A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions

Stephen Thompson; Qingzhi Zhang; Mayca Ónega; Stephen McMahon; Ian Fleming; Sharon  Ashworth; Jim Naismith; Jan Passchier; David O'Hagan

doi:10.1002/anie.201403345

A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions

Stephen Thompson, Qingzhi Zhang, Mayca Ónega, Stephen McMahon, Ian Fleming, Sharon Ashworth, Jim Naismith, Jan Passchier, David O'Hagan

Research output: Contribution to journal › Article › peer-review

Abstract

A strategy for last-step ¹⁸F fluorination of bioconjugated peptides is reported that exploits an “Achilles heel” in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5′-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5′-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for ¹⁸F labelling. The method uses an aqueous solution (H₂¹⁸O) of [¹⁸F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).

Original language	English
Pages (from-to)	8913-8918
Number of pages	6
Journal	Angewandte Chemie International Edition
Volume	53
Issue number	34
Early online date	2 Jul 2014
DOIs	https://doi.org/10.1002/anie.201403345
Publication status	Published - 18 Aug 2014

Keywords

Bioconjugated peptides
Enzyme catalysis
Fluorinase
Fluorine-18
Positron emission tomography

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10.1002/anie.201403345

OHagan_2014_ACIE_Localised_AM
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the accepted version of the following article: Thompson, S., Zhang, Q., Onega, M., McMahon, S., Fleming, I., Ashworth, S., Naismith, J. H., Passchier, J. and O'Hagan, D. (2014), A Localized Tolerance in the Substrate Specificity of the Fluorinase Enzyme enables “Last-Step” 18F Fluorination of a RGD Peptide under Ambient Aqueous Conditions. Angew. Chem. Int. Ed., 53: 8913–8918, which has been published in final form at http://dx.doi.org/10.1002/anie.201403345
Accepted author manuscript, 979 KB

Cite this

Thompson, S., Zhang, Q., Ónega, M., McMahon, S., Fleming, I., Ashworth, S., Naismith, J., Passchier, J., & O'Hagan, D. (2014). A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions. Angewandte Chemie International Edition, 53(34), 8913-8918. https://doi.org/10.1002/anie.201403345

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abstract = "A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an “Achilles heel” in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5′-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5′-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).",

keywords = "Bioconjugated peptides, Enzyme catalysis, Fluorinase, Fluorine-18, Positron emission tomography",

author = "Stephen Thompson and Qingzhi Zhang and Mayca {\'O}nega and Stephen McMahon and Ian Fleming and Sharon Ashworth and Jim Naismith and Jan Passchier and David O'Hagan",

note = "The authors thank the ERC, EPSRC and the Scottish Imaging Network (SINAPSE) for grants, and the John and Kathleen Watson Scholarship (S.T.) for financial support.",

year = "2014",

month = aug,

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Thompson, S, Zhang, Q, Ónega, M, McMahon, S, Fleming, I, Ashworth, S, Naismith, J, Passchier, J & O'Hagan, D 2014, 'A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions', Angewandte Chemie International Edition, vol. 53, no. 34, pp. 8913-8918. https://doi.org/10.1002/anie.201403345

A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions. / Thompson, Stephen; Zhang, Qingzhi; Ónega, Mayca et al.
In: Angewandte Chemie International Edition, Vol. 53, No. 34, 18.08.2014, p. 8913-8918.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions

AU - Thompson, Stephen

AU - Zhang, Qingzhi

AU - Ónega, Mayca

AU - McMahon, Stephen

AU - Fleming, Ian

AU - Ashworth, Sharon

AU - Naismith, Jim

AU - Passchier, Jan

AU - O'Hagan, David

N1 - The authors thank the ERC, EPSRC and the Scottish Imaging Network (SINAPSE) for grants, and the John and Kathleen Watson Scholarship (S.T.) for financial support.

PY - 2014/8/18

Y1 - 2014/8/18

N2 - A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an “Achilles heel” in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5′-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5′-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).

AB - A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an “Achilles heel” in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5′-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5′-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).

KW - Bioconjugated peptides

KW - Enzyme catalysis

KW - Fluorinase

KW - Fluorine-18

KW - Positron emission tomography

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U2 - 10.1002/anie.201403345

DO - 10.1002/anie.201403345

M3 - Article

SN - 1433-7851

VL - 53

SP - 8913

EP - 8918

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 34

ER -

A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions

Abstract

Keywords

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Extending fluorinase C-18F-bond: Extending fluorinase [C-18F]-bond biocatalysis for Positron Emission Tomography (PET)

bb/c000080/1: The pyrrolnitrin biosynthetic pathway

David O'Hagan

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A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

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Extending fluorinase C-18F-bond: Extending fluorinase [C-18F]-bond biocatalysis for Positron Emission Tomography (PET)

bb/c000080/1: The pyrrolnitrin biosynthetic pathway

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David O'Hagan

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A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" ¹⁸F fluorination of a RGD peptide under ambient aqueous conditions