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  1. Article ; Online: Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD.

    Shelton, Catherine L / Meneely, Kathleen M / Ronnebaum, Trey A / Chilton, Annemarie S / Riley, Andrew P / Prisinzano, Thomas E / Lamb, Audrey L

    Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry

    2022  Volume 27, Issue 6, Page(s) 541–551

    Abstract: Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections. P. aeruginosa produces the siderophore pyochelin through the use of a non-ribosomal peptide ... ...

    Abstract Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections. P. aeruginosa produces the siderophore pyochelin through the use of a non-ribosomal peptide synthetase (NRPS) biosynthetic pathway. Targeting members of siderophore NRPS proteins is one avenue currently under investigation for the development of new antibiotics against antibiotic-resistant organisms. Here, the crystal structure of the pyochelin adenylation domain PchD is reported. The structure was solved to 2.11 Å when co-crystallized with the adenylation inhibitor 5'-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 Å with a modified version of salicyl-AMS designed to target an active site cysteine (4-cyano-salicyl-AMS). In the structures, PchD adopts the adenylation conformation, similar to that reported for AB3403 from Acinetobacter baumannii.
    MeSH term(s) Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology ; Phenols ; Pseudomonas aeruginosa/metabolism ; Salicylates/metabolism ; Siderophores/chemistry ; Thiazoles
    Chemical Substances Anti-Bacterial Agents ; Phenols ; Salicylates ; Siderophores ; Thiazoles ; pyochelin (69772-54-9)
    Language English
    Publishing date 2022-05-05
    Publishing country Germany
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1464026-0
    ISSN 1432-1327 ; 0949-8257
    ISSN (online) 1432-1327
    ISSN 0949-8257
    DOI 10.1007/s00775-022-01941-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The 3-His Metal Coordination Site Promotes the Coupling of Oxygen Activation to Cysteine Oxidation in Cysteine Dioxygenase.

    Forbes, Dianna L / Meneely, Kathleen M / Chilton, Annemarie S / Lamb, Audrey L / Ellis, Holly R

    Biochemistry

    2020  Volume 59, Issue 21, Page(s) 2022–2031

    Abstract: Cysteine dioxygenase (CDO) structurally resembles cupin enzymes that use a 3-His/1-Glu coordination scheme. However, the glutamate ligand is substituted with a cysteine (Cys93) residue, which forms a thioether bond with tyrosine (Tyr157) under ... ...

    Abstract Cysteine dioxygenase (CDO) structurally resembles cupin enzymes that use a 3-His/1-Glu coordination scheme. However, the glutamate ligand is substituted with a cysteine (Cys93) residue, which forms a thioether bond with tyrosine (Tyr157) under physiological conditions. The reversion variant, C93E CDO, was generated in order to reestablish the more common 3-His/1-Glu metal ligands of the cupin superfamily. This variant provides a framework for testing the structural and functional significance of Cys93 and the cross-link in CDO. Although dioxygen consumption was observed with C93E CDO, it was not coupled with l-cysteine oxidation. Substrate analogues (d-cysteine, cysteamine, and 3-mercaptopropionate) were not viable substrates for the C93E CDO variant, although they showed variable coordinations to the iron center. The structures of C93E and cross-linked and non-cross-linked wild-type CDO were solved by X-ray crystallography to 1.91, 2.49, and 2.30 Å, respectively. The C93E CDO variant had similar overall structural properties compared to cross-linked CDO; however, the iron was coordinated by a 3-His/1-Glu geometry, leaving only two coordination sites available for dioxygen and bidentate l-cysteine binding. The hydroxyl group of Tyr157 shifted in both non-cross-linked and C93E CDO, and this displacement prevented the residue from participating in substrate stabilization. Based on these results, the divergence of the metal center of cysteine dioxygenase from the 3-His/1-Glu geometry seen with many cupin enzymes was essential for effective substrate binding. The substitution of Glu with Cys in CDO allows for a third coordination site on the iron for bidentate cysteine and monodentate oxygen binding.
    MeSH term(s) Crystallography, X-Ray ; Cysteine/chemistry ; Cysteine/metabolism ; Cysteine Dioxygenase/chemistry ; Cysteine Dioxygenase/metabolism ; Ferric Compounds/chemistry ; Ferric Compounds/metabolism ; Histidine/chemistry ; Histidine/metabolism ; Models, Molecular ; Molecular Conformation ; Oxidation-Reduction ; Oxygen/chemistry ; Oxygen/metabolism
    Chemical Substances Ferric Compounds ; Histidine (4QD397987E) ; Cysteine Dioxygenase (EC 1.13.11.20) ; Cysteine (K848JZ4886) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2020-05-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.9b01085
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 217: Show issues Location:
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  3. Article: The 3-His Metal Coordination Site Promotes the Coupling of Oxygen Activation to Cysteine Oxidation in Cysteine Dioxygenase

    Forbes, Dianna L / Meneely, Kathleen M / Chilton, Annemarie S / Lamb, Audrey L / Ellis, Holly R

    Biochemistry. 2020 May 05, v. 59, no. 21

    2020  

    Abstract: Cysteine dioxygenase (CDO) structurally resembles cupin enzymes that use a 3-His/1-Glu coordination scheme. However, the glutamate ligand is substituted with a cysteine (Cys93) residue, which forms a thioether bond with tyrosine (Tyr157) under ... ...

