between these enzymes. The quaternary structure of glucose dehydrogenase may provide a model for other tetrameric alcohol/polyol dehydrogenases. The predicted mode of nucleotide binding provides a plausible explanation for the observed dual-cofactor specificity, the molecular basis of which can be tested by site-directed mutagenesis.
The crystal structure of glucose dehydrogenase from Thermoplasma acidophilum
Structure, 1994
Background: The archaea are a group of organisms distinct from bacteria and eukaryotes. Structures of proteins from archaea are of interest because they function in extreme environments and because structural studies may reveal evolutionary relationships between proteins. The enzyme glucose dehydrogenase from the thermophilic archaeon Thermoplasma acidophilum is of additional interest because it is involved in an unusual pathway of sugar metabolism. Results: We have determined the crystal structure of this glucose dehydrogenase to 2.9 A resolution. The monomer comprises a central nucleotide-binding domain, common to other nucleotide-binding dehydroge-nases, flanked by the catalytic domain. Unexpectedly, we observed significant structural homology between the catalytic domain of horse liver alcohol dehydrogenase and T acidophilum glucose dehydrogenase. Conclusions: The structural homology between glucose dehydrogenase and alcohol dehydrogenase suggests an evolutionary relationship between these enzymes. The quaternary structure of glucose dehydrogenase may provide a model for other tetrameric alcohol/polyol dehydrogenases. The predicted mode of nucleotide binding provides a plausible explanation for the observed dual-cofactor specificity, the molecular basis of which can be tested by site-directed mutagenesis.
An integrated prediction of secondary, tertiary and quaternary structure of glucose dehydrogenase
FEBS Letters, 1987
Based on homology of partial sequences, on physico~hemi~al evidence and on studies using chemical modification, we came to the tentative conclusion that tetrameric glucose dehydrogenases from Bacillus megaterium and B. subtilis should have a structure closely related to that of lactate dehydrogenase. The overall homology of primary structures was found to be very low, however, and independent predictions of secondary structure produced a clearly different pattern of p-strands and cr-helices. We nevertheless tried a manual prediction based on the hydrophobic nature of internal B-sheet and on the amphiphili~ character of external helices. This treatment led to the identification of analogues of all the b-strands present in lactate dehydrogenase with the exception of j-X. Six amphiphilic helices were identified corresponding to uB, ctC, uD, cllF, u2F and a3G in lactate dehydrogenase. Conserved functional residues were found at analogous positions. The Q and R intersubunit contacts could be identified and partial proteolysis was found to occur on the outer surface of the tetramer. The structure was found to explain the better binding of NADP as compared to NAD' and offered a rationalization of the role of the essential lysine at position 201.
Acta Crystallographica Section D Biological Crystallography, 2013
Bifunctional alcohol/aldehyde dehydrogenase (ADHE) enzymes are found within many fermentative microorganisms. They catalyse the conversion of an acyl-coenzyme A to an alcoholviaan aldehyde intermediate; this is coupled to the oxidation of two NADH molecules to maintain the NAD+pool during fermentative metabolism. The structure of the alcohol dehydrogenase (ADH) domain of an ADHE protein from the ethanol-producing thermophileGeobacillus thermoglucosidasiushas been determined to 2.5 Å resolution. This is the first structure to be reported for such a domain.In silicomodelling has been carried out to generate a homology model of the aldehyde dehydrogenase domain, and this was subsequently docked with the ADH-domain structure to model the structure of the complete ADHE protein. This model suggests, for the first time, a structural mechanism for the formation of the large multimeric assemblies or `spirosomes' that are observed for this ADHE protein and which have previously been repor...
Archives of Biochemistry and Biophysics, 1996
Quinone oxidoreductase, zeta-crystallin, glucose dehydrogenase, and alcohol dehydrogenase belong to a superfamily of medium-chain dehydrogenase/reductases. The crystal structures of Escherichia coli quinone oxidoreductase (QOR) and Thermoplasma acidophilum glucose dehydrogenase have recently been determined and are compared here with the well-known structure of horse liver alcohol dehydrogenase. A structurally based comparison of these three enzymes confirms that they possess extensive overall structural homology despite low sequence identity. The most significant difference is the absence of the catalytic and structural zinc ions in QOR. A multiple structure-based sequence alignment has been constructed for the three enzymes and extended to include zeta-crystallin, an eye lens structural protein with quinone oxidoreductase activity and high sequence identity to E. coli quinone oxidoreductase. Residues which are important for catalysis have been altered and the functions and activities of the enzymes have diverged, illustrating a classic example of divergent evolution among a superfamily of enzymes.
