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Inhibition of lactoperoxidase by its own catalytic product: crystal structure of the hypothiocyanate-inhibited bovine lactoperoxidase at 2.3-A resolution.

Singh AK, Singh N, Sharma S, Shin K, Takase M, Kaur P, Srinivasan A, Singh TP
Biophys J 96 646-54 (2009)
Cited: 35 times
EuropePMC logo PMID: 19167310

Abstract

To the best of our knowledge, this is the first report on the structure of product-inhibited mammalian peroxidase. Lactoperoxidase is a heme containing an enzyme that catalyzes the inactivation of a wide range of microorganisms. In the presence of hydrogen peroxide, it preferentially converts thiocyanate ion into a toxic hypothiocyanate ion. Samples of bovine lactoperoxidase containing thiocyanate (SCN(-)) and hypothiocyanate (OSCN(-)) ions were purified and crystallized. The structure was determined at 2.3-A resolution and refined to R(cryst) and R(free) factors of 0.184 and 0.221, respectively. The determination of structure revealed the presence of an OSCN(-) ion at the distal heme cavity. The presence of OSCN(-) ions in crystal samples was also confirmed by chemical and spectroscopic analysis. The OSCN(-) ion interacts with the heme iron, Gln-105 N(epsilon1), His-109 N(epsilon2), and a water molecule W96. The sulfur atom of the OSCN(-) ion forms a hypervalent bond with a nitrogen atom of the pyrrole ring D of the heme moiety at an S-N distance of 2.8 A. The heme group is covalently bound to the protein through two ester linkages involving carboxylic groups of Glu-258 and Asp-108 and the modified methyl groups of pyrrole rings A and C, respectively. The heme moiety is significantly distorted from planarity, whereas pyrrole rings A, B, C, and D are essentially planar. The iron atom is displaced by approximately 0.2 A from the plane of the heme group toward the proximal site. The substrate channel resembles a long tunnel whose inner walls contain predominantly aromatic residues such as Phe-113, Phe-239, Phe-254, Phe-380, Phe-381, Phe-422, and Pro-424. A phosphorylated Ser-198 was evident at the surface, in the proximity of the calcium-binding channel.

Reviews - 3bxi mentioned but not cited (1)

  1. Dual oxidase: a novel therapeutic target in allergic disease. van der Vliet A, Danyal K, Heppner DE. Br J Pharmacol 175 1401-1418 (2018)

Articles - 3bxi mentioned but not cited (7)

  1. Inhibition of lactoperoxidase by its own catalytic product: crystal structure of the hypothiocyanate-inhibited bovine lactoperoxidase at 2.3-A resolution. Singh AK, Singh N, Sharma S, Shin K, Takase M, Kaur P, Srinivasan A, Singh TP. Biophys J 96 646-654 (2009)
  2. Conserved cysteine residues provide a protein-protein interaction surface in dual oxidase (DUOX) proteins. Meitzler JL, Hinde S, Bánfi B, Nauseef WM, Ortiz de Montellano PR. J Biol Chem 288 7147-7157 (2013)
  3. Perturbed heme binding is responsible for the blistering phenotype associated with mutations in the Caenorhabditis elegans dual oxidase 1 (DUOX1) peroxidase domain. Meitzler JL, Brandman R, Ortiz de Montellano PR. J Biol Chem 285 40991-41000 (2010)
  4. Structural stability and heme binding potential of the truncated human dual oxidase 2 (DUOX2) peroxidase domain. Meitzler JL, Ortiz de Montellano PR. Arch Biochem Biophys 512 197-203 (2011)
  5. A stable bacterial peroxidase with novel halogenating activity and an autocatalytically linked heme prosthetic group. Auer M, Gruber C, Bellei M, Pirker KF, Zamocky M, Kroiss D, Teufer SA, Hofbauer S, Soudi M, Battistuzzi G, Furtmüller PG, Obinger C. J Biol Chem 288 27181-27199 (2013)
  6. Structural evidence of the oxidation of iodide ion into hyper-reactive hypoiodite ion by mammalian heme lactoperoxidase. Singh PK, Ahmad N, Yamini S, Singh RP, Singh AK, Sharma P, Smith ML, Sharma S, Singh TP. Protein Sci 31 384-395 (2022)
  7. Variation in prostaglandin metabolism during growth of the diatom Thalassiosira rotula. Di Dato V, Barbarinaldi R, Amato A, Di Costanzo F, Fontanarosa C, Perna A, Amoresano A, Esposito F, Cutignano A, Ianora A, Romano G. Sci Rep 10 5374 (2020)


