Alcohol dehydrogenase

A zinc containing metalloenzyme

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Ethanol dehydrogenase, a large number of which exist in human and animal livers, plants and microbial cells as the main organism Short chain Alcoholic key enzyme It plays an important role in many physiological processes. It is a kind of zinc Metalloenzyme , with a wide range of substrates Specificity 。

Chinese name: Alcohol dehydrogenase
Foreign name: Alcohol dehydrogenase

Description: Zinc metalloenzyme
Nature: With a wide range of substrates Specificity
Abbreviation: ADH

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brief introduction

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Alcohol dehydrogenase

B Alcohol dehydrogenase Alcohol dehydrogenase (ADH for short) is a zinc containing enzyme that exists in large quantities in human and animal livers, plants and microbial cells Metalloenzyme , with a wide range of substrates Specificity 。 Ethanol dehydrogenase is sufficient to Nicotinamide adenine dinucleotide (NAD) is a coenzyme that catalyzes Reversible reaction ：CH3CH2OH+ NAD+→ CH3CHO +NADH+ H+。 In humans and mammals, alcohol dehydrogenase is associated with Acetaldehyde dehydrogenase (ALDH) constitutes an alcohol dehydrogenase system, participates in the metabolism of ethanol in the body, and is an important Metabolic enzyme 。 As the main body Short chain Alcoholic key enzyme It plays an important role in many physiological processes. It is a kind of extensive Specificity Zinc containing metalloenzyme. Ethanol dehydrogenase ethanol oxidation system is a major pathway for alcohol metabolism in the liver. The alcohol dehydrogenase oxidation system includes alcohol dehydrogenase (ADH) and Aldehyde dehydrogenase (ALDH)。

Evolutionary discovery

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2.1 Evolution

Many evidences of biological genetics show that, glutathione Like ADH3, formaldehyde dehydrogenase may be the ancestor of the entire alcohol dehydrogenase family. Early in evolution, effective elimination endogenous and Exogenous The method of formaldehyde is very important, and this ability has been retained in ADH3 through time. Due to a series of mutations in the gene, the duplicate gene of ADH3 evolved into other alcohol dehydrogenase. It is believed that the ability to convert sugars into alcohol has been found in yeast. Yeast cells can poison other organisms by producing high concentrations of alcohol, so as to effectively eliminate their competition. Since rotten fruits can contain more than 4% ethanol, animals need a system to metabolize exogenous ethanol when eating fruits. This may explain why other species need ADH more than yeast.

2.2 Findings

Ethanol dehydrogenase (ADH) was first isolated in 1937 from Saccharomyces cerevisiae （ Baker's yeast ）It is purified in. Hugo Theorell and his colleagues studied many aspects of the catalytic mechanism of alcohol dehydrogenase in horse liver. Ethanol dehydrogenase was first determined amino acid Sequence and protein three-dimensional structure Of Oligomerase one of. At the beginning of 1960 Drosophila Drosophila melanogaster Ethanol dehydrogenase was also found in.

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ethanol Dehydrogenase is an 80 kDa Dimer , including a set of isozyme These isoenzymes can convert ethanol into acetaldehyde 。 stay mammal This is a case of coenzyme Nicotinamide adenine dinucleotide （ NAD +) Redox reaction 。 Ethanol dehydrogenase is responsible for catalytic oxidation Primary alcohol And secondary alcohol Aldehydes and ketones Can also affect their Reverse reaction 。 But for primary alcohols, this Catalysis It is not strong, but has strong catalytic effect in secondary alcohols and cyclic alcohols. The optimal pH value of alcohol dehydrogenase is 7 0-10 . 0, pH 8.0 enzyme activity When the pH value is 7.0, the enzyme activity is relatively stable; ADH Optimum of Operating temperature The enzyme activity was relatively stable at 37 ℃ and 30-40 ℃, and decreased sharply when the temperature exceeded 45 ℃.

Ethanol oxidation

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Action mechanism

Binding coenzyme NAD+→ Binding ethanol substrate through zinc → His-51 Deprotonation → nicotinamide riboside Deprotonation of → Deprotonation of Ser-48 → Deprotonation of ethanol → hydride from Alkoxide The ions are transferred to NAD+, making NADH and zinc combine with aldehyde or ketone → releasing the product aldehyde. These steps are based on kinetic research. In yeast and bacteria, the above steps are just the opposite.

