Dynamic Regulation of Phenylalanine Hydroxylase by Simulated Redox Manipulation
Publication Date
December 31, 2012
Journal
PLOS ONE
Authors
Julian E. Fuchs, Roland G. Huber, Susanne Von Grafenstein, Hannes G. Wallnoefer, et al
Volume
7
Issue
12
Pages
e53005
DOI
https://dx.plos.org/10.1371/journal.pone.0053005
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0053005
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23300845
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534100
Europe PMC
http://europepmc.org/abstract/MED/23300845
Web of Science
000313872600046
Scopus
84871724352
Mendeley
http://www.mendeley.com/research/dynamic-regulation-phenylalanine-hydroxylase-simulated-redox-manipulation
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Mendeley | Further Information

{"title"=>"Dynamic Regulation of Phenylalanine Hydroxylase by Simulated Redox Manipulation", "type"=>"journal", "authors"=>[{"first_name"=>"Julian E.", "last_name"=>"Fuchs", "scopus_author_id"=>"25929124900"}, {"first_name"=>"Roland G.", "last_name"=>"Huber", "scopus_author_id"=>"55180370500"}, {"first_name"=>"Susanne", "last_name"=>"von Grafenstein", "scopus_author_id"=>"49862209900"}, {"first_name"=>"Hannes G.", "last_name"=>"Wallnoefer", "scopus_author_id"=>"36126928000"}, {"first_name"=>"Gudrun M.", "last_name"=>"Spitzer", "scopus_author_id"=>"18435459800"}, {"first_name"=>"Dietmar", "last_name"=>"Fuchs", "scopus_author_id"=>"35414205100"}, {"first_name"=>"Klaus R.", "last_name"=>"Liedl", "scopus_author_id"=>"7005835871"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"368034347", "sgr"=>"84871724352", "issn"=>"19326203", "pmid"=>"23300845", "scopus"=>"2-s2.0-84871724352", "doi"=>"10.1371/journal.pone.0053005", "isbn"=>"1932-6203"}, "id"=>"c0fdc69a-2596-3d9c-aeea-150e77974fb8", "abstract"=>"Recent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon in vivo immune activation. Though the structural damage of oxidative stress is expected to be comparably small, a structural rationale for this experimental finding was lacking. Hence, we investigated the impact of side chain oxidation at two vicinal cysteine residues on local conformational flexibility in the protein by comparative molecular dynamics simulations. Analysis of backbone dynamics revealed a highly flexible loop region (Tyr138-loop) in proximity to the active center of phenylalanine hydroxylase. We observed elevated loop dynamics in connection with a loop movement towards the active site in the oxidized state, thereby partially blocking access for the substrate phenylalanine. These findings were confirmed by extensive replica exchange molecular dynamics simulations and serve as a first structural explanation for decreased enzyme turnover in situations of oxidative stress.", "link"=>"http://www.mendeley.com/research/dynamic-regulation-phenylalanine-hydroxylase-simulated-redox-manipulation", "reader_count"=>20, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>2, "Chemistry"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Spain"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/514356"], "description"=>"<p>The catalytic domain of native phenylalanine hydroxylase in blue cartoon representation (top left). The biopterin co-factor in the active site is shown as sticks, the catalytic iron as brown sphere. Cysteine residues 203 and 334 are shown as sticks to highlight the artificially introduced oxidation site distant from the catalytic center (red, top right). A zoom at the site of oxidation at the back of the top figures is shown at the bottom. Cys203 and Cys334 in proximity to each other (native state, blue, bottom left) are closed to a disulfide bond (oxidized state, red, bottom right).</p>", "links"=>[], "tags"=>["overview", "oxidized", "phenylalanine"], "article_id"=>184844, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_overview_of_native_and_oxidized_phenylalanine_hydroxylase_/184844", "title"=>"Structural overview of native and oxidized phenylalanine hydroxylase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-31 01:20:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/514477"], "description"=>"<p>A: RMSD of Cα-atoms over the simulation time of 200 ns standard MD simulations for the two systems PAH<sub>nat</sub> (blue) and PAH<sub>ox</sub> (red). After an initial phase of loop reorientation for the oxidized system PAH<sub>ox</sub> (around 20 ns simulation time), simulations yield stable trajectories. B: Residue-wise B-factors for the simulated systems highlight residues 130–145 as particularly altered by the introduced cysteine oxidation. Elevated B-factors in this loop region (Tyr138-loop) in PAH<sub>ox</sub> are caused by a reorientation of the loop in an early stage of the simulation. Dynamics of residues around the oxidation sites (Cys-203, Cys334) are similar in both systems.