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Mechanism of enzymatic fluorination in Streptomyces cattleya.

Zhu X, Robinson DA, McEwan AR, O'Hagan D, Naismith JH
J Am Chem Soc 129 14597-604 (2007)
Related entries: 2v7t, 2v7u, 2v7v, 2v7x

Cited: 45 times
EuropePMC logo PMID: 17985882

Abstract

Recently a fluorination enzyme was identified and isolated from Streptomyces cattleya, as the first committed step on the metabolic pathway to the fluorinated metabolites, fluoroacetate and 4-fluorothreonine. This enzyme, 5'-fluoro-5'-deoxy adenosine synthetase (FDAS), has been shown to catalyze C-F bond formation by nucleophilic attack of fluoride ion to S-adenosyl-l-methionine (SAM) with the concomitant displacement of l-methionine to generate 5'-fluoro-5'-deoxy adenosine (5'-FDA). Although the structures of FDAS bound to both SAM and products have been solved, the molecular mechanism remained to be elucidated. We now report site-directed mutagenesis studies, structural analyses, and isothermal calorimetry (ITC) experiments. The data establish the key residues required for catalysis and the order of substrate binding. Fluoride ion is not readily distinguished from water by protein X-ray crystallography; however, using chloride ion (also a substrate) with a mutant of low activity has enabled the halide ion to be located in nonproductive co-complexes with SAH and SAM. The kinetic data suggest the positively charged sulfur of SAM is a key requirement in stabilizing the transition state. We propose a molecular mechanism for FDAS in which fluoride weakly associates with the enzyme exchanging two water molecules for protein ligation. The binding of SAM expels remaining water associated with fluoride ion and traps the ion in a pocket positioned to react with SAM, generating l-methionine and 5'-FDA. l-methionine then dissociates from the enzyme followed by 5'-FDA.

Reviews - 2v7w mentioned but not cited (1)

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  2. Engineering fluorometabolite production: fluorinase expression in Salinispora tropica Yields Fluorosalinosporamide. Eustáquio AS, O'Hagan D, Moore BS. J Nat Prod 73 378-382 (2010)
  3. Identification of fluorinases from Streptomyces sp MA37, Norcardia brasiliensis, and Actinoplanes sp N902-109 by genome mining. Deng H, Ma L, Bandaranayaka N, Qin Z, Mann G, Kyeremeh K, Yu Y, Shepherd T, Naismith JH, O'Hagan D. Chembiochem 15 364-368 (2014)
  4. Chemoenzymatic synthesis and in situ application of S-adenosyl-L-methionine analogs. Thomsen M, Vogensen SB, Buchardt J, Burkart MD, Clausen RP. Org Biomol Chem 11 7606-7610 (2013)
  5. Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis. Pupo G, Ibba F, Ascough DMH, Vicini AC, Ricci P, Christensen KE, Pfeifer L, Morphy JR, Brown JM, Paton RS, Gouverneur V. Science 360 638-642 (2018)
  6. Mapping the reaction coordinates of enzymatic defluorination. Chan PW, Yakunin AF, Edwards EA, Pai EF. J Am Chem Soc 133 7461-7468 (2011)
  7. A fluoride-responsive genetic circuit enables in vivo biofluorination in engineered Pseudomonas putida. Calero P, Volke DC, Lowe PT, Gotfredsen CH, O'Hagan D, Nikel PI. Nat Commun 11 5045 (2020)
  8. A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds. Song H, van der Velden NS, Shiran SL, Bleiziffer P, Zach C, Sieber R, Imani AS, Krausbeck F, Aebi M, Freeman MF, Riniker S, Künzler M, Naismith JH. Sci Adv 4 eaat2720 (2018)
  9. S-Adenosyl-L-methionine hydrolase (adenosine-forming), a conserved bacterial and archaeal protein related to SAM-dependent halogenases. Eustáquio AS, Härle J, Noel JP, Moore BS. Chembiochem 9 2215-2219 (2008)
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  11. Directed Evolution of a Fluorinase for Improved Fluorination Efficiency with a Non-native Substrate. Sun H, Yeo WL, Lim YH, Chew X, Smith DJ, Xue B, Chan KP, Robinson RC, Robins EG, Zhao H, Ang EL. Angew Chem Int Ed Engl 55 14277-14280 (2016)
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  13. Characterization of a SAM-dependent fluorinase from a latent biosynthetic pathway for fluoroacetate and 4-fluorothreonine formation in Nocardia brasiliensis. Wang Y, Deng Z, Qu X. F1000Res 3 61 (2014)
  14. Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines. Roagna G, Ascough DMH, Ibba F, Vicini AC, Fontana A, Christensen KE, Peschiulli A, Oehlrich D, Misale A, Trabanco AA, Paton RS, Pupo G, Gouverneur V. J Am Chem Soc 142 14045-14051 (2020)
  15. Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design. Axer A, Jumde RP, Adam S, Faust A, Schäfers M, Fobker M, Koehnke J, Hirsch AKH, Gilmour R. Chem Sci 12 1286-1294 (2020)
  16. S-adenosyl-L-methionine:hydroxide adenosyltransferase: a SAM enzyme. Deng H, Botting CH, Hamilton JT, Russell RJ, O'Hagan D. Angew Chem Int Ed Engl 47 5357-5361 (2008)
  17. Independent Evolution of Six Families of Halogenating Enzymes. Xu G, Wang BG. PLoS One 11 e0154619 (2016)
  18. Probing the molecular determinants of fluorinase specificity. Yeo WL, Chew X, Smith DJ, Chan KP, Sun H, Zhao H, Lim YH, Ang EL. Chem Commun (Camb) 53 2559-2562 (2017)
  19. A coupled chlorinase-fluorinase system with a high efficiency of trans-halogenation and a shared substrate tolerance. Sun H, Zhao H, Ang EL. Chem Commun (Camb) 54 9458-9461 (2018)
  20. An enzymatic Finkelstein reaction: fluorinase catalyses direct halogen exchange. Lowe PT, Cobb SL, O'Hagan D. Org Biomol Chem 17 7493-7496 (2019)
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  22. A Nonconventional Archaeal Fluorinase Identified by In Silico Mining for Enhanced Fluorine Biocatalysis. Pardo I, Bednar D, Calero P, Volke DC, Damborský J, Nikel PI. ACS Catal 12 6570-6577 (2022)
  23. Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond. Pupo G, Gouverneur V. J Am Chem Soc 144 5200-5213 (2022)
  24. An Enzyme Containing the Conserved Domain of Unknown Function DUF62 Acts as a Stereoselective (Rs ,Sc )-S-Adenosylmethionine Hydrolase. Kornfuehrer T, Romanowski S, de Crécy-Lagard V, Hanson AD, Eustáquio AS. Chembiochem 21 3495-3499 (2020)
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  26. Functional characterisation of the transcriptome from leaf tissue of the fluoroacetate-producing plant, Dichapetalum cymosum, in response to mechanical wounding. Sooklal SA, Mpangase PT, Tomescu MS, Aron S, Hazelhurst S, Archer RH, Rumbold K. Sci Rep 10 20539 (2020)
  27. Identification of Two Novel Fluorinases From Amycolatopsis sp. CA-128772 and Methanosaeta sp. PtaU1.Bin055 and a Mutant With Improved Catalytic Efficiency With Native Substrate. Feng X, Cao Y, Liu W, Xian M. Front Bioeng Biotechnol 10 881326 (2022)


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