Reviews citing this publication (3)

  1. Lactoperoxidase: structural insights into the function,ligand binding and inhibition. Sharma S, Singh AK, Kaushik S, Sinha M, Singh RP, Sharma P, Sirohi H, Kaur P, Singh TP. Int J Biochem Mol Biol 4 108-128 (2013)
  2. Hypervalent nonbonded interactions of a divalent sulfur atom. Implications in protein architecture and the functions. Iwaoka M, Isozumi N. Molecules 17 7266-7283 (2012)
  3. Lactoperoxidase as a potential drug target. Flemmig J, Gau J, Schlorke D, Arnhold J. Expert Opin Ther Targets 20 447-461 (2016)

Articles citing this publication (24)

  1. Thiocyanate: a potentially useful therapeutic agent with host defense and antioxidant properties. Chandler JD, Day BJ. Biochem Pharmacol 84 1381-1387 (2012)
  2. Structural evidence of substrate specificity in mammalian peroxidases: structure of the thiocyanate complex with lactoperoxidase and its interactions at 2.4 A resolution. Sheikh IA, Singh AK, Singh N, Sinha M, Singh SB, Bhushan A, Kaur P, Srinivasan A, Sharma S, Singh TP. J Biol Chem 284 14849-14856 (2009)
  3. Mode of binding of the tuberculosis prodrug isoniazid to heme peroxidases: binding studies and crystal structure of bovine lactoperoxidase with isoniazid at 2.7 A resolution. Singh AK, Kumar RP, Pandey N, Singh N, Sinha M, Bhushan A, Kaur P, Sharma S, Singh TP. J Biol Chem 285 1569-1576 (2010)
  4. Binding modes of aromatic ligands to mammalian heme peroxidases with associated functional implications: crystal structures of lactoperoxidase complexes with acetylsalicylic acid, salicylhydroxamic acid, and benzylhydroxamic acid. Singh AK, Singh N, Sinha M, Bhushan A, Kaur P, Srinivasan A, Sharma S, Singh TP. J Biol Chem 284 20311-20318 (2009)
  5. Structure-function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking. Lázár E, Péterfi Z, Sirokmány G, Kovács HA, Klement E, Medzihradszky KF, Geiszt M. Free Radic Biol Med 83 273-282 (2015)
  6. Crystal structure of guaiacol and phenol bound to a heme peroxidase. Murphy EJ, Metcalfe CL, Nnamchi C, Moody PC, Raven EL. FEBS J 279 1632-1639 (2012)
  7. Flavonoids as promoters of the (pseudo-)halogenating activity of lactoperoxidase and myeloperoxidase. Gau J, Furtmüller PG, Obinger C, Prévost M, Van Antwerpen P, Arnhold J, Flemmig J. Free Radic Biol Med 97 307-319 (2016)
  8. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study. Essa BM, Sakr TM, Khedr MA, Khedr MA, El-Essawy FA, El-Mohty AA. Eur J Pharm Sci 76 102-109 (2015)
  9. Structural evidence for the order of preference of inorganic substrates in mammalian heme peroxidases: crystal structure of the complex of lactoperoxidase with four inorganic substrates, SCN, I, Br and Cl. Singh AK, Pandey N, Sinha M, Kaur P, Sharma S, Singh TP. Int J Biochem Mol Biol 2 328-339 (2011)
  10. Bovine carbonyl lactoperoxidase structure at 2.0Å resolution and infrared spectra as a function of pH. Singh AK, Smith ML, Yamini S, Ohlsson PI, Sinha M, Kaur P, Sharma S, Paul JA, Singh TP, Paul KG. Protein J 31 598-608 (2012)
