Molecular Function Prediction for a Family Exhibiting Evolutionary Tendencies Towards Substrate Specificity Swapping : Recurrence of Tyrosine Aminotransferase Activity in the I α Subfamily Short Title : Aminotransferase Substrate Specificity Swapping Keywords : Enzyme , Kinetics , Phylogenetics , Py

1 Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America 2 Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America 3 Current affiliation: Biostatistics & Bioinformatics Department, Department of Statistical Science, Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America 4 Department of Statistics, University of California, Berkeley, California, United States of America 5 Department of Plant and Microbial Biology, University of California, Berkeley, California, United States of America Research Article Proteins: Structure, Function and Bioinformatics DOI 10.1002/prot.24318

[1]  Michael I. Jordan,et al.  Genome-scale phylogenetic function annotation of large and diverse protein families. , 2011, Genome research.

[2]  C. Wrenger,et al.  Specific inhibition of the aspartate aminotransferase of Plasmodium falciparum. , 2011, Journal of molecular biology.

[3]  M. Stephens,et al.  Analysis of Population Structure: A Unifying Framework and Novel Methods Based on Sparse Factor Analysis , 2010, PLoS genetics.

[4]  D. Tagle,et al.  Structure, expression, and function of kynurenine aminotransferases in human and rodent brains , 2010, Cellular and Molecular Life Sciences.

[5]  Patricia C. Babbitt,et al.  Annotation Error in Public Databases: Misannotation of Molecular Function in Enzyme Superfamilies , 2009, PLoS Comput. Biol..

[6]  J. Rougemont,et al.  A rapid bootstrap algorithm for the RAxML Web servers. , 2008, Systematic biology.

[7]  J. Kirsch,et al.  Recombinant expression of twelve evolutionarily diverse subfamily Ialpha aminotransferases. , 2008, Protein expression and purification.

[8]  Cathy H. Wu,et al.  The Universal Protein Resource (UniProt) , 2006, Nucleic Acids Research.

[9]  Alexandros Stamatakis,et al.  RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models , 2006, Bioinform..

[10]  J. Kirsch,et al.  The narrow substrate specificity of human tyrosine aminotransferase – the enzyme deficient in tyrosinemia type II , 2006, The FEBS journal.

[11]  Michael I. Jordan,et al.  Protein Molecular Function Prediction by Bayesian Phylogenomics , 2005, PLoS Comput. Biol..

[12]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[13]  Robert D. Finn,et al.  The Pfam protein families database , 2004, Nucleic Acids Res..

[14]  J. Kirsch,et al.  Escherichia coli cystathionine gamma-synthase does not obey ping-pong kinetics. Novel continuous assays for the elimination and substitution reactions. , 2003, Biochemistry.

[15]  Kimmen Sjölander,et al.  SATCHMO: Sequence Alignment and Tree Construction Using Hidden Markov Models , 2003, Bioinform..

[16]  Jack F Kirsch,et al.  How does an enzyme evolved in vitro compare to naturally occurring homologs possessing the targeted function? Tyrosine aminotransferase from aspartate aminotransferase. , 2003, Journal of molecular biology.

[17]  Maria Jesus Martin,et al.  The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003 , 2003, Nucleic Acids Res..

[18]  J. Kirsch,et al.  Quantitative chimeric analysis of six specificity determinants that differentiate Escherichia coli aspartate from tyrosine aminotransferase , 2002, Protein science : a publication of the Protein Society.

[19]  J. R. Fresco,et al.  Increased Frequency of Cysteine, Tyrosine, and Phenylalanine Residues Since the Last Universal Ancestor* , 2002, Molecular & Cellular Proteomics.

[20]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[21]  A. Valencia,et al.  Intrinsic errors in genome annotation. , 2001, Trends in genetics : TIG.

[22]  B. Berger,et al.  Methionine Regeneration and Aspartate Aminotransferase in Parasitic Protozoa , 2001, Journal of bacteriology.

