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Molecular function prediction for a family exhibiting evolutionary tendencies toward substrate specificity swapping: Recurrence of tyrosine aminotransferase activity in the Iα subfamily

Authors

  • Kathryn E. Muratore,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, California
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  • Barbara E. Engelhardt,

    1. Department of Electrical Engineering and Computer Science, University of California, Berkeley, California
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  • John R. Srouji,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, California
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  • Michael I. Jordan,

    1. Department of Electrical Engineering and Computer Science, University of California, Berkeley, California
    2. Department of Statistics, University of California, Berkeley, California
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  • Steven E. Brenner,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, California
    2. Department of Plant and Microbial Biology, University of California, Berkeley, California
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  • Jack F. Kirsch

    Corresponding author
    1. Department of Molecular and Cell Biology, University of California, Berkeley, California
    2. QB3 Institute, University of California, Berkeley, California
    • Correspondence to: Jack F. Kirsch, University of California, QB3 Institute, 572 Stanley Hall, Berkeley, CA 94720-3220. E-mail: jfkirsch@berkeley.edu

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  • Barbara E. Engelhardt is currently affiliated to Biostatistics and Bioinformatics Department, Department of Statistical Science, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina.

  • This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

The subfamily Iα aminotransferases are typically categorized as having narrow specificity toward carboxylic amino acids (AATases), or broad specificity that includes aromatic amino acid substrates (TATases). Because of their general role in central metabolism and, more specifically, their association with liver-related diseases in humans, this subfamily is biologically interesting. The substrate specificities for only a few members of this subfamily have been reported, and the reliable prediction of substrate specificity from protein sequence has remained elusive. In this study, a diverse set of aminotransferases was chosen for characterization based on a scoring system that measures the sequence divergence of the active site. The enzymes that were experimentally characterized include both narrow-specificity AATases and broad-specificity TATases, as well as AATases with broader-specificity and TATases with narrower-specificity than the previously known family members. Molecular function and phylogenetic analyses underscored the complexity of this family's evolution as the TATase function does not follow a single evolutionary thread, but rather appears independently multiple times during the evolution of the subfamily. The additional functional characterizations described in this article, alongside a detailed sequence and phylogenetic analysis, provide some novel clues to understanding the evolutionary mechanisms at work in this family. Proteins 2013. © 2013 Wiley Periodicals, Inc.

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