    Abstract Cysteine dioxygenase (CDO) structurally resembles cupin enzymes that use a 3-His/1-Glu coordination scheme. However, the glutamate ligand is substituted with a cysteine (Cys93) residue, which forms a thioether bond with tyrosine (Tyr157) under physiological conditions. The reversion variant, C93E CDO, was generated in order to reestablish the more common 3-His/1-Glu metal ligands of the cupin superfamily. This variant provides a framework for testing the structural and functional significance of Cys93 and the cross-link in CDO. Although dioxygen consumption was observed with C93E CDO, it was not coupled with l-cysteine oxidation. Substrate analogues (d-cysteine, cysteamine, and 3-mercaptopropionate) were not viable substrates for the C93E CDO variant, although they showed variable coordinations to the iron center. The structures of C93E and cross-linked and non-cross-linked wild-type CDO were solved by X-ray crystallography to 1.91, 2.49, and 2.30 Å, respectively. The C93E CDO variant had similar overall structural properties compared to cross-linked CDO; however, the iron was coordinated by a 3-His/1-Glu geometry, leaving only two coordination sites available for dioxygen and bidentate l-cysteine binding. The hydroxyl group of Tyr157 shifted in both non-cross-linked and C93E CDO, and this displacement prevented the residue from participating in substrate stabilization. Based on these results, the divergence of the metal center of cysteine dioxygenase from the 3-His/1-Glu geometry seen with many cupin enzymes was essential for effective substrate binding. The substitution of Glu with Cys in CDO allows for a third coordination site on the iron for bidentate cysteine and monodentate oxygen binding.
    Keywords X-ray diffraction ; crosslinking ; cysteamine ; cysteine ; cysteine dioxygenase ; geometry ; glutamic acid ; iron ; ligands ; oxidation ; oxygen ; testing ; tyrosine
    Language English
    Dates of publication 2020-0505
    Size p. 2022-2031.
    Publishing place American Chemical Society
    Document type Article
    Note NAL-light
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.9b01085
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  4. Article ; Online: Structure of an Aspergillus fumigatus old yellow enzyme (EasA) involved in ergot alkaloid biosynthesis.

    Chilton, Annemarie S / Ellis, Ashley L / Lamb, Audrey L

    Acta crystallographica. Section F, Structural biology communications

    2014  Volume 70, Issue Pt 10, Page(s) 1328–1332

    Abstract: The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN- ... ...

    Abstract The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN-loaded EasA was determined to 1.8 Å resolution. The active-site amino acids of OYE are conserved, supporting a similar mechanism for reduction of the α/β-unsaturated aldehyde. The C-terminal tail of one monomer packs into the active site of a monomer in the next asymmetric unit, which is most likely to be a crystallization artifact and not a mechanism of self-regulation.
    MeSH term(s) Aspergillus fumigatus/enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Ergot Alkaloids/biosynthesis ; Flavin Mononucleotide/chemistry ; Fungal Proteins/chemistry ; Models, Molecular ; NADPH Dehydrogenase/chemistry ; Protein Structure, Secondary
    Chemical Substances Ergot Alkaloids ; Fungal Proteins ; Flavin Mononucleotide (7N464URE7E) ; NADPH Dehydrogenase (EC 1.6.99.1)
    Language English
    Publishing date 2014-09-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2053-230X
    ISSN (online) 2053-230X
    DOI 10.1107/S2053230X14018962
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Not as easy as π: An insertional residue does not explain the π-helix gain-of-function in two-component FMN reductases.

    McFarlane, Jeffrey S / Hagen, Richard A / Chilton, Annemarie S / Forbes, Dianna L / Lamb, Audrey L / Ellis, Holly R

    Protein science : a publication of the Protein Society

    2018  Volume 28, Issue 1, Page(s) 123–134

    Abstract: The π-helix located at the tetramer interface of two-component FMN-dependent reductases contributes to the structural divergence from canonical FMN-bound reductases within the NADPH:FMN reductase family. The π-helix in the SsuE FMN-dependent reductase of ...

