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Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids.

Fraley AE, Garcia-Borràs M, Tripathi A, Khare D, Mercado-Marin EV, Tran H, Dan Q, Webb GP, Watts KR, Crews P, Sarpong R, Williams RM, Smith JL, Houk KN, Sherman DH
J Am Chem Soc 139 12060-12068 (2017)
Related entries: 5wgr, 5wgs, 5wgt, 5wgu, 5wgv, 5wgw, 5wgx, 5wgy

Cited: 29 times
EuropePMC logo PMID: 28777910

Abstract

Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from both Malbranchea aurantiaca and Malbranchea graminicola that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the two flavin-dependent halogenases involved in the late-stage halogenation of malbrancheamide in two different fungal strains. MalA and MalA' catalyze the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogues were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA' in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases and provides new insights into a potentially unique reaction mechanism.

Reviews - 5wgz mentioned but not cited (2)

  1. Halogenases: a palette of emerging opportunities for synthetic biology-synthetic chemistry and C-H functionalisation. Crowe C, Molyneux S, Sharma SV, Zhang Y, Gkotsi DS, Connaris H, Goss RJM. Chem Soc Rev 50 9443-9481 (2021)
  2. Halogenase engineering and its utility in medicinal chemistry. Fraley AE, Sherman DH. Bioorg Med Chem Lett 28 1992-1999 (2018)

Articles - 5wgz mentioned but not cited (1)

  1. Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids. Fraley AE, Garcia-Borràs M, Tripathi A, Khare D, Mercado-Marin EV, Tran H, Dan Q, Webb GP, Watts KR, Crews P, Sarpong R, Williams RM, Smith JL, Houk KN, Sherman DH. J Am Chem Soc 139 12060-12068 (2017)


Reviews citing this publication (5)

  1. Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities. Heine T, van Berkel WJH, Gassner G, van Pée KH, Tischler D. Biology (Basel) 7 (2018)
  2. Enzymatic CH functionalizations for natural product synthesis. Li F, Zhang X, Renata H. Curr Opin Chem Biol 49 25-32 (2019)
  3. Enzyme evolution in fungal indole alkaloid biosynthesis. Fraley AE, Sherman DH. FEBS J 287 1381-1402 (2020)
  4. Halogenation in Fungi: What Do We Know and What Remains to Be Discovered? Cochereau B, Meslet-Cladière L, Pouchus YF, Grovel O, Roullier C. Molecules 27 3157 (2022)
  5. Naturally Occurring Organohalogen Compounds-A Comprehensive Review. Gribble GW. Prog Chem Org Nat Prod 121 1-546 (2023)

Articles citing this publication (21)

