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Alcohol dehydrogenase


Official Full Name
Alcohol dehydrogenase
Background
Alcohol dehydrogenases (ADH) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+ to NADH). In Humans and many other animals, they serve to break down alcohols that otherwise are toxic, and they also participate in geneRation of useful aldehyde, ketone, or alcohol groups during biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.
Synonyms
aldehyde reductase; ADH; alcohol dehydrogenase (NAD); aliphatic alcohol dehydrogenase; ethanol dehydrogenase; NAD-dependent alcohol dehydrogenase; NAD-specific aromatic alcohol dehydrogenase; NADH-alcohol dehydrogenase; NADH-aldehyde dehydrogenase; primary alcohol dehydrogenase; yeast alcohol dehydrogenase; EC 1.1.1.1

Catalog
Product Name
EC No.
CAS No.
Source
Price
CatalogNATE-1900
EC No.EC 1.1.1.1
CAS No.9031-72-5
SourceZymomonas mobil...
CatalogNATE-1786
EC No.EC 1.1.1.1
CAS No.9031-72-5
SourceE. coli
CatalogEXWM-0001
EC No.EC 1.1.1.1
CAS No.9031-72-5
Source
CatalogNATE-1584
EC No.EC 1.1.1.1
CAS No.9031-72-5
SourceE. coli
CatalogNATE-1197
EC No.EC 1.1.1.2
CAS No.
SourceHuman
CatalogNATE-0975
EC No.
CAS No.9031-72-5
SourceYeast
CatalogNATE-0034
EC No.EC 1.1.1.1
CAS No.9031-72-5
Source
CatalogNATE-0035
EC No.EC 1.1.1.1
CAS No.9031-72-5
SourceSaccharomyces c...
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Classification of the ADHs

ADH (E.C. 1.1.1.1) is an oxidoreductase that can catalyze the reversible oxidation of alcohols to aldehydes or ketones, with the reduction NAD + or NADP + at the same time. ADH is a large class of enzymes that can be further divided into at least three different enzyme superfamily: medium-chain (MDR) dehydrogenase/reductase, short-chain dehydrogenase/reductase, and iron-activated ADHs. The MDR superfamily consists of 350 amino acid residues (dimers or tetramers), and each subunit has a catalytic domain and a domain that binds to nucleotide NAD + or NADP +. Many enzymes of the MDR family have zinc in their active sites and have a sequence motif known as the zinc-containing ADH signature: GHEX2GX5 (G, A) X2 (I, V, A, C, S). The genes encoding classic ADHs include ADH1, ADH2, ADH3, ADH4 and ADH5. Other genes include SFA1, BDH1, BDH2, SOR1 putative SOR2, the cinnamyl ADH, CDH1, XDH1, ADH6 and ADH7.  

Localization

The envelope structure of eukaryotic cells is organized into complex compartments in order to perform various biological functions. Knowing the position of proteins in the microenvironment of these cells is extremely important for understanding their functions and interactions. In the late 1960s, it was known that there were at least three NAD-dependent ADHs in baker's yeast. Two of these enzymes are located in the cytosol (Adh1p and Adh2p), and Adh3p is located in the mitochondrial matrix. When studying the mechanism of mitochondrial oxidation of cytoplasmic NADH, Overkamp (2000) and Bakker (2000) obtained sufficient evidence that ADH3 is not the sole mitochondrial ADH. The study of Huh (2003) determined that Adh5p is located in the cytoplasm, and in addition to Adh3p, Adh4p is also a mitochondrial enzyme. At present, the location of Adh6p and Adh7p is unclear, because most of the available information on the properties of these two enzymes comes from expression monitoring at the mRNA level or overexpression studies.