[23]  W. Blankenfeldt,et al.  Recombinant tyrosine aminotransferase from Trypanosoma cruzi: structural characterization and site directed mutagenesis of a broad substrate specificity enzyme. , 2001, Biochimica et biophysica acta.

[24]  J. Kirsch,et al.  A general method for the quantitative analysis of functional chimeras: Applications from site‐directed mutagenesis and macromolecular association , 2001, Protein science : a publication of the Protein Society.

[25]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[26]  M. Gerstein,et al.  Assessing annotation transfer for genomics: quantifying the relations between protein sequence, structure and function through traditional and probabilistic scores. , 2000, Journal of molecular biology.

[27]  J. Goldberg,et al.  Characterization of the Serogroup O11 O-Antigen Locus of Pseudomonas aeruginosa PA103 , 1999, Journal of bacteriology.

[28]  S. Brenner.  Errors in genome annotation. , 1999, Trends in genetics : TIG.

[29]  W. Gu,et al.  PhhC is an essential aminotransferase for aromatic amino acid catabolism in Pseudomonas aeruginosa. , 1998, Microbiology.

[30]  J. Cazzulo,et al.  Isolation and partial characterization of a broad specificity aminotransferase from Leishmania mexicana promastigotes. , 1998, Molecular and biochemical parasitology.

[31]  H Hayashi,et al.  Crystal structures of Paracoccus denitrificans aromatic amino acid aminotransferase: a substrate recognition site constructed by rearrangement of hydrogen bond network. , 1998, Journal of molecular biology.

[32]  H. Kagamiyama,et al.  Directed evolution of an aspartate aminotransferase with new substrate specificities. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Warren,et al.  Recombinant expression, purification, and characterization of three isoenzymes of aspartate aminotransferase from Arabidopsis thaliana. , 1998, Protein expression and purification.

[34]  J A Eisen,et al.  Phylogenomics: improving functional predictions for uncharacterized genes by evolutionary analysis. , 1998, Genome research.

[35]  G. Petsko,et al.  Crystal structure of Saccharomyces cerevisiae cytosolic aspartate aminotransferase , 1998, Protein science : a publication of the Protein Society.

[36]  J. Thompson,et al.  The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. , 1997, Nucleic acids research.

[37]  J. Kirsch,et al.  A continuous coupled spectrophotometric assay for tyrosine aminotransferase activity with aromatic and other nonpolar amino acids. , 1997, Analytical biochemistry.

[38]  D. Metzler,et al.  Refinement and Comparisons of the Crystal Structures of Pig Cytosolic Aspartate Aminotransferase and Its Complex with 2-Methylaspartate* , 1997, The Journal of Biological Chemistry.

[39]  J. Felsenstein.  An alternating least squares approach to inferring phylogenies from pairwise distances. , 1997, Systematic biology.

[40]  H Hayashi,et al.  Paracoccus denitrificans aromatic amino acid aminotransferase: a model enzyme for the study of dual substrate recognition mechanism. , 1997, Journal of biochemistry.

[41]  W. Gu,et al.  Evolutionary recruitment of biochemically specialized subdivisions of Family I within the protein superfamily of aminotransferases , 1996, Journal of bacteriology.

[42]  J. Kirsch,et al.  Redesign of the substrate specificity of escherichia coli aspartate aminotransferase to that of escherichia coli tyrosine aminotransferase by homology modeling and site‐directed mutagenesis , 1995, Protein science : a publication of the Protein Society.

[43]  V. Malashkevich,et al.  Crystal structure of the closed form of chicken cytosolic aspartate aminotransferase at 1.9 A resolution. , 1994, Journal of molecular biology.

[44]  G. Coruzzi,et al.  The aspartate aminotransferase gene family of Arabidopsis encodes isoenzymes localized to three distinct subcellular compartments. , 1995, The Plant journal : for cell and molecular biology.