</p>", "links"=>[], "tags"=>["oxidized", "phenylalanine"], "article_id"=>184967, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.g002", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Global_dynamic_behavior_of_native_and_oxidized_phenylalanine_hydroxylase_/184967", "title"=>"Global dynamic behavior of native and oxidized phenylalanine hydroxylase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-31 01:22:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/514573"], "description"=>"<p>A: Distance between the catalytic iron center and the Cα-atom of Glu141 included in the flexible Tyr138-loop near the active site. Whereas this distance remains mostly stable in the native state PAH<sub>nat</sub> over the simulation time (blue), simulation of PAH<sub>ox</sub> shows an initial phase of increased loop flexibility that is followed by decrease of that distance indicating a loop movement towards the active site. This finding is confirmed by calculation of the accessible surface area of the iron center (B). After an initial adaption to the perturbation, PAH<sub>ox</sub> shows a constantly reduced accessibility of the catalytic iron center compared to PAH<sub>nat</sub>. The overall active site volume (C) is similarly reduced over simulation time in PAH<sub>ox</sub> compared to PAH<sub>nat</sub>, suggesting a reduced enzyme turnover.</p>", "links"=>[], "tags"=>["binding", "oxidized", "phenylalanine"], "article_id"=>185064, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_the_binding_site_region_of_native_and_oxidized_phenylalanine_hydroxylase_/185064", "title"=>"Dynamics of the binding site region of native and oxidized phenylalanine hydroxylase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-31 01:24:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/514823"], "description"=>"<p>REMD simulations confirm the reduction in both measures for PAH<sub>ox</sub> in comparison to PAH<sub>nat</sub> for an average over 16 simulations over 100 ns compare to a single observation in a 200 ns standard MD run.</p>", "links"=>[], "tags"=>["deviations", "catalytic", "simulations"], "article_id"=>185313, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.t001", "stats"=>{"downloads"=>2, "page_views"=>39, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Averages_and_standard_deviations_SD_of_accessible_surface_area_of_the_catalytic_iron_as_well_as_the_total_active_site_volume_for_the_simulations_of_PAH_nat_and_PAH_ox_/185313", "title"=>"Averages and standard deviations (SD) of accessible surface area of the catalytic iron as well as the total active site volume for the simulations of PAH<sub>nat</sub> and PAH<sub>ox</sub>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-31 01:28:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/514734"], "description"=>"<p>Residue-wise B-factors for the 2*16 REMD trajectories were calculated for Cα-atoms and compared between simulations of equal temperatures. Rank-based differences were mapped on the protein structure, where blue regions indicate regions more flexible in more of the 16 simulations of PAH<sub>nat</sub>. Unaffected regions are shown in white, whereas red regions indicate regions showing elevated backbone dynamics in more of the 16 simulations of PAH<sub>ox</sub>. Elevated B-factors in the central helices suggest an allosteric signal transduction over this path from the introduced oxidation site (Cys203, Cys334) to the Tyr138-loop near the catalytic center. The bottom picture shows the same structure rotated by 220° to highlight local effects on the oxidation site in the back of the top picture.