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Conformational switch triggered by alpha-ketoglutarate in a halogenase of curacin A biosynthesis.

Khare D, Wang B, Gu L, Razelun J, Sherman DH, Gerwick WH, Håkansson K, Smith JL
Proc Natl Acad Sci U S A 107 14099-104 (2010)
Related entries: 3nnf, 3nnj, 3nnl

Cited: 43 times
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Abstract

The CurA halogenase (Hal) catalyzes a cryptic chlorination leading to cyclopropane ring formation in the synthesis of the natural product curacin A. Hal belongs to a family of enzymes that use Fe(2+), O(2) and alpha-ketoglutarate (alphaKG) to perform a variety of halogenation reactions in natural product biosynthesis. Crystal structures of the enzyme in five ligand states reveal strikingly different open and closed conformations dependent on alphaKG binding. The open form represents ligand-free enzyme, preventing substrate from entering the active site until both alphaKG and chloride are bound, while the closed form represents the holoenzyme with alphaKG and chloride coordinated to iron. Candidate amino acid residues involved in substrate recognition were identified by site-directed mutagenesis. These new structures provide direct evidence of a conformational switch driven by alphaKG leading to chlorination of an early pathway intermediate.

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Articles - 3nnm mentioned but not cited (2)

  1. Conformational switch triggered by alpha-ketoglutarate in a halogenase of curacin A biosynthesis. Khare D, Wang B, Gu L, Razelun J, Sherman DH, Gerwick WH, Håkansson K, Smith JL. Proc Natl Acad Sci U S A 107 14099-14104 (2010)
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  2. A new family of iron-dependent halogenases acts on freestanding substrates. Hillwig ML, Liu X. Nat Chem Biol 10 921-923 (2014)
  3. Structural basis for halogenation by iron- and 2-oxo-glutarate-dependent enzyme WelO5. Mitchell AJ, Zhu Q, Maggiolo AO, Ananth NR, Hillwig ML, Liu X, Boal AK. Nat Chem Biol 12 636-640 (2016)
  4. Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes. Shepherd SA, Karthikeyan C, Latham J, Struck AW, Thompson ML, Menon BRK, Styles MQ, Levy C, Leys D, Micklefield J. Chem Sci 6 3454-3460 (2015)
  5. A Structure-Guided Switch in the Regioselectivity of a Tryptophan Halogenase. Shepherd SA, Menon BR, Fisk H, Struck AW, Levy C, Leys D, Micklefield J. Chembiochem 17 821-824 (2016)
  6. The hidden enzymology of bacterial natural product biosynthesis. Scott TA, Piel J. Nat Rev Chem 3 404-425 (2019)
  7. Structure-Guided Reprogramming of a Hydroxylase To Halogenate Its Small Molecule Substrate. Mitchell AJ, Dunham NP, Bergman JA, Wang B, Zhu Q, Chang WC, Liu X, Boal AK. Biochemistry 56 441-444 (2017)
  8. Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase. Skiba MA, Sikkema AP, Fiers WD, Gerwick WH, Sherman DH, Aldrich CC, Smith JL. ACS Chem Biol 11 3319-3327 (2016)
  9. Protein dynamics control the progression and efficiency of the catalytic reaction cycle of the Escherichia coli DNA-repair enzyme AlkB. Ergel B, Gill ML, Brown L, Yu B, Palmer AG, Hunt JF. J Biol Chem 289 29584-29601 (2014)
  10. Vinylogous Dehydration by a Polyketide Dehydratase Domain in Curacin Biosynthesis. Fiers WD, Dodge GJ, Sherman DH, Smith JL, Aldrich CC. J Am Chem Soc 138 16024-16036 (2016)
  11. Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2. Preisitsch M, Heiden SE, Beerbaum M, Niedermeyer TH, Schneefeld M, Herrmann J, Kumpfmüller J, Thürmer A, Neidhardt I, Wiesner C, Daniel R, Müller R, Bange FC, Schmieder P, Schweder T, Mundt S. Mar Drugs 14 21 (2016)
