A Catalytic Mechanism for Cysteine N-Terminal Nucleophile Hydrolases, as Revealed by Free Energy Simulations
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{"title"=>"A catalytic mechanism for cysteine N-terminal nucleophile hydrolases, as revealed by free energy simulations", "type"=>"journal", "authors"=>[{"first_name"=>"Alessio", "last_name"=>"Lodola", "scopus_author_id"=>"57195239730"}, {"first_name"=>"Davide", "last_name"=>"Branduardi", "scopus_author_id"=>"8503446000"}, {"first_name"=>"Marco", "last_name"=>"de Vivo", "scopus_author_id"=>"7003936444"}, {"first_name"=>"Luigi", "last_name"=>"Capoferri", "scopus_author_id"=>"36996904700"}, {"first_name"=>"Marco", "last_name"=>"Mor", "scopus_author_id"=>"7004911015"}, {"first_name"=>"Daniele", "last_name"=>"Piomelli", "scopus_author_id"=>"7004723880"}, {"first_name"=>"Andrea", "last_name"=>"Cavalli", "scopus_author_id"=>"7101898098"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84857561891", "sgr"=>"84857561891", "pui"=>"364350405", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pmid"=>"22389698", "doi"=>"10.1371/journal.pone.0032397"}, "id"=>"7989ee36-7d05-36eb-8139-ab5bfd00da47", "abstract"=>"The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, the catalytic reactions of cysteine Ntn-hydrolases have never been investigated from a mechanistic point of view. In the present study, we used free energy simulations in the quantum mechanics/molecular mechanics framework to determine the reaction mechanism of amide hydrolysis catalyzed by the prototypical cysteine Ntn-hydrolase, conjugated bile acid hydrolase (CBAH). The computational analyses, which were confirmed in water and using different CBAH mutants, revealed the existence of a chair-like transition state, which might be one of the specific features of the catalytic cycle of Ntn-hydrolases. Our results offer new insights on Ntn-mediated hydrolysis and suggest possible strategies for the creation of therapeutically useful inhibitors.", "link"=>"http://www.mendeley.com/research/catalytic-mechanism-cysteine-nterminal-nucleophile-hydrolases-revealed-free-energy-simulations", "reader_count"=>37, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>17, "Student > Master"=>6, "Student > Bachelor"=>1, "Professor"=>3, "Other"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>17, "Student > Master"=>6, "Student > Bachelor"=>1, "Professor"=>3, "Other"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Mathematics"=>1, "Agricultural and Biological Sciences"=>13, "Medicine and Dentistry"=>1, "Physics and Astronomy"=>3, "Chemistry"=>12, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>12}, "Physics and Astronomy"=>{"Physics and Astronomy"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>13}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Brazil"=>1, "Serbia and Montenegro"=>1, "Italy"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/674855"], "description"=>"<p>Left panel (A). TS structure of TAU (gray carbons) hydrolysis catalyzed by CBAH (black carbons). H<sub>1</sub> is nearly equidistant between N and N<sub>1</sub> favoring the formation of a pseudo chair structure. Right panel (B) Zwitterionic TI. In both panels, H-bonds are shown as dotted green lines, while secondary structure elements of CBAH are omitted for clarity.</p>", "links"=>[], "tags"=>["tetrahedral", "adduct", "geometries"], "article_id"=>345342, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transition_state_TS_and_tetrahedral_adduct_TA_geometries_identified_along_the_path_/345342", "title"=>"Transition state (TS) and tetrahedral adduct (TA) geometries identified along the path.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:29:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/674297"], "description"=>"<p>Panel (A). The reaction begins when the nucleophilic oxygen/sulfur of Thr/Ser/Cys donates its proton to its own alpha-amino group and attacks the carbonyl carbon of the substrate <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032397#pone.0032397-Oinonen1\" target=\"_blank\">[1]</a>, leading to a negatively charged tetrahedral intermediate (X represents oxygen or sulfur). The acylation step is completed when the alpha-amino group of the catalytic residue protonates the nitrogen of the scissile amide bond leading to the expulsion of the leaving group. Panel (B) First reaction of the catalytic mechanism of CBAH. <b>A</b>, <b>B</b>, and <b>C</b> are key steps for the cleavage of TAU amide bond.