Lena Savoie
Alcohol dehydrogenase (ADH) is a group of dehydrogenase enzymes that occur in many organisms, including humans, and facilitate the interconversion between alcohols and aldehydes or ketones. ADH is our primary defense against alcohol, a toxic molecule that compromises the function of our nervous system. The high levels of ADH in our liver and stomach detoxify about one stiff drink each hour. ADH is also used in the production of chiral alcohols for the pharmaceutical industries. The development of ADH in eukaryotic organisms can be attributed to its role in the detoxification of alcohol and its applications in various industries.
| Characteristics | Values |
|---|---|
| Purpose | To break down alcohols and synthesise novel chiral alcohols in high yield |
| Occurrence | Occurs in many organisms |
| Toxicity | Battles the toxic effects of alcohol in humans |
| Enzyme composition | A dimer with a mass of 80kDa, including a set of isoenzymes |
| Conversion | Converts ethanol into acetaldehyde |
| Redox reaction | Involves the coenzyme nicotinamide adenine dinucleotide (NAD+) |
| Oxidation | Catalyses the oxidation of primary and secondary alcohols into aldehydes and ketones |
| Reversibility | Can also affect the reverse reaction |
| pH | Optimal pH value is 7.0-10.0, with maximum enzyme activity at pH 8.0 |
| Temperature | Optimal temperature is 37°C, with stable enzyme activity between 30-40°C |
| Zinc | Contains zinc in its active sites |
| Genes | ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 |
| Alleles | ADH1B and ADH1C alleles encode active ADH enzymes, reducing the risk of alcoholism |
| Arg variant | Detrimental form of the enzyme, lowering reproductive success |
| His variant | Higher frequency in regions with longer rice cultivation history |
| Applications | Production of chiral alcohols for the pharmaceutical industry |
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What You'll Learn
The evolution of the enzyme as a defence mechanism
Alcohol dehydrogenase (ADH) is a group of dehydrogenase enzymes that occur in many organisms, including humans and other animals, plants, yeast, and bacteria. ADH enzymes play a crucial role in the interconversion between alcohols and aldehydes or ketones, with the reduction of nicotinamide adenine dinucleotide (NAD+ to NADH). This process is known as oxidation and is particularly important in breaking down alcohols that are toxic to the body, such as ethanol, which is present in rotting fruit.
In humans, ADH is our primary defense against alcohol, which is a toxic molecule that can compromise the function of our nervous system. The high levels of ADH in our liver and stomach help to detoxify about one stiff drink per hour. The alcohol is first converted to acetaldehyde, an even more toxic molecule, which is then quickly converted into acetate and other molecules that can be easily utilized by our cells. This process essentially converts a dangerous toxin into a harmless foodstuff.
The evolution of ADH as a defence mechanism can be observed in the different variants of the enzyme. For example, the ADH1B gene, which is responsible for the production of an alcohol dehydrogenase polypeptide, has two variants. One variant contains a single nucleotide polymorphism (SNP) that results in either a Histidine or an Arginine residue at position 47 in the mature polypeptide. The Histidine variant is much more effective at converting alcohol to acetaldehyde, providing a protective effect against the risk of alcoholism. Classical Darwinian evolution would act to select against the Arginine variant due to the lowered reproductive success associated with increased susceptibility to alcoholism.
The geographic distribution of these ADH variants provides further evidence for their evolution as a defence mechanism. The frequency of the Histidine variant follows the spread of rice cultivation in inland regions of Asia, with higher frequencies in regions that have cultivated rice for longer periods. This suggests that natural selection has favoured individuals carrying the Histidine variant in regions where alcohol consumption is more prevalent, as they have a lower risk of alcoholism and its associated negative consequences.
In addition to its role in ethanol metabolism, ADH also has other important functions. It can modify retinol, steroids, and fatty acids, and it is involved in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. Furthermore, ADH has applications in the pharmaceutical industry, where it can be used to synthesize novel chiral alcohols in high yield.
