Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292 (2016).
Hong, B., Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci. 6, 622–635 (2020).
Liu, B., Romine, A. M., Rubel, C. Z., Engle, K. M. & Shi, B.-F. Transition-metal-catalyzed, coordination-assisted functionalization of nonactivated C(sp3)–H bonds. Chem. Rev. 121, 14957–15074 (2021).
Ren, X. & Fasan, R. Engineered and artificial metalloenzymes for selective C–H functionalization. Curr. Opin. Green Sustain. Chem. 31, 100494 (2021).
Li, F., Zhang, X. & Renata, H. Enzymatic C–H functionalizations for natural product synthesis. Curr. Opin. Chem. Biol. 49, 25–32 (2019).
Zetzsche, L. E. & Narayan, A. R. H. Broadening the scope of biocatalytic C–C bond formation. Nat. Rev. Chem. 4, 334–346 (2020).
Yang, Y. & Arnold, F. H. Navigating the unnatural reaction space: directed evolution of heme proteins for selective carbene and nitrene transfer. Acc. Chem. Res. 54, 1209–1225 (2021).
Latham, J., Brandenburger, E., Shepherd, S. A., Menon, B. R. K. & Micklefield, J. Development of halogenase enzymes for use in synthesis. Chem. Rev. 118, 232–269 (2018).
Xu, Z. et al. Halogen bond: its role beyond drug-target binding affinity for drug discovery and development. J. Chem. Inf. Model. 54, 69–78 (2014).
Petrone, D. A., Ye, J. & Lautens, M. Modern transition-metal-catalyzed carbon–halogen bond formation. Chem. Rev. 116, 8003–8104 (2016).
Hegarty, E., Büchler, J. & Buller, R. M. Halogenases for the synthesis of small molecules. Curr. Opin. Green Sustain. Chem. 41, 100784 (2023).
Jiang, Y. & Lewis, J. C. Asymmetric catalysis by flavin-dependent halogenases. Chirality 35, 452–460 (2023).
Duewel, S. et al. Directed evolution of an FeII-dependent halogenase for asymmetric C(sp3)−H chlorination. ACS Catal. 10, 1272–1277 (2020).
Vaillancourt, F. H., Yin, J. & Walsh, C. T. SyrB2 in syringomycin E biosynthesis is a nonheme FeII alpha-ketoglutarate- and O2-dependent halogenase. Proc. Natl Acad. Sci. USA 102, 10111–10116 (2005).
Galonić, D. P., Vaillancourt, F. H. & Walsh, C. T. Halogenation of unactivated carbon centers in natural product biosynthesis: trichlorination of leucine during barbamide biosynthesis. J. Am. Chem. Soc. 128, 3900–3901 (2006).
Hillwig, M. L. & Liu, X. A new family of iron-dependent halogenases acts on freestanding substrates. Nat. Chem. Biol. 10, 921–923 (2014).
Neugebauer, M. E. et al. A family of radical halogenases for the engineering of amino-acid-based products. Nat. Chem. Biol. 15, 1009–1016 (2019).
Kim, C. Y. et al. The chloroalkaloid (−)-acutumine is biosynthesized via a Fe(II)- and 2-oxoglutarate-dependent halogenase in Menispermaceae plants. Nat. Commun. 11, 1867 (2020).
Zhao, C. et al. An Fe2+– and α-ketoglutarate-dependent halogenase acts on nucleotide substrates. Angew. Chem. Int. Ed. 59, 9478–9484 (2020).
Krebs, C. & Bollinger, J. M. Non-heme Fe (IV)–oxo intermediates. Acc. Chem. Res. 40, 484–492 (2007).
Huang, X. & Groves, J. T. Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C–H activation. J. Biol. Inorg. Chem. 22, 185–207 (2017).
Blasiak, L. C., Vaillancourt, F. H., Walsh, C. T. & Drennan, C. L. Crystal structure of the non-haem iron halogenase SyrB2 in syringomycin biosynthesis. Nature 440, 368–371 (2006).
