Monday, March 28, 2011

Interesting Functions of Alcohol Dehydrogenase

Protein Data Base Overview

This is a good overview article on the functions and features of my protein.

There are up to 9 different forms of alcohol deydrogenase, however most are found in the liver. Each of the enzymes are dimers, interestingly the two subunits are able to be mixed and matched between the different forms of the protein. Each pair that can be created is still active, all with slightly different functions. While it is the belief of most people that alcohol dehydrogenase only detoxifies ethanol, that is not true. The protein not only can be used in the reverse of the well known reaction, thereby creating ethanol, but the protein can also make important modifications to other alcohols and molecules such as retinol, steroids, and fatty acids. One of the more dangerous modifications the enzyme can make is catalyzing the reaction of methanol into formaldehyde. Yeast and bacteria use a form of alcohol deydrogenase to break down sugars into energy with the side product being ethanol being excreted into liquid surrounding the cell. This process is then used when yeast is allowed to ferment grain sugars to form beer and yeast ferments grapes to form wine. The two important parts of the enzyme are the Zinc atom which is used to hold the -OH group on the alcohol in the active site and the NAD+ cofactor, which actually performs the reaction and is constructed from the vitamin niacin.

Journal of Biological Chemistry

The crystallized beta-3 structure was discovered in this paper. This new discovery has lead to many different insights about the function of the enzyme as well as the differences between the beta-3 and the beta-1 complexes. As mentioned above NAD+ is the active site cofactor, but not mentioned before is the fact that 4-iodopyrazole is a competitive inhibotor. The x-ray structure also shows that Arg-369 is used in the protein to stablize the NAD(H) pyrophosphate complex. The difference between the beta-3,-1 structures is the substitiution of an amino acid. In the beta-1 form Cys-369 has taken the place of the Arg-369 (in the beta-3) complex along with two water molecules which are in place of the guanidino nitrogens of Arg-369 in order to keep the number of hydogen bonding interactions the same thereby stabilizing the NAD(H) for both isozymes. The amino acid substitution does correspond to a change in binding free energies of 3.5 kcal/mol for NAD+ and 4.9 kcal/mol for NADH. This shows that the loss of electrostatic interactions between the in NAD(H) pyrophosphate and the Arg-369 side chain beta-3 destabilizes the interaction between the coenzyme and the beta-3 alcohol dehydrogenase.

Effect of Alcohol Consumption on Coronary Heart Disease

This study shows that the casual consumption of alcohol via alcohol dehydrogenase has a positive effect in lowering the risk of CHD. The specific alcohol deydrogenase that was studied is 1C (ADH1C, also known as ADH3), this is one of the many alcohol dehydrogenase isozymes that oxidizes alcohol to acetaldehyde. The study also looked at the effect of casual alcohol consumption on the production of HDL, however, there was no significant correlation found.