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The role of genetics in the development of the enzyme
The development of the alcohol dehydrogenase enzyme is closely tied to genetics, particularly in the context of ethanol metabolism and its impact on various organisms.
In humans, the sequencing of the ADH1B gene, which is responsible for producing an alcohol dehydrogenase polypeptide, reveals several functional variants. One notable variant involves a single nucleotide polymorphism (SNP) that results in either a Histidine or an Arginine residue at a specific position in the polypeptide. The Histidine variant is significantly more effective at converting ethanol to acetaldehyde, a toxic molecule. This conversion is crucial as it transforms a potentially harmful molecule into a substance that can be easily utilized by the body.
The distribution of the Histidine variant of the ADH1B gene appears to be influenced by natural selection. Regions with a long history of rice cultivation, particularly in Asia, exhibit higher frequencies of this variant. This distribution pattern suggests that individuals carrying the Arginine variant experienced lower reproductive success due to increased susceptibility to alcoholism. However, the persistence of the Arginine variant in other populations indicates that the selective pressure against it was not universally strong.
The ADH gene has also been identified in fruit flies (Drosophila melanogaster), where it plays a crucial role in ethanol metabolism. Flies with mutations in the ADH gene are unable to break down alcohols into aldehydes and ketones, leading to oxidative stress and alcohol intoxication at high ethanol concentrations. Conversely, low concentrations of ethanol can enhance Drosophila's fitness.
Additionally, the alcohol dehydrogenase enzyme exhibits genetic diversity across different organisms. In yeast, plants, and bacteria, alcohol dehydrogenases facilitate the conversion of acetaldehyde to ethanol during fermentation, ensuring a steady supply of NAD+. This process is catalyzed by the enzyme's active site, which involves zinc atoms and specific amino acid ligands.
The multiplicity of ADH genes and their expression patterns in higher eukaryotes, such as humans and plants, suggest parallel duplicatory events that have given rise to distinct families of enzymes. These enzymes have specialized functions, including formaldehyde elimination, aldehyde detoxification, and unique pathways in higher eukaryotes.
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The enzyme's function in the human body
Enzymes are essential for the day-to-day functioning of the human body. They are proteins that act on substrate molecules, facilitating biochemical reactions and speeding up chemical reactions in the body. Enzymes work by combining with molecules to initiate a chemical reaction. They are highly specific, binding to certain substrates for specific reactions. Enzymes are crucial for digestion, breaking down fats, proteins, and carbohydrates into usable nutrients for growth and cell repair. They also play a role in liver function, aiding in the detoxification of toxins like alcohol.
Alcohol dehydrogenase is an example of an enzyme that serves a specific function in the human body. It is primarily found in the liver and stomach, where it plays a crucial role in detoxifying alcohol, a toxic molecule that can compromise the nervous system. Alcohol dehydrogenase converts alcohol into acetaldehyde, which is then quickly converted into acetate and other molecules that our cells can easily utilize. This process effectively transforms a potentially harmful substance into a harmless one.
The activity of alcohol dehydrogenase is not limited to ethanol metabolism. It also modifies other alcohols, such as methanol, which can be converted into the toxic compound formaldehyde. Additionally, alcohol dehydrogenase has applications in the pharmaceutical industry, where it is used to produce chiral alcohols, which are important for drug development.
The human body creates at least nine different forms of alcohol dehydrogenase, each with unique properties. These variations allow for specialized functions, such as the ADH-3 enzyme, which plays a significant role in nitric oxide signaling. The diversity of alcohol dehydrogenase forms ensures that there is an enzyme well-suited for a specific task, contributing to the overall efficiency of metabolic processes in the body.
The function of enzymes, including alcohol dehydrogenase, is influenced by various factors, such as temperature and pH levels. Enzymes in the human body typically work optimally at a temperature of around 98.6°F (37°C), which is the body's normal temperature. Deviations from this temperature range can impact enzyme shape and functionality. Similarly, enzymes have specific pH requirements, with enzymes in the intestines functioning best at a pH of 8, while those in the stomach work optimally at a much lower pH of 1.5 due to the highly acidic environment.
