Bioinformatics Reconstruction and Modeling of a Phage-Encoded Cofactor Metabolism

Bacteriophages can harbor a set of genes that, while not being directly implicated in the infection and replication, can dramatically impact the biology of viruses and ultimately define their evolutionary paths. They are known as auxiliary metabolic genes (AMGs) and are mostly derived from the host genome. These accessory genes are known to alter several cellular processes including photosynthesis and many aspects of host central metabolism, among others. Nevertheless, their functions remain largely obscure. Thus, although there is a general consensus that these genes can benefit the phages, more evidence is needed to support this paradigm. Here, through bioinformatics and comparative genome analysis, It has been revealed that over 10% of all currently sequenced bacteriophages (nearly 2 thousand) encode functional roles related to NAD cofactor metabolism. These phages are all Caudovirales, with a large majority of the T4-like group. Notably, it has been found that this viral NAD synthetic capability is alternative, but not redundant with the bacterial host NAD biosynthesis which is supported by a different set of genes. Furthermore, this enhanced NAD synthesis in phage-infected cells could be rationalized by the occurrence of phage-encoded NAD consuming activities, such as those catalyzed by RNA polymerase ADP-ribosyltransferase (gene alt), NAD-dependent DNA ligases (ligA), and NAD-dependent deacetylase (cobB) which often co-exist with NAD biosynthetic genes in T4-like phage genomes. In conclusion, with the assistance of AI modeling tools, a preliminary exploration of the three-dimensional structures of the identified phage-encoded proteins was conducted, which could serve as a valuable foundation for future comprehensive functional analyses.