Abstract
BackgroundIsoprenoids constitute a vast family of natural compounds performing diverse and essential functions in all domains of life. In most eubacteria, isoprenoids are synthesized through the methylerythritol 4-phosphate (MEP) pathway. The production of MEP is usually catalyzed by deoxyxylulose 5-phosphate reductoisomerase (DXR-I) but a few organisms use an alternative DXR-like enzyme (DXR-II).ResultsSearches through 1498 bacterial complete proteomes detected 130 sequences with similarity to DXR-II. Phylogenetic analysis identified three well-resolved clades: the DXR-II family (clustering 53 sequences including eleven experimentally verified as functional enzymes able to produce MEP), and two previously uncharacterized NAD(P)-dependent oxidoreductase families (designated DLO1 and DLO2 for DXR-II-like oxidoreductases 1 and 2). Our analyses identified amino acid changes critical for the acquisition of DXR-II biochemical function through type-I functional divergence, two of them mapping onto key residues for DXR-II activity. DXR-II showed a markedly discontinuous distribution, which was verified at several levels: taxonomic (being predominantly found in Alphaproteobacteria and Firmicutes), metabolic (being mostly found in bacteria with complete functional MEP pathways with or without DXR-I), and phenotypic (as no biological/phenotypic property was found to be preferentially distributed among DXR-II-containing strains, apart from pathogenicity in animals). By performing a thorough comparative sequence analysis of GC content, 3:1 dinucleotide frequencies, codon usage and codon adaptation indexes (CAI) between DXR-II sequences and their corresponding genomes, we examined the role of horizontal gene transfer (HGT), as opposed to an scenario of massive gene loss, in the evolutionary origin and diversification of the DXR-II subfamily in bacteria.ConclusionsOur analyses support a single origin of the DXR-II family through functional divergence, in which constitutes an exceptional model of acquisition and maintenance of redundant gene functions between non-homologous genes as a result of convergent evolution. Subsequently, although old episodic events of HGT could not be excluded, the results supported a prevalent role of gene loss in explaining the distribution of DXR-II in specific pathogenic eubacteria. Our results highlight the importance of the functional characterization of evolutionary shortcuts in isoprenoid biosynthesis for screening specific antibacterial drugs and for regulating the production of isoprenoids of human interest.
Highlights
Isoprenoids constitute a vast family of natural compounds performing diverse and essential functions in all domains of life
We recently reported the occurrence of a group of bacteria harbouring the entire set of enzymes of the methylerythritol 4-phosphate (MEP) pathway with the exception of 1-deoxy-d-xylulose 5-phosphate (DXP) reductoisomerase (DXR), the enzyme catalyzing the NADPH-dependent production of MEP from DXP in the first committed step of the pathway
Eight sequences were not confirmed as reciprocal best hits, including two identified in a previous survey conducted following a unidirectional BLAST search approach [23], and these were discarded from further analyses. 128 sequence hits were identified in as many bacterial strains (Table 1), belonging to a wide variety of the main bacterial taxonomic groups (Figure 2)
Summary
Isoprenoids constitute a vast family of natural compounds performing diverse and essential functions in all domains of life. Isoprenoids are synthesized through the methylerythritol 4-phosphate (MEP) pathway. Isoprenoids constitute the largest family of natural compounds both at a structural and functional level [1,2,3]. They are found in all the three domains of life (bacteria, archaea, and eukaryotes). Despite their diversity in structures and functions, all isoprenoids derive from the common five-carbon precursors isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). The lack of MEP pathway enzymes in non-plastid bearing eukaryotes suggests that these genes were acquired through gene transfer to the nucleus from the eubacterial endosymbiotic ancestors that gave rise to plastids [5,12]
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