  11. T47D Cells Expressing Myeloperoxidase Are Able to Process, Traffic and Store the Mature Protein in Lysosomes: Studies in T47D Cells Reveal a Role for Cys319 in MPO Biosynthesis that Precedes Its Known Role in Inter-Molecular Disulfide Bond Formation. Laura RP, Dong D, Reynolds WF, Maki RA. PLoS One 11 e0149391 (2016)
  12. CO binding and ligand discrimination in human myeloperoxidase. Murphy EJ, Maréchal A, Segal AW, Rich PR. Biochemistry 49 2150-2158 (2010)
  13. Effects of mono- and disaccharides on the antimicrobial activity of bovine lactoperoxidase system. Al-Baarri AN, Hayashi M, Ogawa M, Hayakawa S. J Food Prot 74 134-139 (2011)
  14. Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents. Awad SM, Zohny YM, Ali SA, Mahgoub S, Said AM. Molecules 23 E2913 (2018)
  15. Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution. Singh RP, Singh A, Sirohi HV, Singh AK, Kaur P, Sharma S, Singh TP. FEBS Open Bio 6 640-650 (2016)
  16. Mode of binding of the antithyroid drug propylthiouracil to mammalian haem peroxidases. Singh RP, Singh A, Kushwaha GS, Singh AK, Kaur P, Sharma S, Singh TP. Acta Crystallogr F Struct Biol Commun 71 304-310 (2015)
  17. Enhanced Antibacterial Activity of Lactoperoxidase-Thiocyanate-Hydrogen Peroxide System in Reduced-Lactose Milk Whey. Al-Baarri AN, Damayanti NT, Legowo AM, Tekiner İH, Hayakawa S. Int J Food Sci 2019 8013402 (2019)
  18. N-glycosylation proteomic characterization and cross-species comparison of milk whey proteins from dairy animals. Yang Y, Zheng N, Zhao X, Zhang Y, Han R, Zhao S, Yang J, Li S, Guo T, Zang C, Wang J. Proteomics 17 (2017)
  19. Improved chromatographic method for purification of lactoperoxidase from different milk sources. Köksal Z, Usanmaz H, Bayrak S, Ozdemir H. Prep Biochem Biotechnol 47 129-136 (2017)
  20. Structure of Yak Lactoperoxidase at 1.55 Å Resolution. Viswanathan V, Rani C, Ahmad N, Singh PK, Sharma P, Kaur P, Sharma S, Singh TP. Protein J 40 8-18 (2021)
  21. Activation of lactoperoxidase by heme-linked protonation and heme-independent iodide binding. Toyama A, Tominaga A, Inoue T, Takeuchi H. Biopolymers 93 113-120 (2010)
  22. Cryo-electron microscopy structures of human thyroid peroxidase (TPO) in complex with TPO antibodies. Baker S, Miguel RN, Thomas D, Powell M, Furmaniak J, Smith BR. J Mol Endocrinol 70 e220149 (2023)
  23. Design of anti-thyroid drugs: Binding studies and structure determination of the complex of lactoperoxidase with 2-mercaptoimidazole at 2.30 Å resolution. Sirohi HV, Singh PK, Iqbal N, Sharma P, Singh AK, Kaur P, Sharma S, Singh TP. Proteins 85 1882-1890 (2017)
  24. Quantitative N-glycoproteome analysis of bovine milk and yogurt. Xiao J, Wang J, Gan R, Wu D, Xu Y, Peng L, Geng F. Curr Res Food Sci 5 182-190 (2022)


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