The enzyme alcohol dehydrogenase plays a central role in the most ancient form of biotechnology: alcoholic fermentation. Yeast and many bacteria produce alcohol dehydrogenases. These microbial enzymes catalyze the last step in the conversion of food into metabolic energy, creating ethanol. Sugars are broken down and used for energy, forming ethanol as the waste product, which is excreted into the liquid surrounding the cell. We have harnessed this process to produce alcoholic beverages: yeast is allowed to ferment grain sugars to form beer, and yeast is allowed to ferment grape juice to form wine. Making Alcohol
Microbial ADH Tetramer 4 x 352 amino acid residues 4 zinc ions (Zn ++ ) 4 NAD cofactors
Alcohol dehydrogenases in microbes function as tetramers. They are zinc-containing enzymes that utilize glucose. Each glucose molecule is broken down in a 10-step process called glycolysis. The product of glycolysis is two three-carbon sugars, called pyruvates, and ATP (adenosine triphosphate). The two pyruvates are then converted into ethanol and carbon dioxide. Making Alcohol The overall process of fermentation is to convert glucose sugar to alcohol and carbon dioxide gas: C 6 H 12 O 6 2 CH 3 CH 2 OH + 2 CO 2 sugar alcohol carbon dioxide gas (glucose) (ethyl alcohol or ethanol)
In 1997, Americans drank an average of 2 gallons (7.6 liters) of alcohol per person. This translates roughly into one six-pack of beer, two glasses of wine and three or four mixed drinks per wee. So while recovering from the excesses at the Anthill Pub [last night] after it reopens next fall, we might ponder the human alcohol dehydrogenase enzyme, which ceaselessly battles all the beer & wine that we have consumed. Breaking Down Alcohol
Alcohol dehydrogenase is our primary defense against alcohol, a toxic molecule that compromises the function of our nervous system. The high levels of alcohol dehydrogenase in our liver and stomach detoxify about one drink each hour. The alcohol is converted to acetaldehyde, an even more toxic molecule and the main cause of hangovers! Acetaldehyde in turn is converted to acetate and other molecules that are easily processed by our cells. Breaking Down Alcohol
Human ADH Homodimer (two molecules) 2 x 373 amino acid residues 6 zinc ions (Zn ++ ) 2 NAD cofactors
Breaking Down Alcohol Alcohol dehydrogenase CH 3 CH 2 OH + 2 NAD CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (ethanol) (acetaldehyde) Acetaldehyde dehydrogenase 2 CH 3 CHO + H 2 O CH 3 COOH aldehyde acid (acetaldehyde) (acetic acid or vinegar)
Breaking Down Alcohol Acetaldehyde dehydrogenase 2 CH 3 CHO + H 2 O CH 3 COOH aldehyde acid (acetaldehyde) (acetic acid or vinegar) The acetic acid can be used to form fatty acids (watch that waistline!), or it can be further broken down into CO 2 and water.
Alcohol dehydrogenase provides a line of defense against a common toxin in our environment. But alcohol dehydrogenase also modifies other alcohols, sometimes producing even more dangerous products: Methanol, which is commonly used to “denature” ethanol rendering it undrinkable, is converted to formaldehyde by alcohol dehydrogenase. The formaldehyde then causes severe damage, attacking proteins and embalming them. Small amounts of methanol cause blindness, as the sensitive proteins in the retina are attacked, and larger amounts, perhaps a glassful, lead to widespread damage and death. Dangers of Alcohol
Breaking Down Methanol Alcohol dehydrogenase CH 3 OH + 2 NAD CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (methanol) (formaldehyde) Alcohol dehydrogenase CH 3 CH 2 OH + 2 NAD CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (ethanol) (acetaldehyde)
Our bodies create at least nine different forms of alcohol dehydrogenase, each with slightly different properties. Most of these are found primarily in the liver, including the 3 form The form is found in the lining of the stomach. Each enzyme is composed of two subunits. Ethanol is not the only target or substrate of these enzymes, they also make important modifications to retinol, steroids, and fatty acids. Structure (Form) & Function
Human alcohol dehydrogenases use two “helpers” to perform their reaction on ethanol. The first are zinc ions (Zn ++ ), which are used to hold and position the alcohol group on ethanol. The second is the NAD cofactor (constructed using the vitamin niacin), which actually performs the chemical reaction. The zinc atom, shown in light blue, is cradled by three amino acids from the protein: cysteine 46 to the left, cysteine 174 to the right, and histidine 67 above. The ethanol, shown in green and magenta, binds to the zinc and is positioned next to the NAD cofactor, which extends below the ethanol molecule in this illustration. Structure (Form) & Function
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