The evolutionary history of the genes involved in the biosynthesis of the antioxidant ergothioneine

Abstract

Ergothioneine (EGT) is a histidine betaine derivative that exhibits antioxidant action in humans. EGT is primarily synthesized by fungal species and a number of bacterial species. A five-gene cluster (egtA, egtB, egtC, egtD & egtE) responsible for EGT production in Mycobacteria smegmatis has recently been identified. The first fungal biosynthetic EGT gene (NcEgt-1) has also been identified in Neurospora crassa. NcEgt-1 contains domains similar to those found in M. smegmatis egtB and egtD. EGT is biomembrane impermeable. Here we inferred the evolutionary history of the EGT cluster in prokaryotes as well as examining the phyletic distribution of Egt-1 in the fungal kingdom. A genomic survey of 2509 prokaryotes showed that the five-gene EGT cluster is only found in the Actinobacteria. Our survey identified more than 400 diverse prokaryotes that contain genetically linked orthologs of egtB and egtD. Phylogenetic analyses of Egt proteins show a complex evolutionary history and multiple incidences of horizontal gene transfer. Our analysis also identified two independent incidences of a fusion event of egtB and egtD in bacterial species. A genomic survey of over 100 fungal genomes shows that Egt-1 is found in all fungal phyla, except species that belong to the Saccharomycotina subphylum. This analysis provides a comprehensive analysis of the distribution of the key genes involved in the synthesis of EGT in prokaryotes and fungi. Our phylogenetic inferences illuminate the complex evolutionary history of the genes involved in EGT synthesis in prokaryotes. The potential to synthesize EGT is a fungal trait except for species belonging to the Saccharomycotina subphylum.

Structure of the Ergothioneine‐Biosynthesis Amidohydrolase EgtC

“…[11] Conversely, our structure-based survey identified EgtC-like enzyme in organisms that do not contain EgtD/B homologues, or are not involved in ergothioneine production (Scheme 1). [11] Conversely, our structure-based survey identified EgtC-like enzyme in organisms that do not contain EgtD/B homologues, or are not involved in ergothioneine production (Scheme 1).…”

“…Ar ecent phylogenetic studyi dentified many bacterial species that encodeE gtD and EgtB (ergothioneine biosynthesis) but lack ar ecognizable EgtC homologue. [11] Conversely, our structure-based survey identified EgtC-like enzyme in organisms that do not contain EgtD/B homologues, or are not involved in ergothioneine production (Scheme 1). [10a, b] Both analyses demonstrate that phylogenetic distribution of EgtC and EgtD/Bi s poorly correlated.…”

“…[8a] The g-glutamyl cysteine( gGC) synthase EgtA [9] and the SAM-dependenth istidine methyltransferase EgtD [8b] provide the substrates for the EgtB-catalyzed production of the central intermediate, g-glutamyl cysteines ulfoxide trimeth-yl histidinyl conjugate (sulfoxide 3,S cheme 1). [10] As the complete egtABCDE gene cluster [11] is exclusive to actinobacterial genomes, it is conceivable that the EgtC-dependent route is limited to this phylum. [8a] This pathway is not universal;for example, Neurospora crassa and Schizosaccharomyces pombe use cysteine directly as the sulfur donort om ake 4,a nd consequently bypass the EgtC-catalyzed step (gray,S cheme 1).…”

“…[8a] This pathway is not universal;for example, Neurospora crassa and Schizosaccharomyces pombe use cysteine directly as the sulfur donort om ake 4,a nd consequently bypass the EgtC-catalyzed step (gray,S cheme 1). [10] As the complete egtABCDE gene cluster [11] is exclusive to actinobacterial genomes, it is conceivable that the EgtC-dependent route is limited to this phylum. On the other hand, EgtC-like enzymes frequently occur in proteobacteria, cyanobacteria, and fungi, including N. crassa,a nd it is impossible to infer from sequence data alonew hether these homologuesa re bona fide EgtCs or whetherthey serve unrelated functions.…”

Proteomic analysis of Aspergillus fumigatus – clinical implications

“…Indeed, given the essential nature of SAM for a plethora of cellular transmethylation reactions including, but not limited to, epigenetic regulation [85], and the potential inhibitory action of SAH on cellular methyltransferases [86], the metabolically catastrophic potential of dysregulating GliT-mediated control of gliotoxin/BmGT biosynthesis is only just becoming apparent. Further systems impacts of interfering with gliotoxin biosynthesis are only just emerging and, surprisingly, it appears that the biosynthesis of apparently unrelated natural products, like the antioxidant ergothioneine, is influenced either by gliotoxin [87,88] (and unpublished data), or specific reactions within its biosynthetic pathway [72]. So, the activity of gliotoxin against fungi and animal cells, often mediated by interference with redox homeostasis, is revealing new metabolic interactions within eukaryotic systems.…”