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Alcohol Dehydrogenase: Structure And Function

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Question:

Write a short essay on the structure and function of a protein from the following list: Phosphoglycerate mutase, Glycogen synthase, Aconitase, Alcohol dehydrogenase ?

 

 

Answer:

Function

NAD (P) dependent oxido-reducatases catalyse the reversible oxidation of primary and secondary alcohols into aldehydes and ketones, respectively. Among them, alcohol dehydrogenase (ADH1) comprises a group of dehydrogenase enzymes which catalyzes the interconversion between alcohols and aldehydes or ketones with the concomitant reduction of NAD+ or NADP+. The said enzyme is a 146.8KDa protein, found in animals, plant, fungi, algae, bacteria and other related species (Ying & Ma, 2011). The principal metabolic purpose that is being facilitated with this enzyme functioning is the breakdown of alcoholic substances in the body, which otherwise can be toxic. On the contrary, in case of yeast and certain other bacterial species, ADH1 plays a crucial role in an opposite reaction as part of the process of fermentation, for continuous production of NAD+. The enzyme is composed of 347 amino acids and its isoelectric point is 6.23 (Hansch, 1972). This ubiquitous group of enzymes are present in diverse tissues like liver, kidneys, gastric mucosa and mammary glands in human and other developed species. To cope up with the alcoholic substrates this group of enzymes evolved in the course of evolution, which is capable of decomposing or processing such organic compounds. The regulation of ADH is being studied in diverse organisms, notably yeast, drosophila, maize and human. Multiple ADH isozymes are differentially expressed in each of these organisms. Mutants lacking each of the isozymes show greater tolerance to allyl alcohol, which is converted to the toxin acrolein by ADH.

 

Structure

Structurally, the enzyme composed of a tetramer where each of the subunit contains a zinc atom (Zn+2). The zinc ion is stabilized with the close state formed by four Cysteine residues, viz. Cysteine 97, Cysteine 100, Cysteine 103 and Cysteine 111. The coordination of these residues with Zn+ ion gives a positioning of symmetric tetrahedron. The said coordination is important for the enzyme functioning, which is believed to be governed by electrostatic interaction (Bergquist, 2000). Each monomer is distinguished into two domains, a ‘co-enzyme’ binding and a ‘catalytic’ domain. Three dimensional structure of the active site explored the presence of a hydrogen-bonded proton-relay system. Two distinct active site sulfhydryl groups are there which are responsible for differential reactivity to iodoacetate and butyl isocyante (Eklund, 1976). Therefore the ‘active centre’ in the quaternary structure of the active enzyme corresponds to each individual chain consisting of one reactive sulfhydryl group, which in turn is bound to one atom of zinc and 1 mole of NAD+/NADP+. Here the zinc acts as an electron attractor, where it gives rise to increased electrophilic character of the aldehyde. Therefore its mechanism of action essentially based on the electrophilic catalysis mediated by the active site zinc atom. With the reduction of nicotinamide adenine dinucleotide, this enzyme catalyzes interconversion between alcohols and aldehydes or ketones. The first-ever isolated alcohol dehydrogenase was purified from the yeast Saccharomyces cerevisiae (baker’s yeast). Yeast ADH (YALD1) is one of the first enzymes to be crystalized (Leskovac, 2002). In 1937, crystallized ADH form was isolated from brewer’s yeast by Negelein and Wulff (1937). Later seven genes were identified to express ScADH1 in large amounts in presence of glucose. YADHD1 is a constitutive enzyme that reduces acetaldehyde into ethanol during fermentation of glucose. It is a zinc-containing protein, and it accounts for the major part of ADH activity in growing baker’s yeast (Branden, 1973). Glycolysis and aerobic respiration are the two metabolic pathways observed in Saccharomyces cerevisiae. Ethanol is the important metabolite in yeast metabolic system, being the end product of glycolysis and ethanolic fermentation. Pyruvate synthesized in glycolysis is converted to acetaldehyde and CO2 and acetaldehyde in turn is then reduced to ADH1. Therefore in yeast, YADHD1 performs the last step in the conversion of food into metabolic energy by creating ethanol instead of detoxifying it. For industrial purpose, humans exploit this metabolic pathway in order to produce alcoholic beverages (Parlesak, 2002).

 

Relationship between Structure and Function

The main mechanism of action of the enzyme, can be narrated in the following steps. It is noteworthy to mention that the following points can be considered as the key steps of the reaction catalysed by ADH (Danielsson, 1992).

  • Binding of the ADH enzyme to the coenzyme NAD+ for functional activation.
  • Binding of the alcohol (as substrate) with ADH. This binding of enzyme and substrate is facilitated with coordination to zinc atom.
  • Deprotonation in the enzyme at Histidine 51 position.
  • This deprotonation is subsequently followed by deprotonation of nicotinamide ribose.
  • Deprotonation of another residue in protein, Threonine 48, for accompanying the alcohol molecule.
  • Final deprotonation of the alcohol molecule.
  • Hydride transfer mechanism mediated from the corresponding alkoxide ion to NAD+
  • Formation and release of the final product (aldehyde).