  1. A flavin-dependent halogenase from metagenomic analysis prefers bromination over chlorination. Neubauer PR, Widmann C, Wibberg D, Schröder L, Frese M, Kottke T, Kalinowski J, Niemann HH, Sewald N. PLoS One 13 e0196797 (2018)
  2. Site-Selective C-H Halogenation Using Flavin-Dependent Halogenases Identified via Family-Wide Activity Profiling. Fisher BF, Snodgrass HM, Jones KA, Andorfer MC, Lewis JC. ACS Cent Sci 5 1844-1856 (2019)
  3. Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels-Alderase. Dan Q, Newmister SA, Klas KR, Fraley AE, McAfoos TJ, Somoza AD, Sunderhaus JD, Ye Y, Shende VV, Yu F, Sanders JN, Brown WC, Zhao L, Paton RS, Houk KN, Smith JL, Sherman DH, Williams RM. Nat Chem 11 972-980 (2019)
  4. Structure-based switch of regioselectivity in the flavin-dependent tryptophan 6-halogenase Thal. Moritzer AC, Minges H, Prior T, Frese M, Sewald N, Niemann HH. J Biol Chem 294 2529-2542 (2019)
  5. Flavin-dependent biocatalysts in synthesis. Baker Dockrey SA, Narayan ARH. Tetrahedron 75 1115-1121 (2019)
  6. Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe. Beyett TS, Fraley AE, Labudde E, Patra D, Coleman RC, Eguchi A, Glukhova A, Chen Q, Williams RM, Koch WJ, Sherman DH, Tesmer JJG. Proc Natl Acad Sci U S A 116 15895-15900 (2019)
  7. Binding of FAD and tryptophan to the tryptophan 6-halogenase Thal is negatively coupled. Moritzer AC, Niemann HH. Protein Sci 28 2112-2118 (2019)
  8. Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway. Fraley AE, Caddell Haatveit K, Ye Y, Kelly SP, Newmister SA, Yu F, Williams RM, Smith JL, Houk KN, Sherman DH. J Am Chem Soc 142 2244-2252 (2020)
  9. Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins. Liu Z, Zhao F, Zhao B, Yang J, Ferrara J, Sankaran B, Venkataram Prasad BV, Kundu BB, Phillips GN, Gao Y, Hu L, Zhu T, Gao X. Nat Commun 12 4158 (2021)
  10. PKS-NRPS Enzymology and Structural Biology: Considerations in Protein Production. Skiba MA, Maloney FP, Dan Q, Fraley AE, Aldrich CC, Smith JL, Brown WC. Methods Enzymol 604 45-88 (2018)
  11. Biosynthesis of rumbrins and inspiration for discovery of HIV inhibitors. Zhong B, Wan J, Shang C, Wen J, Wang Y, Bai J, Cen S, Hu Y. Acta Pharm Sin B 12 4193-4203 (2022)
  12. Analysis of Laboratory-Evolved Flavin-Dependent Halogenases Affords a Computational Model for Predicting Halogenase Site Selectivity. Andorfer MC, Evans D, Yang S, He CQ, Girlich AM, Vergara-Coll J, Sukumar N, Houk KN, Lewis JC. Chem Catal 2 2658-2674 (2022)
  13. Combining OSMAC, metabolomic and genomic methods for the production and annotation of halogenated azaphilones and ilicicolins in termite symbiotic fungi. Hebra T, Pollet N, Touboul D, Eparvier V. Sci Rep 12 17310 (2022)
  14. Enzymatic Late-Stage Halogenation of Peptides. Schnepel C, Moritzer AC, Gäfe S, Montua N, Minges H, Nieß A, Niemann HH, Sewald N. Chembiochem 24 e202200569 (2023)
  15. Mechanism of Action of Flavin-Dependent Halogenases. Barker RD, Yu Y, De Maria L, Johannissen LO, Scrutton NS. ACS Catal 12 15352-15360 (2022)
  16. The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions. Reetz MT, Garcia-Borràs M. J Am Chem Soc 143 14939-14950 (2021)
  17. Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (-)-Eurotiumin A. Kelly SP, Shende VV, Flynn AR, Dan Q, Ye Y, Smith JL, Tsukamoto S, Sigman MS, Sherman DH. J Am Chem Soc 144 19326-19336 (2022)
  18. Indole and azaindole halogenation catalyzed by the RebH enzyme variant 3-LSR utilizing co-purified E. coli reductase. Li EHY, Sana B, Ho T, Ke D, Ghadessy FJ, Duong HA, Seayad J. Front Bioeng Biotechnol 10 1032707 (2022)
  19. Insights into Ag(i)-catalyzed addition reactions of amino alcohols to electron-deficient olefins: competing mechanisms, role of catalyst, and origin of chemoselectivity. Liu C, Han P, Xie Z, Xu Z, Wei D. RSC Adv 8 40338-40346 (2018)
  20. Perfect merohedral twinning combined with noncrystallographic symmetry potentially causes the failure of molecular replacement with low-homology search models for the flavin-dependent halogenase HalX from Xanthomonas campestris. Buss M, Geerds C, Patschkowski T, Niehaus K, Niemann HH. Acta Crystallogr F Struct Biol Commun 74 345-350 (2018)
  21. Structural basis of regioselective tryptophan dibromination by the single-component flavin-dependent halogenase AetF. Gäfe S, Niemann HH. Acta Crystallogr D Struct Biol 79 596-609 (2023)


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