Ethanol metabolism
This article possibly contains original research. (January 2008) |
Human metabolic physiology
Ethanol and evolution
The average human digestive system produces approximately 3 g of ethanol per day through fermentation of its contents.
Physiologic structures
A basic organizing theme in biological systems is that increasing complexity in specialized
Thermodynamic considerations
Energy thermodynamics
Energy calculations
The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in at least 11 steps in humans. Below, the Gibbs free energy of formation for each step is shown with ΔGf values given in the CRC.[8]
Complete reaction:
C2H6O(ethanol) → C2H4O(acetaldehyde) → C2H4O2(acetic acid) → acetyl-CoA → 3H2O + 2CO2.
ΔGf = Σ ΔGfp − ΔGfo
Step one
C2H6O(ethanol) +
Ethanol: −174.8 kJ/mol
Acetaldehyde: −127.6 kJ/mol
ΔGf1 = −127.6 kJ/mol + 174.8 kJ/mol = 47.2 kJ/mol (endergonic)
ΣΔGf = 47.2 kJ/mol (endergonic, but this does not take into consideration the simultaneous reduction of NAD+.)
Step two
C2H4O(acetaldehyde) +
Acetaldehyde: −127.6 kJ/mol
Acetic acid: −389.9 kJ/mol
ΔGf2 = −389.9 kJ/mol + 127.6 kJ/mol = −262.3 kJ/mol (exergonic)
ΣΔGf = −262.3 kJ/mol + 47.2 kJ/mol = −215.1 kJ/mol (exergonic, but again this does not take into consideration the reduction of
Step three
C2H4O2(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PPi
ΔGf3 = −46.8 kJ/mol[9]
Steps 4 through 11
After this the acetyl-CoA enters the TCA cycle and is converted to 2 CO2 molecules in 8 reactions.
Because the Gibbs energy is a state function, we can ignore all of these, and indeed can ignore even the above 3 reactions. Overall, the free energy is simply calculated from the free energy of formation of the product and reactants.
For the oxidation of acetic acid we have:
Acetic acid: −389.9 kJ/mol
3H2O + 2CO2: −1500.1 kJ/mol
ΔGf4 = −1500 kJ/mol + 389.6 kJ/mol = −1110.5 kJ/mol (exergonic)
ΣΔGf = −1110.5 kJ/mol − 215.1 kJ/mol = −1325.6 kJ/mol (exergonic)
Discussion of calculations
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 −1325.6 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 adenosine triphosphate (ATP) per molecule of ethanol.
Organic reaction scheme
Steps of the reaction
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. However, under alcoholic conditions, the citric acid cycle has been stalled by the oversupply of NADH derived from ethanol oxidation. The resulting backup of acetate shifts the reaction equilibrium for acetaldehyde dehydrogenase back towards acetaldehyde. Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic adducts that, eventually, lead to death of the cell. This same excess of NADH from ethanol oxidation causes the liver to move away from fatty acid oxidation, which produces NADH, towards fatty acid synthesis, which consumes NADH. This consequent
Gene expression and ethanol metabolism
Ethanol to acetaldehyde in human adults
In human adults, ethanol is oxidized to
Ethanol to acetaldehyde in human fetuses
In human embryos and fetuses, ethanol is not metabolized via this mechanism as ADH enzymes are not yet expressed to any significant quantity in human fetal liver (the induction of ADH only starts after birth, and requires years to reach adult levels).[12] Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver.[13] CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation).[14] Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called Microsomal Ethanol Oxidizing System (MEOS)[15] and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption.[12][16] In presence of ethanol and oxygen, CYP2E1 is known[by whom?] to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).[citation needed]
Acetaldehyde to acetic acid
At this point in the metabolic process, the ACS alcohol point system is utilized. It standardizes ethanol concentration regardless of volume, based on fermentation and reaction coordinates, cascading through the β-1,6 linkage. Acetaldehyde is a highly unstable compound and quickly forms free radical structures which are highly toxic if not quenched by
The enzyme associated with the chemical transformation from acetaldehyde to acetic acid is aldehyde dehydrogenase 2 family (ALDH2, EC 1.2.1.3). In humans, the gene coding for this enzyme is found on chromosome 12, locus q24.2.[18] There is variation in this gene leading to observable differences in catalytic efficiency between people.[19]
Acetic acid to acetyl-CoA
Two enzymes are associated with the conversion of acetic acid to acetyl-CoA. The first is acyl-CoA synthetase short-chain family member 2 ACSS2 (EC 6.2.1.1).[20] The second enzyme is acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria.
Acetyl-CoA to water and carbon dioxide
Once acetyl-CoA is formed, it enters the normal citric acid cycle.
See also
References
- ISBN 952-91-2603-4PDF
- ^ group, NIH/NLM/NCBI/IEB/CDD. "NCBI CDD Conserved Protein Domain ADH_zinc_N". www.ncbi.nlm.nih.gov. Retrieved 2018-04-28.
- ^ "Fatty Acid Synthesis".
- ^ "Glycerolipid Metabolism".
- ^ "Bile Acid Biosynthesis".
- PMID 9194910.
- PMID 11762132.
- ^ CRC Handbook of Chemistry and Physics, 81st Edition, 2000
- ^ "MetaCyc EC 6.2.1.1".
- ^ https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NC_000004.10&from=100446552&to=100461581&strand=2&dopt=gb 4q21-q23
- ^ "ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide [Homo sapiens (human)] – Gene – NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-28.
- ^ a b Ernst van Faassen and Onni Niemelä, Biochemistry of prenatal alcohol exposure, NOVA Science Publishers, New York 2011.[page needed]
- PMID 15135856.
- PMID 10336564.
- S2CID 27992318.
- ^ Pregnancy and Alcohol Consumption, ed. J.D. Hoffmann, NOVA Science Publishers, New York 2011.[page needed]
- ^ "Acetaldehyde" (PDF). Archived (PDF) from the original on 2010-06-05. Retrieved 2010-04-11.
- ^ "Homo sapiens chromosome 12, reference assembly, complete sequence – Nucleotide – NCBI". www.ncbi.nlm.nih.gov. 3 March 2008. Retrieved 2018-04-28.
- ^ "ALDH2 aldehyde dehydrogenase 2 family member [Homo sapiens (human)] – Gene – NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-28.
- ^ "ACSS2 acyl-CoA synthetase short chain family member 2 [Homo sapiens (human)] – Gene – NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-28.
Further reading
- Carrigan, Matthew A.; Uryasev, Oleg; Frye, Carole B.; Eckman, Blair L.; Myers, Candace R.; Hurley, Thomas D.; Benner, Steven A. (13 January 2015). "Hominids adapted to metabolize ethanol long before human-directed fermentation". Proceedings of the National Academy of Sciences. 112 (2): 458–463. PMID 25453080.