Properties and evolution of an alcohol dehydrogenase from the Crenarchaeota Pyrobaculum aerophilum
Gene, 2010
The gene encoding a novel alcohol dehydrogenase (ADH) that belongs to the medium chain dehydrogenase/ reductase (MDR) superfamily was identified in the hyperthermophilic archaeon, Pyrobaculum aerophilum. The P. aerophilum ADH gene (Pae2687) was over-expressed in Escherichia coli, and the protein (PyAeADHII) was purified to homogeneity and characterized. The PyAeADHII belongs to a medium chain class because its monomer size is 330 residues and even if it is structurally similar to other enzymes belonging to MDR superfamily, it lacks key residues involved in the coordination of the catalytic Zn ion and in the binding of alcoholic substrates typical of other ADHs. Consistently, PyAeADHII does not show activity on a large number of alcohols, aldheydes or ketones. It is active only when α-tetralone is used as a substrate. The enzyme has a strict requirement for NADP(H) as the coenzyme and has remarkable thermophilicity, displaying activity at temperatures up to 95°C. The study of the metabolic pathways of P. aerophilum can provide information on the evolution of genes and enzymes and may be crucial for understanding the evolution of eukaryotic cells.
Chemico-Biological Interactions, 2011
Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.
Biochemistry, 1989
The complete amino acid sequence of alcohol dehydrogenase of Thermoanaerobium brockii (TBAD) is presented. The S-carboxymethylated protein was cleaved at methionine residues (with cyanogen bromide) to provide a set of 10 nonoverlapping fragments accounting for 90% of the sequence. These fragments were then overlapped and aligned, and the sequence was completed by using peptides generated by proteolytic cleavage a t lysine residues (with Achromobacter protease I). The protein subunit contained 352 amino acid residues corresponding to a molecular weight of 37 652. The sequence showed about 35% identity with that of the prokaryotic Alcaligenes eutrophus alcohol dehydrogenase and about 25% identity with any one of the eukaryotic alcohol/polyol dehydrogenases known today. Of these, only 18 residues (5%) are strictly conserved: 11 Gly, 2 Asp, and 1 each of Cys, His, Glu, Pro, and Val.
Stereopecificity and Other Properties of a Novel Secondary-Alcohol-Specific Alcohol Dehydrogenase
European Journal of Biochemistry, 1981
NAD-dependent alcohol dehydrogenase from the methanol-grown Methylcoccus sp. CRL MI (type I membrane), Methylosinus zrichosporium OB3b (type I1 membrane), Mc.thylobucierium organophillum CRL 26 (type I1 membrane, facultative methylotroph), Psrudomonas sp. ATCC 21 439, and Pichia pusioris Y-55 are secondaryalcohol-specific and that from P. pu.stori.v Y-7556 is not. This novel secondary-alcohol-specific alcohol dehydrogenase (secondary-alcohol dehydrogenase) has been purified from methanol-grown Pseudomonus sp. ATCC 21 439. Secondary-alcohol dehydrogenase shows a single protein band on acrylamide gel electrophoresis and has a molecular weight of 95000. It consists of two subunits of M,48000 daltons and two atoms of zinc per molecule of enzyme protein. It oxidizes secondary alcohols, notably 2-propanol and 2-butanol. Primary alcohols are not oxidized. The pH and temperature optima for secondary-alcohol dehydrogenase are 8-9, and 30-35 'C, respectively. The activation energy calculated is 82.8 kJ. Secondary-alcohol dehydrogenase also catalyzes the reduction of methyl ketones to their corresponding 2-alcohols in the presence of NADH (a reverse reaction). The K,,,
Molecular Biology and Evolution, 2001
Short-chain alcohol dehydrogenases (SCAD) constitute a large and diverse family of ancient origin. Several of its members play an important role in human physiology and disease, especially in the metabolism of steroid substrates (e.g., prostaglandins, estrogens, androgens, and corticosteroids). Their involvement in common human disorders such as endocrine-related cancer, osteoporosis, and Alzheimer disease makes them an important candidate for drug targets. Recent phylogenetic analysis of SCAD is incomplete and does not allow any conclusions on very ancient divergences or on a functional characterization of novel proteins within this complex family. We have developed a 3D structure-based approach to establish the deep-branching pattern within the SCAD family. In this approach, pairwise superpositions of X-ray structures were used to calculate similarity scores as an input for a tree-building algorithm. The resulting phylogeny was validated by comparison with the results of sequence-based algorithms and biochemical data. It was possible to use the 3D data as a template for the reliable determination of the phylogenetic position of novel proteins as a first step toward functional predictions. We were able to discern new patterns in the phylogenetic relationships of the SCAD family, including a basal dichotomy of the 17beta-hydroxysteroid dehydrogenases (17beta-HSDs). These data provide an important contribution toward the development of type-specific inhibitors for 17beta-HSDs for the treatment and prevention of disease. Our structure-based phylogenetic approach can also be applied to increase the reliability of evolutionary reconstructions in other large protein families. Abbreviations: 17beta-HSD, 17beta-hydroxysteroid dehydrogenase; SCAD, short-chain alcohol dehydrogenase.