Structure Solution Overview

Saccharomyces cerevisiae alcohol dehydrogenase I (ADH1) is a constitutive enzyme that reduces acetaldehyde to ethanol during glucose fermentation. The structure of ADH1 was determined by X-ray crystallography at 2.4 Å resolution. The asymmetric unit contains four different subunits arranged as similar dimers, called AB and CD, which are similar to the horse liver ADH (Figure 1). Each subunit in the dimer has a typical Rossmann fold coenzyme binding domain, that is, a six-strand parallel β- pleated sheet, and there are two helices on each side of the sheet, and the coenzyme binds at the carboxyl terminal end. The extensive interaction of the two coenzyme binding domains produces an extended β-sheet in the dimer. Each subunit also has a catalytic domain, which contains a zinc atom to which the alcohol binds and a remote structural zinc ring in a distant loop. The A and C subunits have a "closed" conformation and contain NAD and TFE bonded to the catalytic zinc in a "classical" coordination, while the B and D subunits have an "open" conformation, which has an alternative coordination, and there is no binding coenzyme. A unit cell contains three biological molecules, each of which is two different tetramers with AB: AB and CD: CD subunits. 

Stereoviews of one asymmetric unit, an AB dimer, and of the biologic AB:AB tetramer in a back-to-back orientation Figure 1. Stereoviews of one asymmetric unit, an AB dimer, and of the biologic AB:AB tetramer in a back-to-back orientation (Raj, S.B.; et al. 2014)

Zinc Content and Coordination

Each subunit in the crystal structure of yeast ADH1 contains "catalytic" zinc and "structural" zinc, and its function is currently unclear. Although the biochemical experiments to determine the number of zinc atoms in yeast ADH1 produced different results, crystallography clearly showed that there is two zinc in each subunit, and these zincs exist in tetrahedral coordination. In the closed conformation, one subunit (A or C) in each asymmetric dimer binds NAD and TFE with the catalytic zinc in a "classical" manner with Cys-43, His-66, Cys-153 and the oxygen of TFE. In the open conformation, the other subunit (B or D) coordinates the catalytic zinc in an alternative manner, to Cys-43, His-66, Glu-67, and Cys-153 with the oxygen of TFE in the second sphere. The overlay of the catalytic domains of subunits A and B show that when zinc moves about 2.6 Å from Glu-67, the coordination of zinc is reversed, accompanied by a small amount of movement of zinc ligands. The structure of human ADH3 can illustrate an intermediate in the mechanism after coenzyme binding and before substrate binding. Obviously, alternative coordination is common, and the active site zinc coordination is flexible, so scientists have proposed a mechanism, that is, using alcohol or aldehyde instead of zinc-bound water.

Two different types of coordination of the catalytic zinc Figure 2. Two different types of coordination of the catalytic zinc (Raj, S.B.; et al. 2014)

Properties

Alcohol dehydrogenase is a dimer with a mass of 80kDa, including a set of isoenzymes, which can convert ethanol into acetaldehyde. In mammals, this is a redox reaction involving the coenzyme nicotinamide adenine dinucleotide (NAD+). Alcohol dehydrogenase is responsible for catalyzing the oxidation of primary and secondary alcohols into aldehydes and ketones, and can also affect their reverse reactions. But for primary alcohols, this catalytic effect is not strong, while for secondary alcohols and cyclic alcohols, the catalytic effect is strong. The optimal pH value of alcohol dehydrogenase is 7.0-10.0, the enzyme activity reaches the maximum when the pH value is 8.0, and the enzyme activity is relatively stable when the pH value is 7.0; the optimal temperature of ADH is 37℃ and the temperature is 30-40 The enzyme activity is relatively stable at ℃, and the enzyme activity drops sharply after the temperature exceeds 45℃.

Application

Clinical Significance

References

  1. Raj, S.B.; et al. Yeast Alcohol Dehydrogenase Structure and Catalysis. Biochemistry. 2014, 53(36): 5791-5803.
  2. Smitd, O.; et al. The alcohol dehydrogenases of Saccharomyces cerevisiae: a comprehensive review. FEMS Yeast Research. 2018, 8(7).
  3. Gutheil, W.G.; et al. Purification, characterization, and partial sequence of the glutathione-dependent formaldehyde dehydrogenase from Escherichia coli: a class III alcohol dehydrogenase. Biochemistry. 31 (2): 475–81.

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