A hierarchical orthology framework reveals viral carbohydrate-active genes across the global virosphere

Carbohydrate-active enzymes (CAZymes) shape virus–host interactions by modifying virion structures, host surfaces and extracellular glycans. However, the diversity and evolutionary origins of viral carbohydrate-active enzymes remain poorly understood, partly due to limited viral protein annotations. To address this, we present VirGenes, a database of viral orthologous groups constructed from the KEGG viral gene dataset. VirGenes uses a hierarchical framework that integrates sequence similarity, remote homology, and structural similarity to support evolutionary and functional analyses of viral proteins. By screening the sequence space of VirGenes, we identified 558 CAZyme-associated gene clusters spanning 102 CAZyme families, revealing particularly enriched repertoires in dsDNA viral lineages. Two bacteriophage families, Kleczkowskaviridae and Pootjesviridae , encoded more than 10 CAZymes per genome, followed by Mimiviridae , a representative family of eukaryotic giant viruses. Phylogenetic analyses systematically revealed divergent evolutionary histories of viral carbohydrate-active genes, including frequent horizontal transfer of endolysin genes from bacteria, which likely represents a viral strategy in the ongoing evolutionary arms race with their cellular hosts. Within the structural space of VirGenes, a large number of viral genes were found to contain CAZyme-like folds despite more than 85% of them lacking detectable sequence similarity to annotated CAZyme sequences. Notably, numerous hypothetical sequences from giant viruses exhibited glycoside hydrolase–like five-bladed β-propeller folds. Overall, by integrating sequence, structural and functional evidence, we show that viral carbohydrate-active systems exemplify how distributed innovations, constrained by ancient folds, collectively build the functional complexity of the global virosphere. VirGenes is publicly accessible at https://www.genome.jp/vogdb/ .