Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal ...drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in
genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3
,4
-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-resistant
strains. The dehydroxylated compounds did not significantly affect the viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistant
strains, which contain mutations in the
1 and/or
2 genes of the parental strains, identified amino acids of the Fks proteins that are likely to reside in proximity to the l-homotyrosine residue of the bound drug. This study describes the first example of a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal of antifungal drugs, against resistant fungal pathogens.
The origin of eukaryotes has been defined as the major evolutionary transition since the origin of life itself. Most hallmark traits of eukaryotes, such as their intricate intracellular organization, ...can be traced back to a putative common ancestor that predated the broad diversity of extant eukaryotes. However, little is known about the nature and relative order of events that occurred in the path from preexisting prokaryotes to this already sophisticated ancestor. The origin of mitochondria from the endosymbiosis of an alphaproteobacterium is one of the few robustly established events to which most hypotheses on the origin of eukaryotes are anchored, but the debate is still open regarding the time of this acquisition, the nature of the host, and the ecological and metabolic interactions between the symbiotic partners. After the acquisition of mitochondria, eukaryotes underwent a fast radiation into several major clades whose phylogenetic relationships have been largely elusive. Recent progress in the comparative analyses of a growing number of genomes is shedding light on the early events of eukaryotic evolution as well as on the root and branching patterns of the tree of eukaryotes. Here I discuss current knowledge and debates on the origin and early evolution of eukaryotes. I focus particularly on how phylogenomic analyses have challenged some of the early assumptions about eukaryotic evolution, including the widespread idea that mitochondrial symbiosis in an archaeal host was the earliest event in eukaryogenesis.
ABSTRACT
Hybrids originate from the mating of two diverged organisms, resulting in novel lineages that have chimeric genomes. Hybrids may exhibit unique phenotypic traits that are not necessarily ...intermediate between those present in the progenitors. These unique traits may enable them to thrive in new environments. Many hybrid lineages have been discovered among yeasts in the Saccharomycotina, of which many have industrial or clinical relevance, but this might reflect a bias toward investigating species with relevance to humans. Hybridization has also been proposed to be at the root of the whole-genome duplication in the lineage leading to Saccharomyces cerevisiae. Thus, hybridization seems to have played a prominent role in the evolution of Saccharomycotina yeasts, although it is still unclear how common this evolutionary process has been during the evolution of this and other fungal clades. Similarly, the evolutionary aftermath of hybridization, including implications at the genomic, transcriptional, physiological or ecological levels, remains poorly understood. In this review, I survey recent findings from genomic analysis of yeast hybrids of industrial or clinical relevance, and discuss the evolutionary implications of genomic hybridization for the origin of new lineages, including when such hybridization results in a whole-genome duplication.
Here, the consequences of hybridization at the genetic and ecological levels are discussed.
Our ability to fight infectious diseases is being increasingly compromised due to the emergence and spread of pathogens that become resistant to one or several drugs. This phenomenon is ubiquitous ...among pathogens and has parallels in cancer treatment. Given the urgency of the problem, there is a need for a paradigm shift in drug therapy toward one in which the objective to prevent the evolution of drug resistance is considered alongside the main objective of eliminating the infection or tumor. Here, I stress the importance of considering an evolutionary perspective to achieve this goal, and review recent advances in this direction, including therapies that exploit the fitness trade-offs of resistance.
Evolution of eukaryotic species and their genomes has been traditionally understood as a vertical process in which genetic material is transmitted from parents to offspring along a lineage, and in ...which genetic exchange is restricted within species boundaries. However, mounting evidence from comparative genomics indicates that this paradigm is often violated. Horizontal gene transfer and mating between diverged lineages blur species boundaries and challenge the reconstruction of evolutionary histories of species and their genomes. Nonvertical evolution might be more restricted in eukaryotes than in prokaryotes, yet it is not negligible and can be common in certain groups. Recognition of such processes brings about the need to incorporate this complexity into our models, as well as to conceptually reframe eukaryotic diversity and evolution. Here, I review the recent work from genomics studies that supports the effects of nonvertical modes of evolution including introgression, hybridization, and horizontal gene transfer in different eukaryotic groups. I then discuss emerging patterns and effects, illustrated by specific examples, that support the conclusion that nonvertical processes are often at the root of important evolutionary transitions and adaptations. I will argue that a paradigm shift is needed to naturally accommodate nonvertical processes in eukaryotic evolution.
Here, I review recent work from genomics studies that supports the significant effect of nonvertical modes of evolution, including introgression, hybridization, and horizontal gene transfer in different eukaryotic groups. I then discuss emerging patterns and impacts, illustrated by specific examples, that support the conclusion that nonvertical processes are often at the root of important evolutionary transitions and adaptations. I will argue that a paradigm shift is needed to naturally accommodate nonvertical processes in eukaryotic evolution.
