Abstract
BackgroundThe glucose–methanol–choline (GMC) superfamily is a large and functionally diverse family of oxidoreductases that share a common structural fold. Fungal members of this superfamily that are characterised and relevant for lignocellulose degradation include aryl-alcohol oxidoreductase, alcohol oxidase, cellobiose dehydrogenase, glucose oxidase, glucose dehydrogenase, pyranose dehydrogenase, and pyranose oxidase, which together form family AA3 of the auxiliary activities in the CAZy database of carbohydrate-active enzymes. Overall, little is known about the extant sequence space of these GMC oxidoreductases and their phylogenetic relations. Although some individual forms are well characterised, it is still unclear how they compare in respect of the complete enzyme class and, therefore, also how generalizable are their characteristics.ResultsTo improve the understanding of the GMC superfamily as a whole, we used sequence similarity networks to cluster large numbers of fungal GMC sequences and annotate them according to functionality. Subsequently, different members of the GMC superfamily were analysed in detail with regard to their sequences and phylogeny. This allowed us to define the currently characterised sequence space and show that complete clades of some enzymes have not been studied in any detail to date. Finally, we interpret our results from an evolutionary perspective, where we could show, for example, that pyranose dehydrogenase evolved from aryl-alcohol oxidoreductase after a change in substrate specificity and that the cytochrome domain of cellobiose dehydrogenase was regularly lost during evolution.ConclusionsThis study offers new insights into the sequence variation and phylogenetic relationships of fungal GMC/AA3 sequences. Certain clades of these GMC enzymes identified in our phylogenetic analyses are completely uncharacterised to date, and might include enzyme activities of varying specificities and/or activities that are hitherto unstudied.
Highlights
The glucose–methanol–choline (GMC) superfamily is a large and functionally diverse family of oxidoreductases that share a common structural fold
To ascertain that we study a nonredundant set of all available sequences that can be associated with the GMC superfamily, we first conducted a wide database search and collected all sequences that can be associated with fungal GMC oxidoreductases, and only narrowed the analysis down to its respective enzymatic functions
We found that topologies for the clusters aryl-alcohol oxidoreductase (AAO)–pyranose dehydrogenase (PDH), cellobiose dehydrogenase (CDH), and glucose oxidase (GOx)– glucose dehydrogenase (GDH) were more affected by the sequence selection and alignment algorithm while topologies for the clusters alcohol oxidase (AOx) and pyranose oxidase (POx) were more stable
Summary
The glucose–methanol–choline (GMC) superfamily is a large and functionally diverse family of oxidoreductases that share a common structural fold. Fungal members of this superfamily that are characterised and relevant for lignocellulose degradation include aryl-alcohol oxidoreductase, alcohol oxidase, cellobiose dehydrogenase, glucose oxidase, glucose dehydrogenase, pyranose dehydrogenase, and pyranose oxidase, which together form family AA3 of the auxiliary activities in the CAZy database of carbohydrate-active enzymes. Known electron donor substrates for GMC oxidoreductases range from various sugars and alcohols to cholesterol and choline. Despite this broad range of chemically diverse substrates, the overall reaction mechanism is similar for these FAD-dependent oxidoreductases. Varying preferences for these electron acceptors separate GMC enzymes into oxidases (which can utilise O 2 as electron acceptor) and dehydrogenases (which show negligible or very low reactivity with O 2)
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