</p>", "links"=>[], "tags"=>["phenylalanine", "hydroxylase"], "article_id"=>185227, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.g005", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Alteration_in_local_dynamics_in_phenylalanine_hydroxylase_upon_side_chain_oxidation_/185227", "title"=>"Alteration in local dynamics in phenylalanine hydroxylase upon side chain oxidation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-31 01:27:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/514639"], "description"=>"<p>Starting coordinates of both simulations (blue cartoon) overlaid with an average structure of the time frames 150–160 ns of standard MD simulation PAH<sub>ox</sub> (red cartoon). The pronounced loop movement towards the catalytic center (iron ion as brown sphere, co-factor as sticks) was measured as distance of the Cα-atom of Glu141 (red and blue sphere respectively) to the catalytic iron (brown). This rearrangement is paralleled by a reorientation of Tyr138 (shown as sticks, left), in turn concertedly blocking access to the active site of PAH<sub>ox</sub>.</p>", "links"=>[], "tags"=>["phenylalanine", "hydroxylase", "introduced"], "article_id"=>185130, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053005.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Changes_in_the_active_site_of_phenylalanine_hydroxylase_introduced_by_side_chain_oxidation_/185130", "title"=>"Changes in the active site of phenylalanine hydroxylase introduced by side chain oxidation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-31 01:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/279647", "https://ndownloader.figshare.com/files/279684"], "description"=>"<div><p>Recent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon <em>in vivo</em> immune activation. Though the structural damage of oxidative stress is expected to be comparably small, a structural rationale for this experimental finding was lacking. Hence, we investigated the impact of side chain oxidation at two vicinal cysteine residues on local conformational flexibility in the protein by comparative molecular dynamics simulations. Analysis of backbone dynamics revealed a highly flexible loop region (Tyr138-loop) in proximity to the active center of phenylalanine hydroxylase. We observed elevated loop dynamics in connection with a loop movement towards the active site in the oxidized state, thereby partially blocking access for the substrate phenylalanine. These findings were confirmed by extensive replica exchange molecular dynamics simulations and serve as a first structural explanation for decreased enzyme turnover in situations of oxidative stress.</p> </div>", "links"=>[], "tags"=>["phenylalanine", "hydroxylase", "simulated", "redox", "manipulation"], "article_id"=>115137, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry", "Genetics"], "users"=>["Julian E. Fuchs", "Roland G. Huber", "Susanne von Grafenstein", "Hannes G. Wallnoefer", "Gudrun M. Spitzer", "Dietmar Fuchs", "Klaus R. Liedl"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0053005.s001", "https://dx.doi.org/10.1371/journal.pone.0053005.s002"], "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Dynamic_Regulation_of_Phenylalanine_Hydroxylase_by_Simulated_Redox_Manipulation__/115137", "title"=>"Dynamic Regulation of Phenylalanine Hydroxylase by Simulated Redox Manipulation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-12-31 01:25:37"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"5", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"12", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"16", "full-text"=>"19", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"14", "full-text"=>"17", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"12", "full-text"=>"17", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"13", "full-text"=>"12", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biophysics", "average_usage"=>[314, 536, 650, 747, 817, 883, 967, 1049, 1130, 1217, 1277, 1348, 1401, 1458, 1522, 1577, 1627, 1707, 1762, 1816, 1874, 1931, 1969, 2026, 2084]}, {"subject_area"=>"/Physical sciences/Chemistry", "average_usage"=>[302, 508, 622, 720, 804, 888, 973, 1054, 1141, 1219, 1299, 1370, 1442, 1511, 1574, 1644, 1711, 1782, 1846, 1911, 1971, 2030, 2097, 2155, 2217]}, {"subject_area"=>"/Physical sciences/Physics", "average_usage"=>[298, 476, 578, 665, 743, 821, 891, 962, 1036, 1108, 1174, 1240, 1312, 1371, 1430, 1494, 1551, 1609, 1673, 1736, 1795, 1857, 1913, 1976, 2035]}]}
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