Ethanol is metabolized through a very complex catabolic metabolic pathway.
Contents |
The average human digestive system produces approximately 3g of ethanol per day merely through fermentation of its contents. Catabolic degradation of ethanol is thus essential to life, not only of humans, but of almost all living organisms. In fact, certain amino acid sequences in the enzymes used to oxidize ethanol are conserved all the way back to single cell bacteria.[1] Such a functionality is needed because all organisms actually produce alcohol in small amounts by several pathways, primary amongst the fatty acid synthesis,[2] glycerolipid metabolism,[3] and bile acid biosynthesis.[4] If the body had no mechanism for catabolizing the alcohols, they would build up in the body and become toxic. This could be an evolutionary rationale for alcohol catabolism also by sulfotransferase.
As is a basic organizing theme in biological systems, greater complexity of a body system, such as tissues and organs allows for greater specificity of function. This occurs for the processing of ethanol in the human body. We find that all the enzymes needed to accomplish the oxidation reactions are confined to certain tissues. In particular, we find much higher concentration of such enzymes in the kidneys and in the liver,[5] making such organs the primary site for alcohol catabolism.
The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in three steps. Below, the Gibbs Free Energy of Formation for each step is shown with ΔGf values given in the CRC.[6]
Complete Reaction: C2H6O(Ethanol)→C2H4O(Acetaldehyde)→C2H4O2(acetic Acid) →Acetyl-CoA→3H2O+2CO2.
ΔGf = Σ ΔGfp - ΔGfo
Step One: Ethanol: -174.8 kJ/mol
Ethanal(Acetaldehyde): -127.6 kJ/mol
ΔGf1 = -127.6 + 174.8 = 47.2 kJ/mol(Endergonic)
ΣΔGf = 47.2 kJ/mol (Endergonic)
Step Two: Ethanal: -127.6 kJ/mol
Acetic Acid: -389.9 kJ/mol
ΔGf2 = -389.9 + 127.6 = -262.3 kJ/mol (Exergonic)
ΣΔGf = -215.1 kJ/mol (Exergonic)
Step Four: (Because the Gibbs energy is a state function, we can skip the Acetyl-CoA (step 3), for which themodynamic values are not known).
Acetic Acid: -389.9 kJ/mol
3H2O+2CO2: -1500.1 kJ/mol
ΔGf4 = -1500 + 389.6 = -1110.5 kJ/mol (Exergonic)
ΣΔGf = -1325.3 kJ/mol (Exergonic)
If catabolism of alcohol goes all the way to completion, then, we have a very exothermic event yielding some 1325 kJ/mol of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only 215.1 kJ/mol. At the very least, the theoretical limits on energy yield are determined to be 215.1 kJ/mol to 1325.3 kJ/mol. It is also important to note that step 1 on this reaction is endothermic, requiring 47.2 kJ/mol of alcohol, or about 3 molecules of ATP (adenosine triphosphate) per molecule of ethanol.
The first three steps of the reaction pathways lead from ethanol to acetaldehyde to acetic acid to acetyl-CoA. Once acetyl-CoA is formed, it is free to enter directly into the citric acid cycle.
The reactions that transform ethanol into an aldehyde and then into a carboxylic acid are examples of oxidation reactions, which in organic chemistry, are typically characterized by the addition of oxygen onto a functional group.[7] The third reaction, the enzyme mediated formation of acetyl-CoA from acetic acid is an example of an enzymatic synthetase reaction where, through a complex intramolecular interaction a product molecule is formed from reactants.
Glycolysis Pathway
Ethanol is oxidized to acetaldehyde via the enzyme alcohol dehydrogenase IB (class I), beta polypeptide (ADH1B). The gene coding for this enzyme is 1.1.1.1 on chromosome 4, locus 4q21-q23. The enzyme "encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster." [8]
Acetaldehyde is a highly unstable compound and quickly forms free radical structures which are highly toxic if not quenched by antioxidants such as ascorbic acid (Vitamin C) and Vitamin B1 (thiamine). These free radicals can result in damage to embryonic neural crest cells and can lead to severe birth defects. Prolonged exposure of the kidney and liver to these compounds in chronic alcoholics can lead to severe damage.[9] The literature also suggests that these toxins may have a hand in causing some of the ill effects associated with hang-overs.
The enzyme associated with the chemical transformation from acetaldehyde to acetic acid is aldehyde dehydrogenase 2 family (ALDH2). The gene encoding for this enzyme is 1.2.1.3 and is found on chromosome 12, locus q24.2.[10]
"This enzyme is alcohol dehydrogenase 1A (class I), alpha polypeptide. This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of this enzyme, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of Asians have only the cytosolic isozyme, missing the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among Asians than among Caucasians could be related to the absence of the mitochondrial isozyme. This gene encodes a mitochondrial isoform, which has a low Km for ethanol, and is localized in mitochondrial matrix." [11]
The enzyme associated with the conversion of acetic acid to acetyl-CoA is ACSS2; it is expressed by gene 6.2.1.1 located on chromosome 20 locus q11.22. "This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Two transcript variants encoding different isoforms have been found for this gene."[12]
Gene 6.2.1.1 on Chromosome 20
Once acetyl-CoA is formed it enters the normal citric acid cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||