</p>", "links"=>[], "tags"=>["chemistry", "Computational biology", "Biochemistry"], "article_id"=>344777, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Catalytic_mechanism_of_Ntn_hydrolases_/344777", "title"=>"Catalytic mechanism of Ntn-hydrolases.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:19:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/674628"], "description"=>"<p>The initial pulling showing the nucleophilic attack (described by the S, C distance), occurring before the proton transfer reaction (N, H<sub>1</sub> distance), is displayed as a black line. The first steered-MD round is featured by a similar reaction path. Conversely, the last three steered-MD runs show a different mechanism, where protonation of the nitrogen (N) occurs at the same time (run three) or even before the nucleophilic attack. The steered-MD rounds third and fourth displayed a very similar distributions of the S-C and N-H<sub>1</sub> distances, indicating the reaction path is converged in terms of explored configurations of the system.</p>", "links"=>[], "tags"=>["chemistry", "Computational biology", "Biochemistry"], "article_id"=>345114, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evolution_of_the_reaction_path_from_steered_MD_PCVs_simulations_/345114", "title"=>"Evolution of the reaction path from steered-MD/PCVs simulations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:25:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/674384"], "description"=>"<p>Secondary structure elements of CBAH are displayed with gray cartoons, while carbon atoms are in black.</p>", "links"=>[], "tags"=>["residues", "interacting", "cys2"], "article_id"=>344871, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CBAH_residues_interacting_with_Cys2_as_found_in_the_crystal_structure_/344871", "title"=>"CBAH residues interacting with Cys2 as found in the crystal structure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:21:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/674445"], "description"=>"<p>Free energy profile along S, H<sub>1</sub> distance as obtained from umbrella sampling calculations and WHAM.</p>", "links"=>[], "tags"=>["cys2", "proton"], "article_id"=>344931, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Free_energy_profile_for_Cys2_internal_proton_transfer_/344931", "title"=>"Free energy profile for Cys2 internal proton transfer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:22:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/674922"], "description"=>"<p>Barriers are estimated from work profiles and are refereed to CBAH wild type (wt) and to zero-point charge mutants.</p>", "links"=>[], "tags"=>["barriers", "tau", "hydrolysis"], "article_id"=>345406, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g008", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_barriers_for_TAU_hydrolysis_as_obtained_from_steered_MD_PCVs_simulations_/345406", "title"=>"Activation barriers for TAU hydrolysis as obtained from steered-MD/PCVs simulations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:30:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/674547"], "description"=>"<p>CBAH carbon atoms are in black, while TAU carbon atoms are in gray. The CBAH active site is represented as a solid van der Waals surface (white), which is occupied by TAU substrate. Relevant CBAH residues are displayed and labeled. Relevant H-bonds between the substrate and CBAH are shown as dotted green lines.</p>", "links"=>[], "tags"=>["michaelis"], "article_id"=>345035, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CBAH_in_its_Michaelis_complex_with_TAU_/345035", "title"=>"CBAH in its Michaelis complex with TAU.