[45]  P. Christen,et al.  Shift in pH-rate profile and enhanced discrimination between dicarboxylic and aromatic substrates in mitochondrial aspartate aminotransferase Y70H. , 1994, Biochemistry.

[46]  J. Kirsch,et al.  Characterization of the apparent negative co-operativity induced in Escherichia coli aspartate aminotransferase by the replacement of Asp222 with alanine. Evidence for an extremely slow conformational change. , 1994, Protein engineering.

[47]  A. Okamoto,et al.  Construction of aminotransferase chimeras and analysis of their substrate specificity. , 1994, Journal of biochemistry.

[48]  J. Song,et al.  Pseudomonas aeruginosa possesses homologues of mammalian phenylalanine hydroxylase and 4 alpha-carbinolamine dehydratase/DCoH as part of a three-component gene cluster. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Tanase,et al.  Functional roles of valine 37 and glycine 38 in the mobile loop of porcine cytosolic aspartate aminotransferase. , 1993, The Journal of biological chemistry.

[50]  H. Hayashi,et al.  Escherichia coli aromatic amino acid aminotransferase: characterization and comparison with aspartate aminotransferase. , 1993, Biochemistry.

[51]  P. Christen,et al.  Aminotransferases: demonstration of homology and division into evolutionary subgroups. , 1993, European journal of biochemistry.

[52]  P. Morin,et al.  AAT1, a gene encoding a mitochondrial aspartate aminotransferase in Saccharomyces cerevisiae. , 1992, Biochimica et biophysica acta.

[53]  J. Kirsch,et al.  Contribution to catalysis and stability of the five cysteines in Escherichia coli aspartate aminotransferase. Preparation and properties of a cysteine-free enzyme. , 1992, Biochemistry.

[54]  B. Maras,et al.  The amino acid sequence of the aspartate aminotransferase from baker's yeast (Saccharomyces cerevisiae). , 1991, The Biochemical journal.

[55]  S. Tanase,et al.  Structural and functional role of the amino-terminal region of porcine cytosolic aspartate aminotransferase. Catalytic and structural properties of enzyme derivatives truncated on the amino-terminal side. , 1991, The Journal of biological chemistry.

[56]  A. Okamoto,et al.  Three-dimensional structures of aspartate aminotransferase from Escherichia coli and its mutant enzyme at 2.5 A resolution. , 1990, Journal of biochemistry.

[57]  D. Pilgrim,et al.  Isolation and DNA sequence of ADH3, a nuclear gene encoding the mitochondrial isozyme of alcohol dehydrogenase in Saccharomyces cerevisiae , 1985, Molecular and cellular biology.

[58]  G. Eichele,et al.  Three-dimensional structure of mitochondrial aspartate aminotransferase and some functional derivatives: implications for its mode of action. , 1984, Biochemical Society transactions.

[59]  P. Christen,et al.  Chemical modification of a functional arginyl residue (Arg 292) of mitochondrial aspartate aminotransferase. Identification as the binding site for the distal carboxylate group of the substrate. , 1982, The Journal of biological chemistry.

[60]  G. Eichele,et al.  Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[61]  D. Gelfand,et al.  Escherichia coli mutants deficient in the aspartate and aromatic amino acid aminotransferases , 1977, Journal of bacteriology.

[62]  J. C. Slebe,et al.  Carbamylation of aspartate transaminase and the pK value of the active site lysyl residue. , 1976, The Journal of biological chemistry.

[63]  O. H. Lowry,et al.  The effect of carbon and nitrogen sources on the level of metabolic intermediates in Escherichia coli. , 1971, The Journal of biological chemistry.

[64]  S. Velick,et al.  A kinetic and equilibrium analysis of the glutamic oxaloacetate transaminase mechanism. , 1962, The Journal of biological chemistry.

[65]  A. Karmen,et al.  Transaminase activity in human blood. , 1955, The Journal of clinical investigation.