Wong, S. D. et al. Elucidation of the Fe(IV)=O intermediate in the catalytic cycle of the halogenase SyrB2. Nature 499, 320–323 (2013).
Matthews, M. L. et al. Direct nitration and azidation of aliphatic carbons by an iron-dependent halogenase. Nat. Chem. Biol. 10, 209–215 (2014).
Chan, N. H. et al. Non-native anionic ligand binding and reactivity in engineered variants of the Fe(II)- and α-ketoglutarate-dependent oxygenase SadA. Inorg. Chem. 61, 14477–14485 (2022).
Gomez, C. A., Mondal, D., Du, Q., Chan, N. & Lewis, J. C. Directed evolution of an iron(II)- and α-ketoglutarate-dependent dioxygenase for site-selective azidation of unactivated aliphatic C−H bonds. Angew. Chem. Int. Ed. 62, e202301370 (2023).
Vennelakanti, V., Li, G. L. & Kulik, H. J. Why nonheme iron halogenases do not fluorinate C−H bonds: a computational investigation. Inorg. Chem. 62, 19758–19770 (2023).
Umemura, M. et al. Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus. Fungal Genet. Biol. 68, 23–30 (2014).
Ye, Y. et al. Unveiling the biosynthetic pathway of the ribosomally synthesized and post-translationally modified peptide ustiloxin B in filamentous fungi. Angew. Chem. Int. Ed. 55, 8072–8075 (2016).
Ye, Y. et al. Heterologous production of asperipin-2a: proposal for sequential oxidative macrocyclization by a fungi-specific DUF3328 oxidase. Org. Biomol. Chem. 17, 39–43 (2019).
Kessler, S. C. et al. Victorin, the host-selective cyclic peptide toxin from the oat pathogen Cochliobolus victoriae, is ribosomally encoded. Proc. Natl Acad. Sci. USA 117, 24243–24250 (2020).
Sogahata, K. et al. Biosynthetic studies of phomopsins unveil posttranslational installation of dehydroamino acids by UstYa family proteins. Angew. Chem. Int. Ed. 60, 25729–25734 (2021).
Jiang, Y. et al. Biosynthesis of cyclochlorotine: identification of the genes involved in oxidative transformations and intramolecular O, N-transacylation. Org. Lett. 23, 2616–2620 (2021).
Bat-Erdene, U. et al. Iterative catalysis in the biosynthesis of mitochondrial complex II inhibitors harzianopyridone and atpenin B. J. Am. Chem. Soc. 142, 8550–8554 (2020).
Nagano, N. et al. Class of cyclic ribosomal peptide synthetic genes in filamentous fungi. Fungal Genet. Biol. 86, 58–70 (2016).
Umemura, M., Kuriiwa, K., Tamano, K. & Kawarabayasi, Y. Ustiloxin biosynthetic machinery is not compatible between Aspergillus flavus and Ustilaginoidea virens. Fungal Genet. Biol. 143, 103434 (2020).
Kessler, S. C. & Chooi, Y. H. Out for a RiPP: challenges and advances in genome mining of ribosomal peptides from fungi. Nat. Prod. Rep. 39, 222–230 (2022).
Jasniewski, A. J. & Que, L. Dioxygen activation by nonheme diiron enzymes: diverse dioxygen adducts, high-valent intermediates, and related model complexes. Chem. Rev. 118, 2554–2592 (2018).
Von Wachenfeldt, C., Richardson, T. H., Cosme, J. & Johnson, E. F. Microsomal P450 2C3 is expressed as a soluble dimer in Escherichia coli following modifications of its N-terminus. Arch. Biochem. Biophys. 339, 107–114 (1997).
Otsuka, T., Takase, S., Terano, H. & Okuhara, M. New angiogenesis inhibitors, WF-16775 A1 and A2. J. Antibiot. 45, 1970–1973 (1992).
Kawada, M., Momose, I., Someno, T., Tsujiuchi, G. & Ikeda, D. New atpenins, NBRI23477 A and B, inhibit the growth of human prostate cancer cells. J. Antibiot. 62, 243–246 (2009).
