On the occurrence of cytochrome P450 in viruses

David C. Lamb, Alec H. Follmer, Jared V. Goldstone, David R. Nelson, Andrew G. Warrilow, Claire L. Price, Marie Y. True, Steven L. Kelly, Thomas L. Poulos, and John J. Stegeman

 PNAS June 18, 2019 116 (25) 12343-12352

 EVOLUTION

Significance

Cytochrome P450 monooxygenase enzymes metabolize drugs, carcinogens, and endogenous molecules in the Eukarya, the Bacteria, and the Archaea. The notion that viral genomes contain P450 genes was not considered until discovery of the giant viruses. We have uncovered multiple and unique P450 genes in giant viruses from the deep ocean, terrestrial sources, and human patients. P450s were also found in a herpesvirus and a mycobacteriophage, and we report a crystal structure of the phage P450. Our findings herald an era of research regarding the evolution of this important gene family, with implications for understanding the biology and the origin of the giant viruses themselves. The findings also present potential drug targets for giant viruses that may be human pathogens.

Abstract

Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles in metabolism of endogenous regulatory molecules and exogenous chemicals. We now report that genes for multiple and unique P450s occur commonly in giant viruses in the Mimiviridae, Pandoraviridae, and other families in the proposed order Megavirales. P450 genes were also identified in a herpesvirus (Ranid herpesvirus 3) and a phage (Mycobacterium phage Adler). The Adler phage P450 was classified as CYP102L1, and the crystal structure of the open form was solved at 2.5 Å. Genes encoding known redox partners for P450s (cytochrome P450 reductase, ferredoxin and ferredoxin reductase, and flavodoxin and flavodoxin reductase) were not found in any viral genome so far described, implying that host redox partners may drive viral P450 activities. Giant virus P450 proteins share no more than 25% identity with the P450 gene products we identified in Acanthamoeba castellanii, an amoeba host for many giant viruses. Thus, the origin of the unique P450 genes in giant viruses remains unknown. If giant virus P450 genes were acquired from a host, we suggest it could have been from an as yet unknown and possibly ancient host. These studies expand the horizon in the evolution and diversity of the enormously important P450 superfamily. Determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.

See https://www.pnas.org/content/116/25/12343

Figure 1: Megavirales phylogeny constructed from the RNAPol2 gene. This ML phylogenetic tree shows the relationship of key members of the Megavirales viruses. The clades that contain encoded cytochrome P450 genes are highlighted in colors that correspond to the cytochrome P450 phylogeny in Fig. 2. Bootstrap support values are derived from 250 replicates, using the HIVB (HIV between-patient) model of amino acid substitution. Only values below 90% are shown.