BackgroundAlcohol dehydrogenase (ADH) activity is widely distributed in the three domains of life. Currently, there are three non-homologous NAD(P)+-dependent ADH families reported: Type I ADH comprises Zn-dependent ADHs; type II ADH comprises short-chain ADHs described first in Drosophila; and, type III ADH comprises iron-containing ADHs (FeADHs). These three families arose independently throughout evolution and possess different structures and mechanisms of reaction. While types I and II ADHs have been extensively studied, analyses about the evolution and diversity of (type III) FeADHs have not been published yet. Therefore in this work, a phylogenetic analysis of FeADHs was performed to get insights into the evolution of this protein family, as well as explore the diversity of FeADHs in eukaryotes.Principal FindingsResults showed that FeADHs from eukaryotes are distributed in thirteen protein subfamilies, eight of them possessing protein sequences distributed in the three domains of life. Interestingly, none of these protein subfamilies possess protein sequences found simultaneously in animals, plants and fungi. Many FeADHs are activated by or contain Fe2+, but many others bind to a variety of metals, or even lack of metal cofactor. Animal FeADHs are found in just one protein subfamily, the hydroxyacid-oxoacid transhydrogenase (HOT) subfamily, which includes protein sequences widely distributed in fungi, but not in plants), and in several taxa from lower eukaryotes, bacteria and archaea. Fungi FeADHs are found mainly in two subfamilies: HOT and maleylacetate reductase (MAR), but some can be found also in other three different protein subfamilies. Plant FeADHs are found only in chlorophyta but not in higher plants, and are distributed in three different protein subfamilies.Conclusions/SignificanceFeADHs are a diverse and ancient protein family that shares a common 3D scaffold with a patchy distribution in eukaryotes. The majority of sequenced FeADHs from eukaryotes are distributed in just two subfamilies, HOT and MAR (found mainly in animals and fungi). These two subfamilies comprise almost 85% of all sequenced FeADHs in eukaryotes.

Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC50) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (−5.9 Kcal/mol) on human TIM compared to the control ligand (−7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Iron‐containing alcohol dehydrogenases (Fe‐ADH) were initially found only in microorganisms. These enzymes catalyze different reactions, all of them assorted as dehydrogenases‐reductases. Later, a Fe‐ADH was discovered in humans and animals. This Fe‐ADH has been characterized in rats and humans displaying activity as a hydroxyacid‐oxoacid transhydrogenase (HOT), however, its metabolic role is not completely understood. The aim of our study was obtain insights to understand how an ancient iron‐containing dehydrogenase/reductase was converted into a HOT in animals. Our study included an exhaustive bioinformatic analysis that comprise structural, phylogenetic and synteny analyses, as well as intracellular location prediction and positive selection analysis.Fe‐ADH sequence analysis in animals showed that these enzymes possess three amino acids insertion, probably related to the new HOT function developed by these enzymes, since these insertion are absent in other non‐eukaryotic Fe‐ADHs. Phylogenetic analysis results suggest that animal Fe‐ADH comprise a monophyletic group (with a high bootstrap support), that originated before the fungi/animal split. Fe‐ADH in animals, without exceptions, corresponds to a single‐copy gene, in spite of the several whole genome duplications that took place during the evolution of vertebrates. Subcellular predictions, as well as experimental data, show that all animal Fe‐ADH are mitochondrial, and synteny analysis shows that the genomic context of Adhfe1 gene is highly conserved only in vertebrates. Finally, positive selection analysis shows that 32 residues from animal Fe‐ADH are subjected to selection.Supported by DGAPA‐UNAM grant IN216513

Protozoan parasite diseases cause significant mortality and morbidity worldwide. Factors such as climate change, extreme poverty, migration, and a lack of life opportunities lead to the propagation of diseases classified as tropical or non-endemic. Although there are several drugs to combat parasitic diseases, strains resistant to routinely used drugs have been reported. In addition, many first-line drugs have adverse effects ranging from mild to severe, including potential carcinogenic effects. Therefore, new lead compounds are needed to combat these parasites. Although little has been studied regarding the epigenetic mechanisms in lower eukaryotes, it is believed that epigenetics plays an essential role in vital aspects of the organism, from controlling the life cycle to the expression of genes involved in pathogenicity. Therefore, using epigenetic targets to combat these parasites is foreseen as an area with great potential for development. This review summarizes the main known epigenetic mechanisms and their potential as therapeutics for a group of medically important protozoal parasites. Different epigenetic mechanisms are discussed, highlighting those that can be used for drug repositioning, such as histone post-translational modifications (HPTMs). Exclusive parasite targets are also emphasized, including the base J and DNA 6 mA. These two categories have the greatest potential for developing drugs to treat or eradicate these diseases.

In vertebrates, ethanol metabolism is performed through the concerted action of two enzymes: a Zn‐dependent alcohol dehydrogenase (Zn‐ADH) that oxidizes ethanol to acetaldehyde, and an aldehyde dehydrogenase (ALDH) that oxidizes acetaldehyde to acetate. The presence of these Zn‐ADHs and several ALDHs in animals has been assumed to be a consequence of chronic ethanol exposure from the diet. The main natural source of ethanol is fermentation of fruit sugars by yeast. The origin of angiosperms with fleshy fruits dates from the Lower Cretaceous (130‐140 million years ago). Because association between yeast and angiosperms dates also from the Cretaceous, dietary exposure of diverse frugivorous taxa to ethanol is similarly ancient. Since substrate availability must precede enzyme selection, then it can be expected that the enzymogenesis of the ADHs/ALDHs began after the appearance of fleshy fruits. Phylogenetic analyses reveal that all different Zn‐ADHs (seven classes) in animals appeared before land plants, independently of ethanol availability. With respect to aldehyde dehydrogenases (ALDH), phylogenetic analyses showed 13 different ALDH families in animals, and all they appeared before land plants. Because all these enzymes are not induced by ethanol and possess a high activity with non‐ethanol endogenous substrates, it can be concluded that Zn‐ADH and ALDH participation in ethanol metabolism can be considered as incidental, and not adaptive.Supported by DGAPA‐UNAM grant IN216513.