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The impact of the enzyme on yeast
Alcohol dehydrogenase (ADH) is a group of enzymes that catalyze the oxidation of primary and secondary alcohols to aldehydes and ketones. ADH is found in yeast, where it is known as Saccharomyces cerevisiae, and plays a crucial role in the fermentation process.
In yeast, the ADH enzyme is known as ADH1 and is composed of four identical subunits, each containing 347 amino acid residues. The structure of ADH1 was determined using X-ray crystallography, revealing two types of dimers, AB and CD, arranged in a "back-to-back" manner. The A and C subunits have a closed conformation with a bound coenzyme, while the B and D subunits have an open conformation without a bound coenzyme. The catalytic zinc in the enzyme plays a vital role in the oxidation process.
The impact of ADH on yeast is significant, particularly during the fermentation of glucose. ADH1 catalyzes the reduction of acetaldehyde to ethanol, which is an essential step in the production of alcohol. This process allows yeast to produce high concentrations of alcohol, which can be toxic to other organisms, effectively eliminating competition for resources. The ability to produce alcohol also provides yeast with a competitive advantage in colonizing new environments, such as rotting fruit, which contains high levels of ethanol.
Furthermore, ADH has economic and industrial implications, especially in the food and beverage industry. The fermentation process, driven by ADH, is fundamental to the production of alcoholic beverages, bread, and other fermented products. The ability to control and manipulate the ADH enzyme has led to the development of new flavors, aromas, and products.
In addition to its role in fermentation, ADH also contributes to yeast's defense mechanisms. ADH can modify other alcohols, such as methanol, converting them into less harmful substances like formaldehyde. This protective function helps yeast survive in environments with toxic compounds.
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The use of the enzyme in pharmaceuticals
Alcohol dehydrogenase (ADH) is an enzyme that is abundant in the liver and present in other tissues. It is responsible for metabolizing the majority of the ethanol consumed as part of the diet. ADH also modifies other alcohols, often producing dangerous products. For instance, methanol, which is commonly used to "denature" ethanol, rendering it undrinkable, is converted into formaldehyde by ADH.
ADH has several applications in the pharmaceutical industry. It can be used not only to break down alcohols but also to synthesize novel chiral alcohols in high yield. Examples of pharmaceuticals that utilize chiral alcohols as intermediates include antihypertensive drugs, calcium- and potassium-channel-blocking drugs, anti-arrhythmic agents, β3-receptor agonists, and anti-cholesterol and antiviral drugs.
A batch process developed by Bristol-Myers Squibb utilizes crude cell extracts of Acinetobacter calcoaceticus containing an alcohol dehydrogenase to produce a chiral intermediate for anti-cholesterol drugs with a 92% yield and 99% ee.
Zinc-containing alcohol dehydrogenases are enzymes that are important in the industrial production of pharmaceutically relevant compounds. The discovery of more stable and versatile enzymes with novel specificities could expand the applications of these enzymes.
The use of a single enzyme versus a whole-cell biocatalyst for pharmaceutical production has several advantages, such as the elimination of side reactions and the simplification of product purification. However, enzyme stability issues and the need for cofactor regeneration are advantages of whole-cell biocatalysis.
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Frequently asked questions
Alcohol dehydrogenase is a defence mechanism against alcohol, a toxic molecule that compromises the nervous system.
Alcohol dehydrogenase enzymes break down alcohols and synthesise novel chiral alcohols in high yield.
Alcohol dehydrogenase uses a zinc atom and a large NAD cofactor to perform its reaction on ethanol.
Alcohol dehydrogenase converts ethanol into acetaldehyde, which is then converted into acetate and other molecules that are easily utilised by cells.
Variations in alcohol dehydrogenase genes can affect the risk of alcoholism. Certain alleles encode more active forms of the enzyme, resulting in a more rapid conversion of alcohol to acetaldehyde, which has a protective effect against alcoholism.
