Natural alcohol exposure: Is ethanol the main substrate for alcohol dehydrogenases in animals?
Introduction
One hundred years ago Federico Battelli and Lina Stern found that extracts from various animal tissues are able to oxidize alcohol, and they made the first preparation of a soluble alcohol dehydrogenase from horse liver [1], [2]. Because the manufacture and consumption of alcoholic beverages are ancient practices common to nearly all cultures, it was considered that this property is inherent to animal metabolism and initially no one questioned the need for an alcohol dehydrogenase (ADH) in animals. Indeed, ADH activity is widely distributed in all kinds of organisms. However, undoubtedly the most common natural source of ethanol is fermentation of fruit sugars by yeast. If ADHs appeared as a response to ethanol exposure, it can be expected that the origin of these enzymes occurred after dietary alcohol was available at significant concentrations. Thus, a concerted evolution of angiosperms that produce fruits, yeast that ferments the sugars contained in ripe fruits to avoid the competition of pathogen microorganisms, and herbivores that eat the fermented fruits and disperse their seeds, can be expected. Otherwise, the capacity of ADHs to oxidize ethanol can be considered as non-specific and incidental rather than as an adaptive response.
Three different types of ADHs have been found in animals, but interestingly, several of these are capable of oxidizing different endogenous substrates with high catalytic efficiency [3], [4], [5], generating doubts concerning the real physiological role of ADHs in animals. The goal of this work was three-fold: the analysis of available data on the properties of ADHs; the evolutionary diversification of these enzymes, and an exploration of the role of ethanol in triggering enzymogenesis inside each of the three ADH families in animals.
Section snippets
Natural ethanol availability
By far the most common natural source of ethanol is fermentation of fruit sugars by yeast. Ethanol production by fermentative yeast appears to have evolved specifically to inhibit the activity of bacterial competitors within ripe fruits [6]. Thus, ethanol is ubiquitous in ripe fruits, and its concentrations range from 0.04 to 0.72% (7–125 mM) [7], hence frugivorous animals cannot avoid ethanol ingestion. In this way, the presence of ethanol within ripe fruits suggests chronic exposure to this
Alcohol dehydrogenases
Alcohol dehydrogenase activity is widely distributed in all phyla in which living organisms are classified [34]. Currently, there are three non-homologous NAD(P)+-dependent alcohol dehydrogenase protein families reported in animals. These three families of enzymes arose independently throughout evolution and possess different structures and mechanisms of reaction [35], [36].
Type I ADHs are the most studied group and belong to the “medium-chain” dehydrogenase/reductase superfamily [34], [37];
Conclusions
Advantageous adaptation to hostile or novel environments has been recognized as a requirement for successful survival in evolutionary studies. In this case, the chronic presence of an abundant and potentially toxic substrate such as ethanol must predate the existence of an enzyme capable of using it as a rich-energy nutrient, i.e., a systematic natural source of enough ethanol must precede cellular ADH for its oxidation. Provided that ethanol is not endogenously produced in animals in
Conflict of interest statement
None.
Acknowledgments
We thank Dr. Henry Weiner for his critical comments and suggestions at the 15th International Meeting on Enzymology and Molecular Biology of Carbonyl Metabolism in Lexington, KY, USA, and Dr. Susana Magallón (Inst. Biología, UNAM) for her advice on paleontological estimates of divergence times. This work was partially supported by grant IN208510 from DGPA-UNAM. AH-T was supported by USPHS NIH grant R13-AA019612 to present this work at the 15th International Meeting on Enzymology and Molecular
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