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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
EuropePMC logo PMID: 20660778

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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  1. Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse. Agarwal V, Miles ZD, Winter JM, Eustáquio AS, El Gamal AA, Moore BS. Chem Rev 117 5619-5674 (2017)
  2. Dioxygen activation by nonheme iron enzymes with the 2-His-1-carboxylate facial triad that generate high-valent oxoiron oxidants. Kal S, Que L. J Biol Inorg Chem 22 339-365 (2017)
  3. A sea of biosynthesis: marine natural products meet the molecular age. Lane AL, Moore BS. Nat Prod Rep 28 411-428 (2011)
  4. Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses. Gao SS, Naowarojna N, Cheng R, Liu X, Liu P. Nat Prod Rep 35 792-837 (2018)
  5. Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers. Buongiorno D, Straganz GD. Coord Chem Rev 257 541-563 (2013)
  6. Unique marine derived cyanobacterial biosynthetic genes for chemical diversity. Kleigrewe K, Gerwick L, Sherman DH, Gerwick WH. Nat Prod Rep 33 348-364 (2016)
  7. Scope and potential of halogenases in biosynthetic applications. Smith DR, Grüschow S, Goss RJ. Curr Opin Chem Biol 17 276-283 (2013)
  8. Structural analysis of protein-protein interactions in type I polyketide synthases. Xu W, Qiao K, Tang Y. Crit Rev Biochem Mol Biol 48 98-122 (2013)
  9. Halogenating Enzymes for Active Agent Synthesis: First Steps Are Done and Many Have to Follow. Fejzagić AV, Gebauer J, Huwa N, Classen T. Molecules 24 E4008 (2019)
  10. Cryptic halogenation reactions in natural product biosynthesis. Adak S, Moore BS. Nat Prod Rep 38 1760-1774 (2021)
  11. Insights into enzymatic halogenation from computational studies. Senn HM. Front Chem 2 98 (2014)
  12. Vanadium Chloroperoxidases: The Missing Link in the Formation of Chlorinated Compounds and Chloroform in the Terrestrial Environment? Wever R, Barnett P. Chem Asian J 12 1997-2007 (2017)
  13. Chemical compounds toxic to invertebrates isolated from marine cyanobacteria of potential relevance to the agricultural industry. Essack M, Alzubaidy HS, Bajic VB, Archer JA. Toxins (Basel) 6 3058-3076 (2014)

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