Chapter One - Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a “Plug and Play” Domain
Section snippets
Introduction: Overview of the Radical SAM Superfamily
The widely studied radical S-adenosylmethionine (SAM) superfamily (RSS) was originally defined using bioinformatics techniques to survey the 650 RSS members available at that time. It described a homologous group of enzymes united by their utilization of SAM in a radical mechanism (Sofia, Chen, Hetzler, Reyes-Spindola, & Miller, 2001). The original sequence set came from 126 species representing all Kingdoms of life and included many of the first RSS enzymes to be characterized: l-lysine
Results and Discussion
In this study, we first describe the RSS from a structural perspective, including the known variations across MDAs that typify the superfamily. Next, we provide a global view of sequence similarity relationships among the RSS using SSNs to illustrate the subgroups into which we partitioned these sequences to establish a comprehensive classification of the entire superfamily based on sequence similarity (in contrast to the majority of previously published RSS classifications that are based on
Collection of RSS Sequences
To initiate populating the RSS for the SFLD, we collected the full-length sequences in September 2012 associated with Pfam model PF04055 and InterPro family IPR007197, removed duplicate sequences and resolved other differences. This set was last updated using the SFLD automated update protocol on 7/9/14. Functional domains of this representative sequence set superfamily were last updated on 11/22/17.
Representative Networks
The full set of 113,776 sequences was clustered using CD-HIT (Li & Godzik, 2006) at 50% pairwise
Acknowledgments
Support for this work acknowledges NIH R01 GM60595 (P. Babbitt), NIH R01 GM-122595 (S. Booker), and NSF DBI-1356193 (P. Babbitt and G. Holliday). Some of the results described in this chapter were initially developed as part of a workshop on the RSS sponsored by the Enzyme Function Initiative with support from NIH U54GM093342 (J. Gerlt). The SFLD was developed as a joint project of the Babbitt lab with support by NIH R01GM60595 and NSF Grants DBI-0234768 and DBI-0640476 (P. Babbitt), NSF
Author Contributions
G.L.H performed the analysis, directed the research, and wrote the manuscript. E.C.M. generated the structure comparisons provided in Figs. 2 and 3 and assisted with analysis and proof reading of the manuscript. E.A. and S.D.B. assisted with analysis and proof reading of the manuscript. S.C., U.P., and A.S. performed the 3D-structure prediction. S.J.B. provided expertise in RSS enzymology and in assigning functions based on the literature. P.C.B. oversaw the project and wrote the manuscript.
Competing Financial Interests Statement
None.
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2022, ChemCitation Excerpt :These were subsequently aligned and used to infer a maximum-likelihood phylogenetic tree (Figure 2A; see supplemental information). Functional predictions of rSAM enzymes are notoriously difficult as reaction types often track poorly with sequence similarity, an issue compounded by a relative dearth of characterized members.20 Given that genes encoding RiPP pathways are typically co-located on the chromosome in BGCs,21 we extracted genomic neighborhoods for sample rSAM-SPASM sequences using RODEO v2.022 and calculated the frequency at which YG substrate motifs occur in the gene products neighboring each rSAM-SPASM gene.
- 2
Current address: Medicines Discovery Catapult, Mereside, Alderley Park, Alderley Edge, Cheshire, United Kingdom.
- 3
Current address: Department of Energy, Joint Genome Institute, Walnut Creek, CA, United States.
- 4
Current address: National Agricultural Library, Agricultural Research Service, United States Department of Agriculture, Beltville, MA, United States.