It is important to mention that there are other amino acids, which are involved in the catalytic action. To be particular, these residues are Cysteine 46, Cysteine 174 and Histidine 67. A simplified illustration of the reaction is given below.

CH3CH2OH -------->          CH3CHO  --------->         CH3COOH

(Ethanol)               (Acetaldehyde)           (Acetic acid)

 

The corresponding reaction between ethanol to acetaldehyde is catalysed by alcohol dehydrogenase, and the subsequent reaction from acetaldehyde to acetic acid is catalysed by aldehyde dehydrogenase.

CH3CH2OH + NAD+   ------------>         CH3CHO + NADH + H+

Thermodynamic and kinetic stabilities of YADHD1 have been measured in solution with different stabilizing additives such as sugar or osmolytes. Thermal denaturation temperature (Td) for yeast ADH without additives has been reported to be 61.3°C. Sucrose, which is known to be a compatible osmolyte, showed maximum increase in the ΔTd by more than 12°C (Eckstein, 2004). On the other hand, the kinetic deactivation process of ADH1 can be explained by first order rate-kinetics. The loss of kinetic stability of ADH1 is correlated with the change in its active site of the protein (Mildvan, 1969). Moreover, the kinetic stability of the enzyme is affected at a much lower temperature than that of its thermodynamic stability. Study indicated that thermal unfolding is not encountered below 60°C whereas the kinetic deactivation is observed even at 50°C. Therefore the kinetic stability is much more delicate compared to its thermodynamic stability, as it needs a large scale of denaturation of the whole protein structure. Kinetic studies of commercially available ADHs revealed that they are capable of oxidizing all primary alcohols of chain length of between 2 and 10 carbon atoms (Klinman, 1981).

 

 

References

Bergquist, C., Storrie, H., Koutcher, L., Bridgewater, B. M., Friesner, R. A., & Parkin, G. (2000). Factors influencing the thermodynamics of zinc alkoxide formation by alcoholysis of the terminal hydroxide complex,[TpBut, Me] ZnOH: an experimental and theoretical study relevant to the mechanism of action of liver alcohol dehydrogenase. Journal of the American Chemical Society, 122(51), 12651-12658.

Brändén, C. I., Eklund, H., Nordström, B., Boiwe, T., Söderlund, G., Zeppezauer, E., ... & Åkeson, Å. (1973). Structure of liver alcohol dehydrogenase at 2.9-Å resolution. Proceedings of the National Academy of Sciences, 70(8), 2439-2442.

Danielsson, O., & Jörnvall, H. (1992). " Enzymogenesis": classical liver alcohol dehydrogenase origin from the glutathione-dependent formaldehyde dehydrogenase line. Proceedings of the National Academy of Sciences, 89(19), 9247-9251.

Eckstein, M., Villela Filho, M., Liese, A., & Kragl, U. (2004). Use of an ionic liquid in a two-phase system to improve an alcohol dehydrogenase catalysed reduction. Chemical communications, (9), 1084-1085.

Eklund, H., Nordström, B., Zeppezauer, E., Söderlund, G., Ohlsson, I., Boiwe, T., ... & Åkeson, Å. (1976). Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 Å resolution. Journal of molecular biology, 102(1), 27-59.

Hansch, C., Schaeffer, J., & Kerley, R. (1972). Alcohol dehydrogenase structure-activity relationships. Journal of Biological Chemistry, 247(14), 4703-4710.

Klinman, J. P. (1981). Probes of mechanism and transition-state structure in the alcohol dehydrogenase reactio. Critical Reviews in Biochemistry and Molecular Biology, 10(1), 39-78.

Leskovac, V., Trivić, S., & Peričin, D. (2002). The three zinc‐containing alcohol dehydrogenases from baker's yeast, Saccharomyces cerevisiae. FEMS yeast research, 2(4), 481-494.

Mildvan, A. S., & Weiner, H. (1969). Interaction of a Spin-labeled Analogue of Nicotinamide Adenine Dinucleotide with Alcohol Dehydrogenase III. thermodynamic, kinetic, and structural properties of ternary complexes as determined by nuclear magnetic resonance. Journal of Biological Chemistry, 244(9), 2465-2475.

Negelein E, Wulff HJ (1937). Biochem. Z. 293: 351

Parlesak, A., Billinger, M. H. U., Bode, C., & Bode, J. C. (2002). Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a Caucasian population. Alcohol and Alcoholism, 37(4), 388-393.

Ying, X., & Ma, K. (2011). Characterization of a zinc-containing alcohol dehydrogenase with stereoselectivity from the hyperthermophilic archaeon Thermococcus guaymasensis. Journal of bacteriology, 193(12), 3009-3019.

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