  12. Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase. Khare D, Hale WA, Tripathi A, Gu L, Sherman DH, Gerwick WH, Håkansson K, Smith JL. Structure 23 2213-2223 (2015)
  13. Characterization of molecular interactions between ACP and halogenase domains in the Curacin A polyketide synthase. Busche A, Gottstein D, Hein C, Ripin N, Pader I, Tufar P, Eisman EB, Gu L, Walsh CT, Sherman DH, Löhr F, Güntert P, Dötsch V. ACS Chem Biol 7 378-386 (2012)
  14. Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily. McCulloch KM, McCranie EK, Smith JA, Sarwar M, Mathieu JL, Gitschlag BL, Du Y, Bachmann BO, Iverson TM. Proc Natl Acad Sci U S A 112 11547-11552 (2015)
  15. Tandem acyl carrier proteins in the curacin biosynthetic pathway promote consecutive multienzyme reactions with a synergistic effect. Gu L, Eisman EB, Dutta S, Franzmann TM, Walter S, Gerwick WH, Skiniotis G, Sherman DH. Angew Chem Int Ed Engl 50 2795-2798 (2011)
  16. Structural basis of functional group activation by sulfotransferases in complex metabolic pathways. McCarthy JG, Eisman EB, Kulkarni S, Gerwick L, Gerwick WH, Wipf P, Sherman DH, Smith JL. ACS Chem Biol 7 1994-2003 (2012)
  17. Crystal structure of halogenase PltA from the pyoluteorin biosynthetic pathway. Pang AH, Garneau-Tsodikova S, Tsodikov OV. J Struct Biol 192 349-357 (2015)
  18. Algorithm-aided engineering of aliphatic halogenase WelO5* for the asymmetric late-stage functionalization of soraphens. Büchler J, Malca SH, Patsch D, Voss M, Turner NJ, Bornscheuer UT, Allemann O, Le Chapelain C, Lumbroso A, Loiseleur O, Buller R. Nat Commun 13 371 (2022)
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  20. Ab initio structural modeling of and experimental validation for Chlamydia trachomatis protein CT296 reveal structural similarity to Fe(II) 2-oxoglutarate-dependent enzymes. Kemege KE, Hickey JM, Lovell S, Battaile KP, Zhang Y, Hefty PS. J Bacteriol 193 6517-6528 (2011)
  21. Reaction pathway engineering converts a radical hydroxylase into a halogenase. Neugebauer ME, Kissman EN, Marchand JA, Pelton JG, Sambold NA, Millar DC, Chang MCY. Nat Chem Biol 18 171-179 (2022)
  22. The role of chloride in the mechanism of O(2) activation at the mononuclear nonheme Fe(II) center of the halogenase HctB. Pratter SM, Light KM, Solomon EI, Straganz GD. J Am Chem Soc 136 9385-9395 (2014)
  23. Adapting to oxygen: 3-Hydroxyanthrinilate 3,4-dioxygenase employs loop dynamics to accommodate two substrates with disparate polarities. Yang Y, Liu F, Liu A. J Biol Chem 293 10415-10424 (2018)
  24. Insight into the structure-function relationship of the nonheme iron halogenases involved in the biosynthesis of 4-chlorothreonine --Thr3 from Streptomyces sp. OH-5093 and SyrB2 from Pseudomonas syringae pv. syringae B301DR. Fullone MR, Paiardini A, Miele R, Marsango S, Gross DC, Omura S, Ros-Herrera E, Bonaccorsi di Patti MC, Laganà A, Pascarella S, Grgurina I. FEBS J 279 4269-4282 (2012)
  25. Independent Evolution of Six Families of Halogenating Enzymes. Xu G, Wang BG. PLoS One 11 e0154619 (2016)
  26. Biocatalytic control of site-selectivity and chain length-selectivity in radical amino acid halogenases. Kissman EN, Neugebauer ME, Sumida KH, Swenson CV, Sambold NA, Marchand JA, Millar DC, Chang MCY. Proc Natl Acad Sci U S A 120 e2214512120 (2023)


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