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:23:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/344980", "https://ndownloader.figshare.com/files/345009", "https://ndownloader.figshare.com/files/345041", "https://ndownloader.figshare.com/files/345072", "https://ndownloader.figshare.com/files/345119", "https://ndownloader.figshare.com/files/345158", "https://ndownloader.figshare.com/files/345194", "https://ndownloader.figshare.com/files/345227", "https://ndownloader.figshare.com/files/345317", "https://ndownloader.figshare.com/files/345358", "https://ndownloader.figshare.com/files/345402", "https://ndownloader.figshare.com/files/345439", "https://ndownloader.figshare.com/files/345499", "https://ndownloader.figshare.com/files/345556", "https://ndownloader.figshare.com/files/345664"], "description"=>"<div><p>The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, the catalytic reactions of cysteine Ntn-hydrolases have never been investigated from a mechanistic point of view. In the present study, we used free energy simulations in the quantum mechanics/molecular mechanics framework to determine the reaction mechanism of amide hydrolysis catalyzed by the prototypical cysteine Ntn-hydrolase, conjugated bile acid hydrolase (CBAH). The computational analyses, which were confirmed in water and using different CBAH mutants, revealed the existence of a chair-like transition state, which might be one of the specific features of the catalytic cycle of Ntn-hydrolases. Our results offer new insights on Ntn-mediated hydrolysis and suggest possible strategies for the creation of therapeutically useful inhibitors.</p> </div>", "links"=>[], "tags"=>["catalytic", "cysteine", "n-terminal", "nucleophile", "revealed", "simulations"], "article_id"=>128199, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0032397.s001", "https://dx.doi.org/10.1371/journal.pone.0032397.s002", "https://dx.doi.org/10.1371/journal.pone.0032397.s003", "https://dx.doi.org/10.1371/journal.pone.0032397.s004", "https://dx.doi.org/10.1371/journal.pone.0032397.s005", "https://dx.doi.org/10.1371/journal.pone.0032397.s006", "https://dx.doi.org/10.1371/journal.pone.0032397.s007", "https://dx.doi.org/10.1371/journal.pone.0032397.s008", "https://dx.doi.org/10.1371/journal.pone.0032397.s009", "https://dx.doi.org/10.1371/journal.pone.0032397.s010", "https://dx.doi.org/10.1371/journal.pone.0032397.s011", "https://dx.doi.org/10.1371/journal.pone.0032397.s012", "https://dx.doi.org/10.1371/journal.pone.0032397.s013", "https://dx.doi.org/10.1371/journal.pone.0032397.s014", "https://dx.doi.org/10.1371/journal.pone.0032397.s015"], "stats"=>{"downloads"=>21, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Catalytic_Mechanism_for_Cysteine_N_Terminal_Nucleophile_Hydrolases_as_Revealed_by_Free_Energy_Simulations/128199", "title"=>"A Catalytic Mechanism for Cysteine N-Terminal Nucleophile Hydrolases, as Revealed by Free Energy Simulations", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-02-28 02:16:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/674765"], "description"=>"<p>Left panel. Bi-dimensional FES in the <i>S</i> and <i>Z</i> space from US simulations. The minimum free energy path is displayed with a continuous black line. Configurations <b>1</b>–<b>5</b> are crucial structures identified along the reaction path, <i>S</i>. Right panel, subpanel (A). Projection of the FES of TAU hydrolysis on <i>S</i>. Right panel, subpanel B. Relevant interatomic distances (reported as average over US with error bars representing the standard deviations) are plotted as function of <i>S</i>. Right panel, subpanel C. Improper torsion of the amide nitrogen (N) of TAU as function of <i>S</i>. Right panel, subpanel D. Nucleophile attacking angle as function of <i>S</i>.</p>", "links"=>[], "tags"=>["tau", "hydrolysis", "catalyzed"], "article_id"=>345249, "categories"=>["Biological Sciences", "Biochemistry", "Chemistry"], "users"=>["Alessio Lodola", "Davide Branduardi", "Marco De Vivo", "Luigi Capoferri", "Marco Mor", "Daniele Piomelli", "Andrea Cavalli"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0032397.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Free_energy_surface_FES_for_TAU_hydrolysis_catalyzed_by_CBAH_/345249", "title"=>"Free energy surface (FES) for TAU hydrolysis catalyzed by CBAH.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-02-28 01:27:29"}

PMC Usage Stats | Further Information

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Relative Metric

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