Subunit

Substrate is coordinated with zinc and alcohol dehydrogenase, each Subunit There are two zinc atoms. One of them is involved in catalysis Active site ， ligand Cys-46, Cys-174, His-67 and one water Molecules. The other subunit involves structure. Under this mechanism, hydride from ethanol reaches NAD+. crystal structure It shows that His-51 removes the proton of nicotinamide ribose, and it is nicotinamide ribose that removes the proton of Ser-48. Finally, Ser - 48 deporotonates ethanol to acetaldehyde. From the mechanical point of view, if the enzyme combines with hydride to reach the NAD+ Re face The generated hydrogen will be included in the pro-R position. When Hydrogenase When added on the Re side, it is considered as a type A dehydrogenase.

Active site

active center It is composed of one zinc atom, His-67, Cys-174, Cys-46, Ser-48, His-51, Ile-269, Val-292, Ala-317 and Phe-319. Zinc is responsible for binding the substrate alcohol. Cys-146, Cys-174 and His-67 bind zinc, Phe-319, Ala-317, His-51, Ile-269 and Val-292 stably bind to NAD+through hydrogen bond. His-51, Ile-269 and nicotinamide And Ribol Hydrogen bonding is formed. Phe-319, Ala-317 and Val-292 form hydrogen bonds with amino groups on NAD+. Regarding the structural zinc sites, mammalian alcohol dehydrogenase also has structural zinc sites. ad locum Zinc ion yes protein structure Stability plays a vital role. With quantum Chemical calculation and molecular dynamics Classic of method study Of Horse liver alcohol dehydrogenase (HLADH) catalytic and structural zinc has suggested that its space structure , structural zinc is closely related by four Cysteine The ligands (Cys97, Cys100, Cys103, and Cys111) are located near symmetric tetrahedron On. A recent study shows that the interaction between zinc and cysteine is mainly through univalent Covalent bonding 。

type

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In human body

In humans, alcohol dehydrogenase exists in the form of a variety of dimers and is encoded by at least seven different genes. There are five classes of alcohol dehydrogenase (Class I-V), but Class I is mainly found in human stomach and liver. It catalyzes ethanol acetaldehyde oxidation It is: CH3CH2OH+NAD+→ CH3CHO+NADH+H+. This makes it possible for humans to drink alcoholic drinks, but the original purpose of its evolution may be to decompose food or alcohol produced by bacteria in the digestive tract. Others believe that the purpose of its evolution is to participate in the metabolism of vitamins calorie It is almost zero, and may provide a small amount of pure energy. Ethanol dehydrogenase is also involved in other types of alcohol reactions: for example, it oxidizes methanol Production of formaldehyde and glycol , finally generated Glycolic acid and oxalate 。 There are at least six slightly different types of alcohol dehydrogenase in humans. Each is a dimer, and every two dimers contain two divalent zinc ions. One of the ions is essential for the enzyme to combine with the substrate.

The activity of alcohol dehydrogenase varies from person to person. For example, young women can't be like Young men They decompose alcohol so quickly because the activity of alcohol dehydrogenase in their bodies is not as high as that in their bodies. However, this situation will reverse after middle age. Of course, not only the expression level can affect the activity of alcohol dehydrogenase, but also depends on the Allele Diversity. The differences of these alleles are related to regions. For example, existing studies show that the number of people with high expression of active alcohol dehydrogenase gene in Europe is far more than that in Asia America 。 This may be related to related evolution, simply because most people in Europe drink a lot Alcohol content Higher spirits will natural selection Those with high expression of active alcohol dehydrogenase gene.

Yeast bacteria

Unlike humans, yeast and bacteria（ lactic acid Bacteria, and under certain conditions Escherichia coli Except) will not glucose They ferment glucose into ethanol and carbon dioxide 。 The total reaction formula is: Glucose+2 ADP+2 Pi → 2 ethanol+2 CO2+2ATP+2 H2O 。 In yeast and many bacteria, alcohol dehydrogenase plays an important role in fermentation: Glycolysis Generated pyruvic acid Convert to acetaldehyde And carbon dioxide, and then acetaldehyde is converted into ethanol under the action of ADHI. The purpose of the latter step is to regenerate NAD+, so the energy generation of glycolysis can continue. Human beings have invented yeast fermentation technology by using this process to ferment fruits and grains into wine. But interestingly, sometimes yeast will "drink" the alcohol produced by itself.

