Abstract
The radical SAM superfamily contains over 100,000 homologous enzymes that catalyze a remarkably broad range of reactions required for life, including metabolism, nucleic acid modification, and biogenesis of cofactors. While the highly conserved SAM-binding motif responsible for formation of the key 5′-deoxyadenosyl radical intermediate is a key structural feature that simplifies identification of superfamily members, our understanding of their structure–function relationships is complicated by the modular nature of their structures, which exhibit varied and complex domain architectures. To gain new insight about these relationships, we classified the entire set of sequences into similarity-based subgroups that could be visualized using sequence similarity networks. This superfamily-wide analysis reveals important features that had not previously been appreciated from studies focused on one or a few members. Functional information mapped to the networks indicates which members have been experimentally or structurally characterized, their known reaction types, and their phylogenetic distribution. Despite the biological importance of radical SAM chemistry, the vast majority of superfamily members have never been experimentally characterized in any way, suggesting that many new reactions remain to be discovered. In addition to 20 subgroups with at least one known function, we identified additional subgroups made up entirely of sequences of unknown function. Importantly, our results indicate that even general reaction types fail to track well with our sequence similarity-based subgroupings, raising major challenges for function prediction for currently identified and new members that continue to be discovered. Interactive similarity networks and other data from this analysis are available from the Structure-Function Linkage Database.
| Original language | English (US) |
|---|---|
| Title of host publication | Methods in Enzymology |
| Editors | Vahe Bandarian |
| Publisher | Academic Press Inc. |
| Pages | 1-71 |
| Number of pages | 71 |
| ISBN (Print) | 9780128127940 |
| DOIs | |
| State | Published - Jan 1 2018 |
Publication series
| Name | Methods in Enzymology |
|---|---|
| Volume | 606 |
| ISSN (Print) | 0076-6879 |
| ISSN (Electronic) | 1557-7988 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
Cite this
}
Atlas of the Radical SAM Superfamily : Divergent Evolution of Function Using a “Plug and Play” Domain. / Holliday, Gemma L.; Akiva, Eyal; Meng, Elaine C.; Brown, Shoshana D.; Calhoun, Sara; Pieper, Ursula; Sali, Andrej; Booker, Squire J.; Babbitt, Patricia C.
Methods in Enzymology. ed. / Vahe Bandarian. Academic Press Inc., 2018. p. 1-71 (Methods in Enzymology; Vol. 606).Research output: Chapter in Book/Report/Conference proceeding › Chapter
TY - CHAP
T1 - Atlas of the Radical SAM Superfamily
T2 - Divergent Evolution of Function Using a “Plug and Play” Domain
AU - Holliday, Gemma L.
AU - Akiva, Eyal
AU - Meng, Elaine C.
AU - Brown, Shoshana D.
AU - Calhoun, Sara
AU - Pieper, Ursula
AU - Sali, Andrej
AU - Booker, Squire J.
AU - Babbitt, Patricia C.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - The radical SAM superfamily contains over 100,000 homologous enzymes that catalyze a remarkably broad range of reactions required for life, including metabolism, nucleic acid modification, and biogenesis of cofactors. While the highly conserved SAM-binding motif responsible for formation of the key 5′-deoxyadenosyl radical intermediate is a key structural feature that simplifies identification of superfamily members, our understanding of their structure–function relationships is complicated by the modular nature of their structures, which exhibit varied and complex domain architectures. To gain new insight about these relationships, we classified the entire set of sequences into similarity-based subgroups that could be visualized using sequence similarity networks. This superfamily-wide analysis reveals important features that had not previously been appreciated from studies focused on one or a few members. Functional information mapped to the networks indicates which members have been experimentally or structurally characterized, their known reaction types, and their phylogenetic distribution. Despite the biological importance of radical SAM chemistry, the vast majority of superfamily members have never been experimentally characterized in any way, suggesting that many new reactions remain to be discovered. In addition to 20 subgroups with at least one known function, we identified additional subgroups made up entirely of sequences of unknown function. Importantly, our results indicate that even general reaction types fail to track well with our sequence similarity-based subgroupings, raising major challenges for function prediction for currently identified and new members that continue to be discovered. Interactive similarity networks and other data from this analysis are available from the Structure-Function Linkage Database.
AB - The radical SAM superfamily contains over 100,000 homologous enzymes that catalyze a remarkably broad range of reactions required for life, including metabolism, nucleic acid modification, and biogenesis of cofactors. While the highly conserved SAM-binding motif responsible for formation of the key 5′-deoxyadenosyl radical intermediate is a key structural feature that simplifies identification of superfamily members, our understanding of their structure–function relationships is complicated by the modular nature of their structures, which exhibit varied and complex domain architectures. To gain new insight about these relationships, we classified the entire set of sequences into similarity-based subgroups that could be visualized using sequence similarity networks. This superfamily-wide analysis reveals important features that had not previously been appreciated from studies focused on one or a few members. Functional information mapped to the networks indicates which members have been experimentally or structurally characterized, their known reaction types, and their phylogenetic distribution. Despite the biological importance of radical SAM chemistry, the vast majority of superfamily members have never been experimentally characterized in any way, suggesting that many new reactions remain to be discovered. In addition to 20 subgroups with at least one known function, we identified additional subgroups made up entirely of sequences of unknown function. Importantly, our results indicate that even general reaction types fail to track well with our sequence similarity-based subgroupings, raising major challenges for function prediction for currently identified and new members that continue to be discovered. Interactive similarity networks and other data from this analysis are available from the Structure-Function Linkage Database.
UR - http://www.scopus.com/inward/record.url?scp=85050283836&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050283836&partnerID=8YFLogxK
U2 - 10.1016/bs.mie.2018.06.004
DO - 10.1016/bs.mie.2018.06.004
M3 - Chapter
C2 - 30097089
AN - SCOPUS:85050283836
SN - 9780128127940
T3 - Methods in Enzymology
SP - 1
EP - 71
BT - Methods in Enzymology
A2 - Bandarian, Vahe
PB - Academic Press Inc.
ER -