Using the Structure‐Function Linkage Database to Characterize Functional Domains in Enzymes

Shoshana Brown1, Patricia Babbitt2

1 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, 2 California Institute for Quantitative Biosciences, University of California, San Francisco, California
Publication Name:  Current Protocols in Bioinformatics
Unit Number:  Unit 2.10
DOI:  10.1002/0471250953.bi0210s48
Online Posting Date:  December, 2014
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Abstract

The Structure‐Function Linkage Database (SFLD; http://sfld.rbvi.ucsf.edu/) is a Web‐accessible database designed to link enzyme sequence, structure, and functional information. This unit describes the protocols by which a user may query the database to predict the function of uncharacterized enzymes and to correct misannotated functional assignments. The information in this unit is especially useful in helping a user discriminate functional capabilities of a sequence that is only distantly related to characterized sequences in publicly available databases. © 2014 by John Wiley & Sons, Inc.

Keywords: protein superfamily analysis; protein sequence analysis; structure‐function relationships; protein function prediction; annotation transfer

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Using The SFLD to Predict the Function of an Uncharacterized Enzyme
  • Alternate Protocol 1: Using the SFLD to Correct Misannotated Functional Assignments
  • Guidelines for Understanding Results
  • Commentary
  • Figures
     
 
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Materials

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Figures

Videos

Literature Cited

Literature Cited
  Akiva, E., Brown, S., Almonacid, D.E., Barber, A.E. 2nd, Custer, A.F., Hicks, M.A., Huang, C.C., Lauck, F., Mashiyama, S.T., Meng, E.C., Mischel, D., Morris, J.H., Ojha, S., Schnoes, A.M., Stryke, D., Yunes, J.M., Ferrin, T.E., Holliday, G.L., and Babbitt, P.C. 2014. The structure‐function linkage database. Nucleic Acids Res. 42:D521‐D530.
  Babbitt, P.C. and Gerlt, J.A. 1997. Understanding enzyme superfamilies. Chemistry As the fundamental determinant in the evolution of new catalytic activities. J. Biol. Chem. 272:30591‐30594.
  Babbitt, P.C., Mrachko, G.T., Hasson, M.S., Huisman, G.W., Kolter, R., Ringe, D., Petsko, G.A., Kenyon, G.L., and Gerlt, J.A. 1995. A functionally diverse enzyme superfamily that abstracts the alpha protons of carboxylic acids. Science 267:1159‐1161.
  Brenner, S.E. 1999. Errors in genome annotation. Trends Genet. 15:132‐133.
  Deacon, J. and Cooper, R.A. 1977. d‐Galactonate utilisation by enteric bacteria. The catabolic pathway in Escherichia coli. FEBS Lett. 77:201‐205.
  Devos, D. and Valencia, A. 2001. Intrinsic errors in genome annotation. Trends Genet. 17:429‐431.
  Eddy, S.R. 1998. Profile hidden Markov models. Bioinformatics 14:755‐763.
  Gerlt, J.A. and Babbitt, P.C. 2001. Divergent evolution of enzymatic function: Mechanistically diverse superfamilies and functionally distinct suprafamilies. Annu. Rev. Biochem. 70:209‐246.
  Gilks, W.R., Audit, B., De Angelis, D., Tsoka, S., and Ouzounis, C.A. 2002. Modeling the percolation of annotation errors in a database of protein sequences. Bioinformatics 18:1641‐1649.
  Glasner, M.E., Fayazmanesh, N., Chiang, R.A., Sakai, A., Jacobson, M.P., Gerlt, J.A., and Babbitt, P.C. 2006. Evolution of structure and function in the o‐succinylbenzoate synthase/N‐acylamino acid racemase family of the enolase superfamily. J. Mol. Biol. 360:228‐250.
  Horowitz, N.H. 1945. On the evolution of biochemical syntheses. Proc. Natl. Acad. Sci. U.S.A. 31:153‐157.
  Horowitz, N.H. 1965. The evolution of biochemical syntheses ‐ retrospect and prospect. In Evolving Genes and Proteins: A Symposium Held at the Institute of Microbiology of Rutgers: the State University with Support from the National Science Foundation (V. Bryson and H. J. Vogel, eds.) pp. 15‐23. Academic Press, New York
  Jensen, R.A. 1976. Enzyme recruitment in evolution of new function. Annu. Rev. Microbiol. 30:409‐425.
  Pegg, S.C., Brown, S.D., Ojha, S., Seffernick, J., Meng, E.C., Morris, J.H., Chang, P.J., Huang, C.C., Ferrin, T.E., and Babbitt, P.C. 2006. Leveraging enzyme structure‐function relationships for functional inference and experimental design: The structure‐function linkage database. Biochemistry 45:2545‐2555.
  Petsko, G.A., Kenyon, G.L., Gerlt, J.A., Ringe, D., and Kozarich, J.W. 1993. On the origin of enzymatic species. Trends Biochem. Sci. 18:372‐376.
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  Rison, S.C., Teichmann, S.A., and Thornton, J.M. 2002. Homology, pathway distance and chromosomal localization of the small molecule metabolism enzymes in Escherichia coli. J. Mol. Biol. 318:911‐932.
  Schnoes, A.M., Brown, S.D., Dodevski, I., and Babbitt, P.C. 2009. Annotation error in public databases: Misannotation of molecular function in enzyme superfamilies. PLoS Computat. Biol. 5:e1000605.
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Key References
  Akiva et al., 2014. See above.
  Describes the SFLD.
  Gerlt and Babbitt, 2001. See above.
  Describes various mechanisms of enzyme evolution, including chemistry‐driven evolution of mechanistically diverse superfamilies. Several mechanistically diverse superfamilies are discussed in detail.
  Babbitt et al., 1995. See above.
  Describes the use of superfamily analysis to elucidate the function of an uncharacterized ORF in Escherichia coli.
Internet Resources
  http://sfld.rbvi.ucsf.edu/
  The Structure‐Function Linkage Database.
  http://www.ncbi.nlm.nih.gov/gene/
  Get genome context information for a specific gene.
  http://www.microbesonline.org/
  Get operon context information for a specific gene.
  http://www.theseed.org/wiki/Main_Page
  Get operon context information for a specific gene.
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