Solomon, E. I. et al. Copper active sites in biology. Chem. Rev. 114, 3659–3853 (2014).
Prigge, S. T., Kolhekar, A. S., Eipper, B. A., Mains, R. E. & Mario Amzel, L. Substrate-mediated electron transfer in peptidylglycine α-hydroxylating monooxygenase. Nat. Struct. Biol. 6, 976–983 (1999).
Klinman, J. P. The copper-enzyme family of dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase: Resolving the chemical pathway for substrate hydroxylation. J. Biol. Chem. 281, 3013–3016 (2006).
Matthews, M. L. et al. Substrate positioning controls the partition between halogenation and hydroxylation in the aliphatic halogenase, SyrB2. Proc. Natl Acad. Sci. USA 106, 17723–17728 (2009).
Morris, H. R., Masento, M. S., Taylor, G. W., Jermyn, K. A. & Kay, R. R. Structure elucidation of two differentiation inducing factors (DIF-2 and DIF-3) from the cellular slime mould Dictyostelium discoideum. Biochem. J 249, 903–906 (1988).
Lima, D. B. et al. Characterization of homodimer interfaces with cross-linking mass spectrometry and isotopically labeled proteins. Nat. Protoc. 13, 431–458 (2018).
Peisach, J. & Blumberg, W. E. Structural implications derived from the analysis of electron paramagnetic resonance spectra of natural and artificial copper proteins. Arch. Biochem. Biophys. 165, 691–708 (1974).
Prigge, S. T., Eipper, B. A., Mains, R. E. & Amzel, L. M. Dioxygen binds end-on to mononuclear copper in a precatalytic enzyme complex. Science 304, 864–867 (2004).
Mydy, L. S. et al. An intramolecular macrocyclase in plant ribosomal peptide biosynthesis. Nat. Chem. Biol. 20, 530–540 (2024).
Wu, P. et al. Theory demonstrated a ‘coupled’ mechanism for O2 activation and substrate hydroxylation by binuclear copper monooxygenases. J. Am. Chem. Soc. 141, 19776–19789 (2019).
Gkotsi, D. S. et al. A marine viral halogenase that iodinates diverse substrates. Nat. Chem. 11, 1091–1097 (2019).
Jiang, Y., Kim, A., Olive, C. & Lewis, J. C. Selective C–H halogenation of alkenes and alkynes using flavin‐dependent halogenases. Angew. Chem. Int. Ed. 63, e2023178 (2024).
Zhao, Q. et al. Engineering nonhaem iron enzymes for enantioselective C(sp3)−F bond formation via radical fluorine transfer. Nat. Synth. 3, 958–966 (2024).
Zhao, L.-P. et al. Biocatalytic enantioselective C(sp3)–H fluorination enabled by directed evolution of non-haem iron enzymes. Nat. Synth. 3, 967–975 (2024).
Omura, S. et al. Atpenins, new antifungal antibiotics produced by Penicillium sp. production, isolation, physico-chemical and biological properties. J. Antibiot. 41, 1769–1773 (1988).
Kumagai, H. et al. The structures of atpenins A4, A5 and B, new antifungal antibiotics produced by Penicillium sp. J. Antibiot. 43, 1553–1558 (1990).
Wittig, I., Braun, H. P. & Schägger, H. Blue native PAGE. Nat. Protoc. 1, 418–428 (2006).
Marty, M. T. et al. Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. Anal. Chem. 87, 4370–4376 (2015).
Lu, S. et al. Mapping native disulfide bonds at a proteome scale. Nat. Methods 12, 329–331 (2015).
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022).
Chaudhury, S., Lyskov, S. & Gray, J. J. PyRosetta: a script-based interface for implementing molecular modeling algorithms using Rosetta. Bioinformatics 26, 689–691 (2010).
Petasis, D. T. & Hendrich, M. P. Quantitative Interpretation of multifrequency multimode EPR spectra of metal containing proteins, enzymes, and biomimetic complexes. Methods Enzymol. 563, 171–208 (2015).
