Alcohol dehydrogenase chain

Figure 1.9 Examples of functionally important intrinsic metal atoms in proteins, (a) The di-iron center of the enzyme ribonucleotide reductase. Two iron atoms form a redox center that produces a free radical in a nearby tyrosine side chain. The iron atoms are bridged by a glutamic acid residue and a negatively charged oxygen atom called a p-oxo bridge. The coordination of the iron atoms is completed by histidine, aspartic acid, and glutamic acid side chains as well as water molecules, (b) The catalytically active zinc atom in the enzyme alcohol dehydrogenase. The zinc atom is coordinated to the protein by one histidine and two cysteine side chains. During catalysis zinc binds an alcohol molecule in a suitable position for hydride transfer to the coenzyme moiety, a nicotinamide, [(a) Adapted from P. Nordlund et al., Nature 345 593-598, 1990.)...

ADH Horse liver alcohol dehydrogenase, an enzyme dimer of identical 374 amino acid polypeptide chains. The amino acid composition of ADH is reasonably representative of die norm for water-solnble proteins. 

Alcohol dehydrogenases found in certain microorganisms utilize a pyrroloquino-line quinone (PQQ) or flavin cofactor to pass electrons released upon oxidation of alcohols to the heme electron-acceptor protein, cytochrome c. These membrane-associated alcohol dehydrogenases form part of a respiratory chain, and the energy from fuel oxidation therefore contributes to generation of a proton gradient across... 

Yang, Y., Zhu, D., Piegat, T.J. and Hua, L. (2007) Enzymatic ketone reduction mapping the substrate profile of a short-chain alcohol dehydrogenase (YMR226c) from Saccharomyces cerevisiae. Tetrahedron Asymmetry, 18 (15), 1799-1803. 

Figure 6.1 Pathways involved in glucose oxidation by plant cells (a) glycolysis, (b) Krebs cycle, (c) mitochondrial cytochrome chain. Under anoxic conditions. Reactions 1, 2 and 3 of glycolysis are catalysed by lactate dehydrogenase, pyruvate decarboxylase and alcohol dehydrogenase, respectively. ATP and ADP, adenosine tri- and diphosphate NAD and NADHa, oxidized and reduced forms of nicotinamide adenine dinucleotide PGA, phosphoglyceraldehyde PEP, phosphoenolpyruvate Acetyl-CoA, acetyl coenzyme A FP, flavoprotein cyt, cytochrome e, electron. (Modified from Fitter and Hay, 2002). Reprinted with permission from Elsevier...

Another zinc-utilizing enzyme is carbonate/dehydratase C (Kannan et al., 1972). Here, the zinc is firmly bound by three histidyl side chains and a water molecule or a hydroxyl ion (Fig. 27). The coordination is that of a distorted tetrahedron. Metals such as Cu(II), Co(Il), and Mn(ll) bind at the same site as zinc. Hg(II) also binds near, but not precisely at, this site (Kannan et al., 1972). Horse liver alcohol dehydrogenase (Schneider et al., 1983) contains two zinc sites, one catalytic and one noncatalytic. X-Ray studies showed that the catalytic Zn(II), bound tetrahedrally to two cysteines, one histidine, and water (or hydroxyl), can be replaced by Co(II) and that the tetrahedral geometry is maintained. This is also true with Ni(Il). Insulin also binds zinc (Adams etai, 1969 Bordas etal., 1983) and forms rhombohedral 2Zn insulin crystals. The coordination of the zinc consists of three symmetry-related histidines (from BIO) and three symmetry-related water molecules. These give an octahedral complex... 

However, this glycine-rich segment has other functions in short-chain alcohol dehydrogenases. Tanaka et al. [37] and our 3D modeling [60] indicate that this glycine rich segment has an important role in cofactor specificity and binding of the nicotinamide moiety to 11P-HSD. 

Persson , Krook M, Jomvall H. Characteristics of short-chain alcohol dehydrogenases and related enzymes. Eur J Biochem 200 1991 537-543. 

Krozowski Z. 11 (3-hydroxysteroid dehydrogenase and the short chain alcohol dehydrogenase (SCAD) superfamily. Mol Cell Endocrinol 84 1992 C25-C31. 

Figure 6.2 Overview of biocatalytic routes to vastatin side chains. PLE pig-liver esterase, ADH alcohol dehydrogenase, HHDH halohydrin dehalogenase, DERA 2-deoxy-D-ribose 5-phosphate aldolase.

The reactions of Eq. 15-19 occur nonenzymatically only under the influence of strong base but dehydrogenases often catalyze similar condensations relatively rapidly and reversibly. Pyruvate inhibits lactate dehydrogenase, 2-oxoglutarate inhibits glutamate dehydrogenase, and ketones inhibit a short-chain alcohol dehydrogenase in this manner.133,693... 

The enzyme consists of three main isozymes formed by the dimeric combination of two different protein chains. The two types of protein chains have been labelled E (for ethanol active) and S (for steroid active). About 90% of liver alcohol dehydrogenase (LADH)) is EE and the remaining 10% consists of ES and SS. SS is also ethanol active, although lower than ES and EE, and vice versa. Polymeric forms of the isozymes are also known. 

The specificities of the enzymes are also nicely explained The enantiomers of the substrates of L-lactate and D-glyceraldehyde 3-phosphate dehydrogenases cannot be productively bound the hydrophobic pocket of alcohol dehydrogenase will not bind the charged side chains of lactate etc. However, we do not know if conformational changes occur during catalysis or if there is strain. 

---