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Title: The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes

Abstract

Chorismate mutase/prephenate dehydrogenase from Haemophilus influenzae Rd KW20 is a bifunctional enzyme that catalyzes the rearrangement of chorismate to prephenate and the NAD(P)+ -dependent oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate in tyrosine biosynthesis. The crystal structure of the prephenate dehydrogenase component (HinfPDH) of the TyrA protein from H. influenzae Rd KW20 in complex with the inhibitor tyrosine and cofactor NAD+ has been determined to 2.0 Å resolution. HinfPDH is a dimeric enzyme, with each monomer consisting of an N-terminal / dinucleotide-binding domain and a C-terminal -helical dimerization domain. The structure reveals key active-site residues at the domain interface, including His200, Arg297 and Ser179 that are involved in catalysis and/or ligand binding and are highly conserved in TyrA proteins from all three kingdoms of life. Tyrosine is bound directly at the catalytic site, suggesting that it is a competitive inhibitor of HinfPDH. Comparisons with its structural homologues reveal important differences around the active site, including the absence of an – motif in HinfPDH that is present in other TyrA proteins, such as Synechocystis sp. arogenate dehydrogenase. Residues from this motif are involved in discrimination between NADP+ and NAD+ . The loop between 5 and 6 in the N-terminal domain is muchmore » shorter in HinfPDH and an extra helix is present at the C-terminus. Furthermore, HinfPDH adopts a more closed conformation compared with TyrA proteins that do not have tyrosine bound. This conformational change brings the substrate, cofactor and active-site residues into close proximity for catalysis. An ionic network consisting of Arg297 (a key residue for tyrosine binding), a water molecule, Asp206 (from the loop between 5 and 6) and Arg3650 (from the additional C-terminal helix of the adjacent monomer) is observed that might be involved in gating the active site.« less

Authors:
 [1];  [2];  [3];  [1];  [4];  [4];  [1];  [4];  [3];  [2];  [2];  [4];  [4];  [5];  [1];  [2];  [2];  [6];  [5];  [1] more »;  [4];  [2];  [1];  [3];  [2];  [2];  [1];  [4];  [1];  [1];  [6];  [1];  [7];  [3];  [4];  [1];  [5];  [8];  [4] « less
+ Show Author Affiliations
  1. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Joint Center for Structural Genomics, http://www.jcsg.org (United States)
  2. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Genomics Institute of the Novartis Research Foundation, San Diego, CA (United States). Protein Sciences Dept.
  3. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Univ. of California, San Diego, La Jolla, CA (United States). Center for Research in Biological Systems
  4. Joint Center for Structural Genomics (United States). http://www.jcsg.org; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
  5. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Univ. of California, San Diego, La Jolla, CA (United States). Center for Research in Biological Systems; Sanford–Burnham Medical Research Institute, La Jolla, CA (United States). Program on Bioinformatics and Systems Biology
  6. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Sanford–Burnham Medical Research Institute, La Jolla, CA (United States). Program on Bioinformatics and Systems Biology
  7. Joint Center for Structural Genomics, http://www.jcsg.org (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Science
  8. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Genomics Institute of the Novartis Research Foundation, San Diego, CA (United States). Protein Sciences Dept.; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
Publication Date:
Research Org.:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Center for Research Resources (NCRR); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1625800
Grant/Contract Number:  
AC02-76SF00515; U54 GM074898
Resource Type:
Accepted Manuscript
Journal Name:
Acta Crystallographica. Section F
Additional Journal Information:
Journal Volume: 66; Journal Issue: 10; Journal ID: ISSN 1744-3091
Publisher:
International Union of Crystallography
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biochemistry & molecular biology; biophysics; crystallography; tyrosine biosynthesis; prephenate; chorismate; Haemophilus influenzae; structural genomics

