This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Fatty Acid and Lipids Degradation → Acetone Degradation|
Expected Taxonomic Range: Mammalia
There are two main sources for acetone production in organisms: the decarboxylation of acetoacetate (EC 220.127.116.11) and the dehydrogenation of isopropanol (EC 18.104.22.168). Acetoacetate decarboxylation is the major source of acetone in mammals, and arises from either lipolysis or amino acid degradation [Kalapos03]. Acetoacetate decarboxylation may happen either enzymatically or non-enzymatically. The enzyme responsible for this reaction, acetoacetate decarboxylase, was first identified in the bacterium Clostridium acetobutylicum. However, the existence of this enzymatic activity in mammals, including rat and humans has been documented [vanStekelenburg72, Koorevaar76].
The conversion of isopropanol to acetone is catalyzed by the class I isozymes of the hepatic alcohol dehydrogenase family [Nordmann73, Kalapos03]. Over the years, differences in the activity of enzymes from different sources have been noted [Davis84]. For example, horse liver alcohol dehydrogenase could not react with isopropanol [Theorell51].
About This Pathway
Once acetone is formed, it can be metabolized in several pathways. One of these pathways involves its conversion to methylglyoxal in two consecutive steps via acetol as intermediate.
The production of methylglyoxal from acetone was proposed in 1984, based on studies of acetone metabolism in the rat [Casazza84]. The possible role of cytochrome P450s in acetone metabolism was recognized in 1980 [Coleman80], and cytochrome P450 2E1 was identified as both the acetone and acetol monooxygenases in liver microsomes from rabbit, rat and mouse [Koop85, Johansson86, Bondoc99].
This pathway is inducible, and can be induced by several agents (acetone, ethanol, pyrazole, imidazole, etc.) or under different physiological and pathological circumstances, such as fasting or diabetes mellitus [Gonzalez89].
Bondoc99: Bondoc FY, Bao Z, Hu WY, Gonzalez FJ, Wang Y, Yang CS, Hong JY (1999). "Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice." Biochem Pharmacol 58(3);461-3. PMID: 10424765
Johansson86: Johansson I, Eliasson E, Norsten C, Ingelman-Sundberg M (1986). "Hydroxylation of acetone by ethanol- and acetone-inducible cytochrome P-450 in liver microsomes and reconstituted membranes." FEBS Lett 196(1);59-64. PMID: 3943633
Koorevaar76: Koorevaar G, Van Stekelenburg GJ (1976). "Mammalian acetoacetate decarboxylase activity. Its distribution in subfractions of human albumin and occurrence in various tissues of the rat." Clin Chim Acta 71(2);173-83. PMID: 963888
Nordmann73: Nordmann R, Ribiere C, Rouach H, Beauge F, Giudicelli Y, Nordmann J (1973). "Metabolic pathways involved in the oxidation of isopropanol into acetone by the intact rat." Life Sci 13(7);919-32. PMID: 4358273
vanStekelenburg72: van Stekelenburg GJ, Koorevaar G (1972). "Evidence for the existence of mammalian acetoacetate decarboxylase: with special reference to human blood serum." Clin Chim Acta 39(1);191-9. PMID: 4624981
Autor70: Autor AP, Fridovich I (1970). "The interactions of acetoacetate decarboxylase with carbonyl compounds, hydrogen cyanide, and an organic mercurial." J Biol Chem 1970;245(20);5214-22. PMID: 5469163
Bohren89: Bohren KM, Bullock B, Wermuth B, Gabbay KH (1989). "The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases." J Biol Chem 264(16);9547-51. PMID: 2498333
Boleda93: Boleda MD, Saubi N, Farres J, Pares X (1993). "Physiological substrates for rat alcohol dehydrogenase classes: aldehydes of lipid peroxidation, omega-hydroxyfatty acids, and retinoids." Arch Biochem Biophys 307(1);85-90. PMID: 8239669
Boyer72: Boyer PD, editor (1972). "Chapter 8- Acetoacetate Decarboxylase." The Enzymes, Third Edition, Volume Six, Carboxylation and decarboxylation (nonoxidative) isomerization, Academic Press New York.
Burnell87: Burnell JC, Carr LG, Dwulet FE, Edenberg HJ, Li TK, Bosron WF (1987). "The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding." Biochem Biophys Res Commun 146(3);1127-33. PMID: 3619918
Chrostek03: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans." J Clin Lab Anal 17(3);93-6. PMID: 12696080
Chrostek03a: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the human pancreas." Dig Dis Sci 48(7);1230-3. PMID: 12870777
Danielsson94: Danielsson O, Shafqat J, Estonius M, Jornvall H (1994). "Alcohol dehydrogenase class III contrasted to class I. Characterization of the cyclostome enzyme, the existence of multiple forms as for the human enzyme, and distant cross-species hybridization." Eur J Biochem 225(3);1081-8. PMID: 7957198
Davis93: Davis JF, Felder MR (1993). "Mouse ethanol-inducible cytochrome P-450 (P450IIE1). Characterization of cDNA clones and testosterone induction in kidney tissue." J Biol Chem 268(22);16584-9. PMID: 8344939
Day91: Day CP, Bashir R, James OF, Bassendine MF, Crabb DW, Thomasson HR, Li TK, Edenberg HJ (1991). "Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage." Hepatology 14(5);798-801. PMID: 1937384
Duester86: Duester G, Smith M, Bilanchone V, Hatfield GW (1986). "Molecular analysis of the human class I alcohol dehydrogenase gene family and nucleotide sequence of the gene encoding the beta subunit." J Biol Chem 261(5);2027-33. PMID: 2935533
Duester99: Duester G, Farres J, Felder MR, Holmes RS, Hoog JO, Pares X, Plapp BV, Yin SJ, Jornvall H (1999). "Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family." Biochem Pharmacol 58(3);389-95. PMID: 10424757
Fairbrother98: Fairbrother KS, Grove J, de Waziers I, Steimel DT, Day CP, Crespi CL, Daly AK (1998). "Detection and characterization of novel polymorphisms in the CYP2E1 gene." Pharmacogenetics 8(6);543-52. PMID: 9918138
Gerischer90: Gerischer U, Durre P (1990). "Cloning, sequencing, and molecular analysis of the acetoacetate decarboxylase gene region from Clostridium acetobutylicum." J Bacteriol 1990;172(12);6907-18. PMID: 2254264
Gillam94: Gillam EM, Guo Z, Guengerich FP (1994). "Expression of modified human cytochrome P450 2E1 in Escherichia coli, purification, and spectral and catalytic properties." Arch Biochem Biophys 312(1);59-66. PMID: 8031147
Grant03b: Grant AW, Steel G, Waugh H, Ellis EM (2003). "A novel aldo-keto reductase from Escherichia coli can increase resistance to methylglyoxal toxicity." FEMS Microbiol Lett 218(1);93-9. PMID: 12583903
Showing only 20 references. To show more, press the button "Show all references".
©2015 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493