Alcohol dehydrogenase structure

The Protein Data Bank PDB ID 1A71 Colby T D Bahnson B J Chin J K Klinman J P Goldstein B M Active Site Modifications m a Double Mutant of Liver Alcohol Dehydrogenase Structural Studies of Two Enzyme Ligand Com plexes To be published... 

Colona-Cesari, F., Perahia, D., Karplus, M., Ecklund, H., Brandem, C. and Tapia, 0. (1986) Interdomain Motion in Liver Alcohol Dehydrogenase Structural and Energetic Analysis of the Hinge Bending Mode, J Biol. Chem. 261, 15273-15289. 

Active site modifications in a double mutant of liver alcohol dehydrogenase structural studies of two enzyme-ligand complexes. Biochemistry 37, 9295-9304. 

Zn 2300 Acts as a Lewis acid (e.g. in hydrolysis processes involving carboxypeptidase, carbonic anhydrase, alcohol dehydrogenase) structural roles... 

Alcohol Dehydrogenase Structure, Catalysis, and Site-Directed Mutagensis... 

Eklund, H., et al. Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 A resolution. 

FIGURE 6.41 The quaternary structure of liver alcohol dehydrogenase. Within each subunit is a six-stranded parallel sheet. Between the two subunits is a two-stranded antiparallel sheet. The point in the center is a C9 symmetry axis. (Jane Richardson)... 

Uncovering of the three dimentional structure of catalytic groups at the active site of an enzyme allows to theorize the catalytic mechanism, and the theory accelerates the designing of model systems. Examples of such enzymes are zinc ion containing carboxypeptidase A 1-5) and carbonic anhydrase6-11. There are many other zinc enzymes with a variety of catalytic functions. For example, alcohol dehydrogenase is also a zinc enzyme and the subject of intensive model studies. However, the topics of this review will be confined to the model studies of the former hydrolytic metallo-enzymes. 

Acylation reaction, 171 Alanine, structure of, 110 Alcohol dehydrogenase, 205 Amide hydrolysis, see also Serine proteases Trypsin... 

Llewellyn, D.J., Finnegan, E.J., Ellis, J.G., Dennis, E.S. Peacock, W.J. (1987). Structure and expression of an alcohol dehydrogenase 1 gene from Pisum sativum (cv. Greenfeast ). Journal of Molecular Biology, 195,115-23. 

Sachs, M.M., Dennis, E.S., Gerlach, W.L. Peacock, W.J. (1986). Two alleles of maize alcohol dehydrogenase I have 3 structural and poly(A) addition polymorphisms. Genetics, 113, 449-67. 

The crystal structure of the HNL isolated from S. bicolor (SbHNL) was determined in a complex with the inhibitor benzoic acid." The folding pattern of SbHNL is similar to that of wheat serine carboxypeptidase (CP-WII)" and alcohol dehydrogenase." A unique two-amino acid deletion in SbHNL, however, is forcing the putative active site residues away from the hydrolase binding site toward a small hydrophobic cleft, thereby defining a completely different active site architecture where the triad of a carboxypeptidase is missing. 

Zinc-containing alcohol dehydrogenases take up two electrons and a proton from alcohols in the form of a hydride. The hydride acceptor is usually NAD(P) (the oxidized form of nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative, NADPH). Several liver alcohol dehydrogenases have been structurally characterized, and Pig. 17.8 shows the environment around the catalytic Zn center and the bound NADH cofactor. 

Figure 17.8 Catal3ftic zinc center of horse liver alcohol dehydrogenase revealed from an X-ray crystallographic structure (PDB file 20HX) [Al-Karadaghi et al., 1994]. The bound NADH cofactor, a molecule of the inhibitor dimethylsulfoxide (DMSO), and the amino acid residues that coordinate the Zn are shown as sticks shaded according to the elements, and the Zn center is shown as a gray sphere, while the protein is shown in thin gray lines.

Al-Karadaghi S, Cedergren-Zeppezauert ES, HovmoUer S. 1994. Refined crystal structure of liver alcohol dehydrogenase-NADH complex at 1.8 A resolution. Acta Crystallogr DSO 793 - 807. 

Oubrie A, Rozeboom HJ, Kalk KH, Huizinga EG, Dijkstra BW. 2002. Crystal structure of qui-nohemoprotein alcohol dehydrogenase from Comamonas testosteroni Structural basis for substrate oxidation and electron transfer. J Biol Chem 211 3727-3732. 

Lapierre, C. Pollet, B. MacKay, J. J. Sederoff, R. R. Lignin structure in a mutant pine deficient in cinnamyl alcohol dehydrogenase. J. Agric. Food Chem. 2000, 48, 2326-2331. 

For a liver alcohol dehydrogenase (LADH) model an NS2O coordination sphere is required. The chelating aldehydes are ideal for the formation of this donor set when combined with bis(pentafluoro-thiophenolato)zinc. Structural data on the complexes with one equivalent of 6-methylpyridine-2-carbaldehyde, 6-methoxypyridine-2-carbaldehyde, 2-(dimethylamino)benzal-dehyde) demonstrate that the coordination sphere for LADH has been reproduced to a close approximation and the corresponding alcohol complexes have also been characterized.354 Other thiophenols have been used to form such complexes but have not been structurally characterized.304... 

Niederhut MS, Gibbons BJ, Perez-Miller S, Hurley TD. Three-dimensional structures of the three human class I alcohol dehydrogenases. Protein Sci 2001 10 697-706. 

Kedishvili NY, Bosron WF, Stone CL, Hurley TD, Peggs CF, Thomasson HR, Popov KM, Carr LG, Edenberg HJ, Li T-K. Cloning and expression of a human stomach alcohol dehydrogenase Comparison of structure and catalytic properties with the liver isoenzymes. J Biol Chem 1995 280 3625-3630. 

Steinmetz CG, Xie P, Weiner H, Hurley TD. Structure of mitochondrial aldehyde dehydrogenase The genetic component of alcohol aversion. Structure 1997 5 701-711. 

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

A. Oubrie, H.J. Rozeboom, K.H. Kalk, E.G. Huizinga, and B.W. Dijkstra, Crystal structure of qui-nohemoprotein alcohol dehydrogenase from Comamonas testosteroni. J. Biol. Chem. Til, 3727-3732 (2002). 

---