MBS Seminar - Approaches to making sense of the diversity in a large protein superfamily: Seeking saturation of cytochrome P450 families phylum by phylum

Title: Approaches to making sense of the diversity in a large protein superfamily: Seeking saturation of cytochrome P450 families phylum by phylum

Speaker:  Prof David Nelson, University of Tennessee

Abstract: Cytochrome P450 enzymes are haem-thiolate proteins found in all kingdoms of life. they act on endogenous and exogenous molecules with diverse roles in chemical communication, mobilisation of carbon sources, manufacture of secondary metabolites, production of defensive compounds, metabolism of foreign chemicals, reproduction, structural support and protection from desiccation. P450s comprise one of the largest annotated enzyme superfamilies and therefore present a challenge for rationalisation of sequence diversity and phylogenetic relationships. Nomenclature began on this family in 1987 so 38 years of accumulated annotation is available. Over 175,000 sequences have been named in more than 11,000 CYP families. It has become my mission to find and name all P450 families on Earth. Though this seems like an impossible task, I will present background on the size of the problem, how the problem can be solved and what is our progress so far with specific examples. The strategy is to name CYP families in a phylum until saturation of the discovery curve occurs. That means that when novel genomes in the phylum are annotated no new families are found. There are an estimated 272 phyla of life on earth, so this problem is really 272 smaller problems. I will show that if the sequence data promised by large consortiums on plants, animals, protists and fungi does get produced, all P450s families could be named.

Bio: David Nelson is a biochemist and bioinformatician who has spent most of his career working on cytochrome P450 enzymes, their evolutionary relationships and their classification. In the early 1980s when only 34 P450 sequences were published, he wrote a first-of-its kind evolutionary analysis of these sequences that led to the formation of a Committee on Standardized Cytochrome P450 Nomenclature. This group of 14 influential authors produced a unifying paper for P450 nomenclature that has since been adopted for the P450 superfamily. This was significant since most labs at the time had their own nomenclature systems, making communication difficult. The nomenclature quickly became too large to be included in a publication so in 1995 David started the Cytochrome P450 Homepage as a repository for P450 sequences and nomenclature which cemented his role as the “nomenclature guy” for cytochromes P450. David was also the first to propose the structure for membrane bound P450s, based on sequence analysis, as a soluble P450 domain attached to the membrane by an N-terminal anchor, a model that has been proven correct by subsequent structural studies. In recent years David has made key contributions to genome projects, resulting in five Nature and six Science publications including many covers e.g. for Drosophila (2000, Science); Western Black Cottonwood first tree genome (2006, Science); papaya a first transgenic crop genome (2008, Nature); tomato (2012 Nature); coelacanth (2013, Nature); sacred lotus (2013, Trop. Plant Biol.) and white spruce (2015, Plant J.). Apart from simply naming enzymes, David’s work has led to the concept of clans, groupings that represent deep clades in the evolution of P450s. Animals and land plants each have 12 clans, with two in common (CYP51 and CYP74). With colleagues at Wood’s Hole Oceanographic Institute, he has laid out the most comprehensive evolutionary theory of how animal P450s arose by mapping the synteny of animal P450s back in time to Cnidarians, Trichoplax, ctenophores and sponges, concluding that animal P450s descended from a single genetic locus via tandem duplication with later migration to new locations. These dispersed P450s gave rise to the known 12 clans.