Many fungal species utilize hydroxyderivatives of benzene and benzoic acid as carbon sources. The yeast Candida parapsilosis metabolizes these compounds via the 3-oxoadipate and gentisate pathways, ...whose components are encoded by two metabolic gene clusters. In this study, we determine the chromosome level assembly of the C. parapsilosis strain CLIB214 and use it for transcriptomic and proteomic investigation of cells cultivated on hydroxyaromatic substrates. We demonstrate that the genes coding for enzymes and plasma membrane transporters involved in the 3-oxoadipate and gentisate pathways are highly upregulated and their expression is controlled in a substrate-specific manner. However, regulatory proteins involved in this process are not known. Using the knockout mutants, we show that putative transcriptional factors encoded by the genes OTF1 and GTF1 located within these gene clusters function as transcriptional activators of the 3-oxoadipate and gentisate pathway, respectively. We also show that the activation of both pathways is accompanied by upregulation of genes for the enzymes involved in β-oxidation of fatty acids, glyoxylate cycle, amino acid metabolism, and peroxisome biogenesis. Transcriptome and proteome profiles of the cells grown on 4-hydroxybenzoate and 3-hydroxybenzoate, which are metabolized via the 3-oxoadipate and gentisate pathway, respectively, reflect their different connection to central metabolism. Yet we find that the expression profiles differ also in the cells assimilating 4-hydroxybenzoate and hydroquinone, which are both metabolized in the same pathway. This finding is consistent with the phenotype of the Otf1p-lacking mutant, which exhibits impaired growth on hydroxybenzoates, but still utilizes hydroxybenzenes, thus indicating that additional, yet unidentified transcription factor could be involved in the 3-oxoadipate pathway regulation. Moreover, we propose that bicarbonate ions resulting from decarboxylation of hydroxybenzoates also contribute to differences in the cell responses to hydroxybenzoates and hydroxybenzenes. Finally, our phylogenetic analysis highlights evolutionary paths leading to metabolic adaptations of yeast cells assimilating hydroxyaromatic substrates.
Orthologues and paralogues are types of homologous genes that are related by speciation or duplication, respectively. Orthologous genes are generally assumed to retain equivalent functions in ...different organisms and to share other key properties. Several recent comparative genomic studies have focused on testing these expectations. Here we discuss the complexity of the evolution of gene-phenotype relationships and assess the validity of the key implications of orthology and paralogy relationships as general statistical trends and guiding principles.
Whole-genome duplications have shaped the genomes of several vertebrate, plant, and fungal lineages. Earlier studies have focused on establishing when these events occurred and on elucidating their ...functional and evolutionary consequences, but we still lack sufficient understanding of how genome duplications first originated. We used phylogenomics to study the ancient genome duplication occurred in the yeast Saccharomyces cerevisiae lineage and found compelling evidence for the existence of a contemporaneous interspecies hybridization. We propose that the genome doubling was a direct consequence of this hybridization and that it served to provide stability to the recently formed allopolyploid. This scenario provides a mechanism for the origin of this ancient duplication and the lineage that originated from it and brings a new perspective to the interpretation of the origin and consequences of whole-genome duplications.
Peroxisome diversity and evolution Gabaldón, Toni
Philosophical transactions - Royal Society. Biological sciences,
03/2010, Letnik:
365, Številka:
1541
Journal Article
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Peroxisomes are organelles bounded by a single membrane that can be found in all major groups of eukaryotes. A single evolutionary origin of this cellular compartment is supported by the presence, in ...diverse organisms, of a common set of proteins implicated in peroxisome biogenesis and maintenance. Their enzymatic content, however, can vary substantially across species, indicating a high level of evolutionary plasticity. Proteomic analyses have greatly expanded our knowledge on peroxisomes in some model organisms, including plants, mammals and yeasts. However, we still have a limited knowledge about the distribution and functionalities of peroxisomes in the vast majority of groups of microbial eukaryotes. Here, I review recent advances in our understanding of peroxisome diversity and evolution, with a special emphasis on peroxisomes in microbial eukaryotes.
Although recent research has revealed high genomic complexity in the earliest-splitting animals and their ancestors, the macroevolutionary trends orchestrating gene repertoire evolution throughout ...the animal phyla remain poorly understood. We used a phylogenomic approach to interrogate genome evolution across all animal phyla. Our analysis uncovered a bimodal distribution of recruitment of orthologous genes, with most genes gained very 'early' (that is, at deep nodes) or very 'late', representing lineage-specific acquisitions. The emergence of animals was characterized by high values of gene birth and duplications. Deuterostomes, ecdysozoans and Xenacoelomorpha were characterized by no gene gain but rampant differential gene loss. Genes considered as animal hallmarks, such as Notch/Delta, were convergently duplicated in all phyla and at different evolutionary depths. Genes duplicated in all nodes from Metazoa to phylum-specific levels were enriched in functions related to the neural system, suggesting that this system has been continuously and independently reshaped throughout evolution across animals. Our results indicate that animal genomes evolved by unparalleled gene duplication followed by differential gene loss, and provide an atlas of gene repertoire evolution throughout the animal tree of life to navigate how, when and how often each gene in each genome was gained, duplicated or lost.