Citation Formats

Chiu, Hsiu-Ju, Abdubek, Polat, Astakhova, Tamara, Axelrod, Herbert L., Carlton, Dennis, Clayton, Thomas, Das, Debanu, Deller, Marc C., Duan, Lian, Feuerhelm, Julie, Grant, Joanna C., Grzechnik, Anna, Han, Gye Won, Jaroszewski, Lukasz, Jin, Kevin K., Klock, Heath E., Knuth, Mark W., Kozbial, Piotr, Krishna, S. Sri, Kumar, Abhinav, Marciano, David, McMullan, Daniel, Miller, Mitchell D., Morse, Andrew T., Nigoghossian, Edward, Okach, Linda, Reyes, Ron, Tien, Henry J., Trame, Christine B., van den Bedem, Henry, Weekes, Dana, Xu, Qingping, Hodgson, Keith O., Wooley, John, Elsliger, Marc-André, Deacon, Ashley M., Godzik, Adam, Lesley, Scott A., and Wilson, Ian A. The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes. United States: N. p., 2010. Web. doi:10.1107/s1744309110021688.
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Chiu, Hsiu-Ju, Abdubek, Polat, Astakhova, Tamara, Axelrod, Herbert L., Carlton, Dennis, Clayton, Thomas, Das, Debanu, Deller, Marc C., Duan, Lian, Feuerhelm, Julie, Grant, Joanna C., Grzechnik, Anna, Han, Gye Won, Jaroszewski, Lukasz, Jin, Kevin K., Klock, Heath E., Knuth, Mark W., Kozbial, Piotr, Krishna, S. Sri, Kumar, Abhinav, Marciano, David, McMullan, Daniel, Miller, Mitchell D., Morse, Andrew T., Nigoghossian, Edward, Okach, Linda, Reyes, Ron, Tien, Henry J., Trame, Christine B., van den Bedem, Henry, Weekes, Dana, Xu, Qingping, Hodgson, Keith O., Wooley, John, Elsliger, Marc-André, Deacon, Ashley M., Godzik, Adam, Lesley, Scott A., & Wilson, Ian A. The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes. United States. https://doi.org/10.1107/s1744309110021688
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Chiu, Hsiu-Ju, Abdubek, Polat, Astakhova, Tamara, Axelrod, Herbert L., Carlton, Dennis, Clayton, Thomas, Das, Debanu, Deller, Marc C., Duan, Lian, Feuerhelm, Julie, Grant, Joanna C., Grzechnik, Anna, Han, Gye Won, Jaroszewski, Lukasz, Jin, Kevin K., Klock, Heath E., Knuth, Mark W., Kozbial, Piotr, Krishna, S. Sri, Kumar, Abhinav, Marciano, David, McMullan, Daniel, Miller, Mitchell D., Morse, Andrew T., Nigoghossian, Edward, Okach, Linda, Reyes, Ron, Tien, Henry J., Trame, Christine B., van den Bedem, Henry, Weekes, Dana, Xu, Qingping, Hodgson, Keith O., Wooley, John, Elsliger, Marc-André, Deacon, Ashley M., Godzik, Adam, Lesley, Scott A., and Wilson, Ian A. Sat . "The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes". United States. https://doi.org/10.1107/s1744309110021688. https://www.osti.gov/servlets/purl/1625800.
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@article{osti_1625800,
title = {The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes},
author = {Chiu, Hsiu-Ju and Abdubek, Polat and Astakhova, Tamara and Axelrod, Herbert L. and Carlton, Dennis and Clayton, Thomas and Das, Debanu and Deller, Marc C. and Duan, Lian and Feuerhelm, Julie and Grant, Joanna C. and Grzechnik, Anna and Han, Gye Won and Jaroszewski, Lukasz and Jin, Kevin K. and Klock, Heath E. and Knuth, Mark W. and Kozbial, Piotr and Krishna, S. Sri and Kumar, Abhinav and Marciano, David and McMullan, Daniel and Miller, Mitchell D. and Morse, Andrew T. and Nigoghossian, Edward and Okach, Linda and Reyes, Ron and Tien, Henry J. and Trame, Christine B. and van den Bedem, Henry and Weekes, Dana and Xu, Qingping and Hodgson, Keith O. and Wooley, John and Elsliger, Marc-André and Deacon, Ashley M. and Godzik, Adam and Lesley, Scott A. and Wilson, Ian A.},
abstractNote = {Chorismate mutase/prephenate dehydrogenase from Haemophilus influenzae Rd KW20 is a bifunctional enzyme that catalyzes the rearrangement of chorismate to prephenate and the NAD(P)+ -dependent oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate in tyrosine biosynthesis. The crystal structure of the prephenate dehydrogenase component (HinfPDH) of the TyrA protein from H. influenzae Rd KW20 in complex with the inhibitor tyrosine and cofactor NAD+ has been determined to 2.0 Å resolution. HinfPDH is a dimeric enzyme, with each monomer consisting of an N-terminal / dinucleotide-binding domain and a C-terminal -helical dimerization domain. The structure reveals key active-site residues at the domain interface, including His200, Arg297 and Ser179 that are involved in catalysis and/or ligand binding and are highly conserved in TyrA proteins from all three kingdoms of life. Tyrosine is bound directly at the catalytic site, suggesting that it is a competitive inhibitor of HinfPDH. Comparisons with its structural homologues reveal important differences around the active site, including the absence of an – motif in HinfPDH that is present in other TyrA proteins, such as Synechocystis sp. arogenate dehydrogenase. Residues from this motif are involved in discrimination between NADP+ and NAD+ . The loop between 5 and 6 in the N-terminal domain is much shorter in HinfPDH and an extra helix is present at the C-terminus. Furthermore, HinfPDH adopts a more closed conformation compared with TyrA proteins that do not have tyrosine bound. This conformational change brings the substrate, cofactor and active-site residues into close proximity for catalysis. An ionic network consisting of Arg297 (a key residue for tyrosine binding), a water molecule, Asp206 (from the loop between 5 and 6) and Arg3650 (from the additional C-terminal helix of the adjacent monomer) is observed that might be involved in gating the active site.},
doi = {10.1107/s1744309110021688},
journal = {Acta Crystallographica. Section F},
number = 10,
volume = 66,
place = {United States},
year = {Sat Jul 31 00:00:00 EDT 2010},
month = {Sat Jul 31 00:00:00 EDT 2010}
}
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