    Abstract The π-helix located at the tetramer interface of two-component FMN-dependent reductases contributes to the structural divergence from canonical FMN-bound reductases within the NADPH:FMN reductase family. The π-helix in the SsuE FMN-dependent reductase of the alkanesulfonate monooxygenase system has been proposed to be generated by the insertion of a Tyr residue in the conserved α4-helix. Variants of Tyr118 were generated, and their X-ray crystal structures determined, to evaluate how these alterations affect the structural integrity of the π-helix. The structure of the Y118A SsuE π-helix was converted to an α-helix, similar to the FMN-bound members of the NADPH:FMN reductase family. Although the π-helix was altered, the FMN binding region remained unchanged. Conversely, deletion of Tyr118 disrupted the secondary structural properties of the π-helix, generating a random coil region in the middle of helix 4. Both the Y118A and Δ118 SsuE SsuE variants crystallize as a dimer. The MsuE FMN reductase involved in the desulfonation of methanesulfonates is structurally similar to SsuE, but the π-helix contains a His insertional residue. Exchanging the π-helix insertional residue of each enzyme did not result in equivalent kinetic properties. Structure-based sequence analysis further demonstrated the presence of a similar Tyr residue in an FMN-bound reductase in the NADPH:FMN reductase family that is not sufficient to generate a π-helix. Results from the structural and functional studies of the FMN-dependent reductases suggest that the insertional residue alone is not solely responsible for generating the π-helix, and additional structural adaptions occur to provide the altered gain of function.
    MeSH term(s) Amino Acid Substitution ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Crystallography, X-Ray ; FMN Reductase/chemistry ; FMN Reductase/genetics ; Flavin Mononucleotide/chemistry ; Mutation, Missense ; NADP/chemistry ; Protein Multimerization ; Protein Structure, Secondary ; Pseudomonas aeruginosa/enzymology ; Pseudomonas aeruginosa/genetics
    Chemical Substances Bacterial Proteins ; NADP (53-59-8) ; Flavin Mononucleotide (7N464URE7E) ; FMN Reductase (EC 1.5.1.38)
    Language English
    Publishing date 2018-11-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.3504
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    Zs.A 3407: Show issues Location:
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  6. Article ; Online: Two structures of an N-hydroxylating flavoprotein monooxygenase: ornithine hydroxylase from Pseudomonas aeruginosa.

    Olucha, Jose / Meneely, Kathleen M / Chilton, Annemarie S / Lamb, Audrey L

    The Journal of biological chemistry

    2011  Volume 286, Issue 36, Page(s) 31789–31798

    Abstract: The ornithine hydroxylase from Pseudomonas aeruginosa (PvdA) catalyzes the FAD-dependent hydroxylation of the side chain amine of ornithine, which is subsequently formylated to generate the iron-chelating hydroxamates of the siderophore pyoverdin. PvdA ... ...

    Abstract The ornithine hydroxylase from Pseudomonas aeruginosa (PvdA) catalyzes the FAD-dependent hydroxylation of the side chain amine of ornithine, which is subsequently formylated to generate the iron-chelating hydroxamates of the siderophore pyoverdin. PvdA belongs to the class B flavoprotein monooxygenases, which catalyze the oxidation of substrates using NADPH as the electron donor and molecular oxygen. Class B enzymes include the well studied flavin-containing monooxygenases and Baeyer-Villiger monooxygenases. The first two structures of a class B N-hydroxylating monooxygenase were determined with FAD in oxidized (1.9 Å resolution) and reduced (3.03 Å resolution) states. PvdA has the two expected Rossmann-like dinucleotide-binding domains for FAD and NADPH and also a substrate-binding domain, with the active site at the interface between the three domains. The structures have NADP(H) and (hydroxy)ornithine bound in a solvent-exposed active site, providing structural evidence for substrate and co-substrate specificity and the inability of PvdA to bind FAD tightly. Structural and biochemical evidence indicates that NADP(+) remains bound throughout the oxidative half-reaction, which is proposed to shelter the flavin intermediates from solvent and thereby prevent uncoupling of NADPH oxidation from hydroxylated product formation.
    MeSH term(s) Catalysis ; Catalytic Domain ; Crystallography, X-Ray ; Flavin-Adenine Dinucleotide ; Mixed Function Oxygenases/chemistry ; NADP ; Ornithine ; Oxidation-Reduction ; Oxygenases/chemistry ; Protein Conformation ; Pseudomonas aeruginosa/enzymology ; Substrate Specificity
    Chemical Substances Flavin-Adenine Dinucleotide (146-14-5) ; NADP (53-59-8) ; Ornithine (E524N2IXA3) ; Mixed Function Oxygenases (EC 1.-) ; Oxygenases (EC 1.13.-) ; ornithine hydroxylase, Pseudomonas aeruginosa (EC 1.14.13.-) ; dimethylaniline monooxygenase (N-oxide forming) (EC 1.14.13.8)
    Language English
    Publishing date 2011-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.265876
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