Cytochromes P450 (CYPs) are important enzymes that undoubtedly appeared very early in evolution — because these genes are found today in archaebacteria, eubacteria, plants, fungi and animals — as well as in several dozen viruses. In mammals, these enzymes carry out oxidative, peroxidative and reductive metabolism of numerous endogenous compounds (e.g. fatty acids, cholesterol, steroids, retinoids, vitamin derivatives, bile acids, porphyrins, thromboxane A2, prostacyclins, and eicosanoids and other lipid mediators) — as well as a wide range of foreign chemicals (e.g. drugs, numerous environmental chemicals and pollutants, natural plant products, and bacterial metabolites from the gut microbiome). Clinically, P450 metabolism of foreign chemicals can frequently produce toxic metabolites, some of which have been implicated in birth defects and other forms of toxicity, and also cancer initiation and progression. Metabolism of toxic foreign chemicals by many P450s can also detoxify the toxicant. Usually, 50–100 P450 functional enzymes exist in mammalian genomes.
Many more CYP genes occur in plant genomes — than in animal genomes — because plants are immobile and must metabolize everything de novo from carbon dioxide (CO2), ammonia (NH3), water, and minerals. Angiosperms contain between 245 (Arabidopsis) and 769 (Eucalyptus) functional CYP genes; even higher numbers (∼1,655 CYP genes) exist in polyploid (i.e. N=2; more than two sets of homologous chromosomes) species such as hexaploid (N=6; six sets of homologous chromosomes) wheat.
Plant P450 enzymes are involved in stress responses, reaction to wounding, sporulation, taste, color and aroma of fruits and flowers, structural support (lignins), water barriers (cutins and suberins), hormone signaling, and synthesis of phytoalexins [antimicrobial (and often anti-oxidative) substances synthesized by plants that are used to fight pathogen infections and other predators). For more information that you might not care to know, 😉 please check out (curator) David R Nelson’s web site, http://drnelson.uthsc.edu/cytochromeP450.html.
Authors [see attached article] describe genes for multiple and unique P450s that occur commonly in giant viruses in the Mimiviridae, Pandoraviridae — and other families in the proposed Order, Megavirales. CYP genes were also found in a herpesvirus and a bacteriophage. Genes encoding the known redox partners for P450 enzymes (cytochrome P450 reductase, ferredoxin, ferredoxin reductase, flavodoxin and flavodoxin reductase) were NOT found in any viral genome so far described — implying that redox partners in the host (infected by the virus) may be required to drive the viral P450 enzyme activities.
Giant virus P450 proteins share no more than 25% amino-acid-sequence identity with P450 gene products identified in the amoeba that is commonly the host for many giant viruses. In conclusion, origin of the unique P450 genes in giant viruses remains unknown; if giant virus CYP genes were acquired from a host, it might have occurred (via horizontal gene transfer) from an unknown (and possibly ancient) host. These exciting findings expand our knowledge in evolution and diversity of this important P450 superfamily. In fact, determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.
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Proc Natl Acad Sci USA June 2019; 116: 12343–12352
COMMENT This is an excellent question and strikes at the very foundation of evolution of this large gene superfamily. To my knowledge, one of the best means to test whether a gene (or subfamily of genes) is essential for life — is to ablate that gene or those genes in a lab animal, such as the mouse.
As summarized [in the attached 2013 review], mammalian genomes comprise 18 CYP gene families. Knocking out any of the three members of the Cyp26 gene family (Cyp26a1, Cyp26b1 and Cyp26c1), as well as knocking out the Cyp51a1 gene, results in embryonic lethality. These findings come as no surprise. Enzymes encoded by the CYP26 genes are all involved in the retinoic acid synthesis/degradation pathway, which is absolutely required for fundamental embryonic development. Lanosterol 14α-demethylase (a principal component of cell membrane formation) is encoded by the CYP51 gene, and of course a cell’s integrity is highly dependent on its membranes being formed correctly. Of additional interest, CYP51 is likely the original ancestral P450 gene, because it is present in all five kingdoms of life (archaebacteria, eubacteria, plants, fungi, animals), and even in viruses.
Other P450 genes/gene families that have been tested — include the Cyp1 family. Ablation of all three members (Cyp1a1, Cyp1a2, Cyp1b1) causes serious morbidity but is not completely embryolethal; the Cyp1 triple knockout has proved highly useful for many types of experiments. Likewise, for several of the other CYP gene families. Little is known about the (biochemical) function of the CYP20A1 gene, which is present in the sea squirt, of the tunicate subphylum (Family Cionidae). Because this gene exists so early in the evolution of animals, many of us suspect that, if it were ablated (in, for example, the mouse), it would be embryolethal (other GEITP readers are invited, please, to update me, if anyone has new information on this fascinating topic).
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