Natural alcohol exposure: Is ethanol the main substrate for alcohol dehydrogenases in animals?

Dedicated to Professors Henry Weiner and Hans Jörnvall in honor of their pioneer contributions to the enzymology of ethanol metabolism.
https://doi.org/10.1016/j.cbi.2011.02.008Get rights and content

Abstract

Alcohol dehydrogenase (ADH) activity is widely distributed in all phyla. In animals, three non-homologous NAD(P)+-dependent ADH protein families are reported. These arose independently throughout evolution and possess different structures and mechanisms of reaction: type I (medium-chain) ADHs are zinc-containing enzymes and comprise the most studied group in vertebrates; type II (short-chain) ADHs lack metal cofactor and have been extensively studied in Drosophila; and type III ADHs are iron-dependent/-activated enzymes that were initially identified only in microorganisms. The presence of these different ADHs in animals has been assumed to be a consequence of chronic exposure to ethanol. By far the most common natural source of ethanol is fermentation of fruit sugars by yeast, and available data support that this fruit trait evolved in concert with the characteristics of their frugivorous seed dispersers. Therefore, if the presence of ADHs in animals evolved as an adaptive response to dietary ethanol exposure, then it can be expected that the enzymogenesis of these enzymes began after the appearance of angiosperms with fleshy fruits, because substrate availability must precede enzyme selection. In this work, available evidence supporting this possibility is discussed.

Phylogenetic analyses reveal that type II ADHs suffered several duplications, all of these restricted to flies (order Diptera). Induction of type II Adh by ethanol exposure, a positive correlation between ADH activity and ethanol resistance, and the fact that flies and type II Adh diversification occurred in concert with angiosperm diversification, strongly suggest that type II ADHs were recruited to allow larval flies to exploit new restricted niches with high ethanol content.

In contrast, phyletic distribution of types I and III ADHs in animals showed that these appeared before angiosperms and land plants, independently of ethanol availability. Because these enzymes are not induced by ethanol exposure and possess a high affinity and/or catalytic efficiency for non-ethanol endogenous substrates, it can be concluded that the participation of types I and III ADHs in ethanol metabolism can be considered as incidental, and not adaptive.

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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