The main alcohol dehydrogenase in yeast is slightly larger than that in human beings. It has four Subunit Instead of two, it also has zinc Active site 。 Unlike humans and mammals, alcohol dehydrogenase in yeast and bacteria often forms a“ Long chain Family ". In addition, in the beer yeast There is also ADHII developed from the ADHI gene. Its function is to convert ethanol back to acetaldehyde. This enzyme will work only when the surrounding sugar concentration is low. Acetaldehyde can poison the sugar in the environment competitor When the sugar concentration returns to normal, this enzyme will no longer function.

Ferritase

It has nothing to do with the above two types of alcohol dehydrogenase, and the third type of alcohol dehydrogenase contains Iron ion They are not very effective and mainly exist in some bacteria and yeast. Compared with the above two enzymes, most of these enzymes are sensitive to oxygen.

Other types

Further alcohol dehydrogenase belongs to quinoenzymes and needs quinone type Cofactor Combined with electrons, a typical example of this enzyme is methanol bacterial dehydrogenase of methanol.

application

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disease diagnosis

In humans, ADH is mainly generated in the liver, so liver diseases may be related to serum ADH activity. use Spectrophotometry To determine the activity of ADH in serum and explore its clinical significance Liver disease It is of great significance in diagnosis. The activity of serum ADH was measured by experiment, so as to reflect whether the liver function was normal or not. The determination of ADH in serum of liver patients showed that the results were significantly higher than those of healthy people reference value 。

Alcohol concentration

In daily communication life, people inevitably have to contact alcohol. Drunken driving Resulting traffic accident It is not uncommon. In addition, excessive drinking can cause alcoholism 。 In view of the serious consequences of drunken accidents and alcoholism, the concentration of ethanol in plasma was rapidly measured Accident prevention Occurrence, early diagnosis and treatment of Acute alcoholism It has very important clinical value. A new enzyme was reported Terminal method The method for determining the concentration of ethanol in plasma does not need to remove protein, and the whole detection process only takes 90 s, which can be used for Automatic biochemical analyzer and Manual operation It is suitable for routine clinical use. In the experiment, they chose tris (hydroxymethyl) Aminomethane — hydrochloric acid (Tris HCL) as a buffer system, under alkaline conditions, alcohol dehydrogenase (ADH) catalyzes the conversion of ethanol to acetaldehyde, and generates Reducing coenzyme （ NADH ）。 Detected at 340 nm wavelength absorbance The concentration of ethanol was calculated according to the standard.

catalyzer

stay chemical industry , using ADH's Catalytic properties Produce many raw materials and intermediates reactant 。 stay carbon dioxide conversion Synthetic methanol In the process of Catalysis 。 In order to realize the conversion of CO2 to methanol, researchers have tried many methods, including Enzyme catalysis With the advantages of high efficiency, specificity and mild reaction conditions, the method has attracted much attention in recent years Reduction reaction Has been applied in. Xu Songwei and others adopted Formate dehydrogenase 、 formaldehyde dehydrogenase And ADH as catalyst, NADH as Electron donor CO2 was converted into methanol through three-step serial reaction, and a new way of CO2 utilization was explored.

Clinical significance

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alcoholism

Some studies have shown that alcohol dehydrogenase may cause patients to metabolize alcohol dependence Of Alcoholism 。 Researchers have preliminarily detected several genes that may be related to alcoholism. If the ADH2 and ADH3 encoded by these gene variants enter the slow metabolism form, it may increase the risk of alcoholism. The study found that the mutant ADH2 and ADH3 Asia People drink too much. However, whether this is really the case still needs further study.

Drug dependence

Drug dependence Another question about alcohol dehydrogenase, which researchers believe may be related to alcoholism. A special study shows that drug dependence is related to seven alcohol dehydrogenase related genes. These results may be helpful for targeted treatment of these specific genes. However, it still needs more in-depth research.

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