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Journal of Natural Medicines

Open Access 19-11-2023 | Review

Three-membered ring formation catalyzed by α-ketoglutarate-dependent nonheme iron enzymes

Author: Richiro Ushimaru

Published in: Journal of Natural Medicines

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Abstract

Epoxides, aziridines, and cyclopropanes are found in various medicinal natural products, including polyketides, terpenes, peptides, and alkaloids. Many classes of biosynthetic enzymes are involved in constructing these ring structures during their biosynthesis. This review summarizes our current knowledge regarding how α-ketoglutarate-dependent nonheme iron enzymes catalyze the formation of epoxides, aziridines, and cyclopropanes in nature, with a focus on enzyme mechanisms.
Literature
1.
Thibodeaux CJ, Chang W-c, Liu H-w (2012) Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis. Chem Rev 112:1681–1709 PubMedCrossRef
2.
3.
Michalopoulos AS, Livaditis IG, Gougoutas V (2011) The revival of fosfomycin. Int J Infect Dis 15:e732–e739 PubMedCrossRef
4.
Silver LL (2017) Fosfomycin: mechanism and resistance. Cold Spring Harb Perspec Med 7:a025262 CrossRef
5.
6.
7.
Suresh Kumar G, Lipman R, Cummings J, Tomasz M (1997) Mitomycin C−DNA adducts generated by DT-diaphorase. Revised mechanism of the enzymatic reductive activation of mitomycin C. Biochemistry 36:14128–14136 PubMedCrossRef
8.
Talele TT (2016) The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules. J Med Chem 59:8712–8756 PubMedCrossRef
9.
Ma S, Mandalapu D, Wang S, Zhang Q (2022) Biosynthesis of cyclopropane in natural products. Nat Prod Rep 39:926–945 PubMedCrossRef
10.
Wessjohann LA, Brandt W, Thiemann T (2003) Biosynthesis and metabolism of cyclopropane rings in natural compounds. Chem Rev 103:1625–1648 PubMedCrossRef
11.
Kelly WL, Boyne MT, Yeh E, Vosburg DA, Galonić DP, Kelleher NL, Walsh CT (2007) Characterization of the aminocarboxycyclopropane-forming enzyme CmaC. Biochemistry 46:359–368 PubMedCrossRef
12.
Kurosawa S, Hasebe F, Okamura H, Yoshida A, Matsuda K, Sone Y, Tomita T, Shinada T, Takikawa H, Kuzuyama T, Kosono S, Nishiyama M (2022) Molecular basis for enzymatic aziridine formation via sulfate elimination. J Am Chem Soc 144:16164–16170 PubMedCrossRef
13.
Zha L, Jiang Y, Henke MT, Wilson MR, Wang JX, Kelleher NL, Balskus EP (2017) Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring. Nat Chem Biol 13:1063–1065 PubMedPubMedCentralCrossRef
14.
Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409:59–71 PubMedCrossRef
15.
Savage TJ, Croteau R (1993) Biosynthesis of monoterpenes: regio-and stereochemistry of (+)-3-carene biosynthesis. Arch Biochem Biophys 305:581–587 PubMedCrossRef
16.
Hoelscher DJ, Williams DC, Wildung MR, Croteau R (2003) A cDNA clone for 3-carene synthase from Salvia stenophylla. Phytochemistry 62:1081–1086 CrossRef
17.
Fäldt J, Martin D, Miller B, Rawat S, Bohlmann J (2003) Traumatic resin defense in Norway spruce (Picea abies): Methyl jasmonate-induced terpene synthase gene expression, and cDNA cloning and functional characterization of (+)-3-carene synthase. Plant Mol Biol 51:119–133 PubMedCrossRef
18.
Ushimaru R, Abe I (2022) Unusual dioxygen-dependent reactions catalyzed by nonheme iron enzymes in natural product biosynthesis. ACS Catal 13:1045–1076 CrossRef
19.
20.
Krebs C, Galonić Fujimori D, Walsh CT, Bollinger JM Jr (2007) Non-heme Fe(IV)–oxo intermediates. Acc Chem Res 40:484–492 PubMedCrossRef
21.
Wu L-F, Meng S, Tang G-L (2016) Ferrous iron and α-ketoglutarate-dependent dioxygenases in the biosynthesis of microbial natural products. Biochim Biophys Acta Proteins Proteom 1864:453–470 CrossRef
22.
Nakamura H, Matsuda Y, Abe I (2018) Unique chemistry of non-heme iron enzymes in fungal biosynthetic pathways. Nat Prod Rep 35:633–645 PubMedCrossRef
23.
Gao S-S, Naowarojna N, Cheng R, Liu X, Liu P (2018) Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses. Nat Prod Rep 35:792–837 PubMedPubMedCentralCrossRef
24.
Klinkenberg I, Blokland A (2010) The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 34:1307–1350 PubMedCrossRef
25.
Renner UD, Oertel R, Kirch W (2005) Pharmacokinetics and pharmacodynamics in clinical use of scopolamine. Ther Drug Monit 27:655–665 PubMedCrossRef
26.
27.
Huang J-P, Wang Y-J, Tian T, Wang L, Yan Y, Huang S-X (2021) Tropane alkaloid biosynthesis: a centennial review. Nat Prod Rep 38:1634–1658 PubMedCrossRef
28.
Fodor G, Romeike A, Janzso G, Koczor I (1959) Epoxidation experiments in vivo with dehydrohyoscyamine and related compounds. Tetrahedron Lett 1:19–23 CrossRef
29.
Hashimoto T, Yamada Y (1986) Hyoscyamine 6β-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, in alkaloid-producing root cultures. Plant Physiol 81:619–625 PubMedPubMedCentralCrossRef
30.
Hashimoto T, Yamada Y (1987) Purification and characterization of hyoscyamine 6β-hydroxylase from root cultures of Hyoscyamus niger L. Hydroxylase and epoxidase activities in the enzyme preparation. Euro J Biochem 164:277–285 CrossRef
31.
Hashimoto T, Kohno J, Yamada Y (1987) Epoxidation in vivo of hyoscyamine to scopolamine does not involve a dehydration step. Plant physiol 84:144–147 PubMedPubMedCentralCrossRef
32.
Hashimoto T, Kohno J, Yamada Y (1989) 6β-Hydroxyhyoscyamine epoxidase from cultured roots of Hyoscyamus niger. Phytochemistry 28:1077–1082 CrossRef
33.
Matsuda J, Okabe S, Hashimoto T, Yamada Y (1991) Molecular cloning of hyoscyamine 6 beta-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, from cultured roots of Hyoscyamus niger. J Biol Chem 266:9460–9464 PubMedCrossRef
34.
Hashimoto T, Matsuda J, Yamada Y (1993) Two-step epoxidation of hyoscyamine to scopolamine is catalyzed by bifunctional hyoscyamine 6β-hydroxylase. FEBS lett 329:35–39 PubMedCrossRef
35.
Li J, van Belkum MJ, Vederas JC (2012) Functional characterization of recombinant hyoscyamine 6β-hydroxylase from Atropa belladonna. Bioorg Med Chem 20:4356–4363 PubMedCrossRef
36.
Ushimaru R, Ruszczycky MW, Chang W-c, Yan F, Liu Y-n, Liu H-w (2018) Substrate conformation correlates with the outcome of hyoscyamine 6β-hydroxylase catalyzed oxidation reactions. J Am Chem Soc 140:7433–7436 PubMedPubMedCentralCrossRef
37.
Ushimaru R, Ruszczycky MW, Liu H-w (2018) Changes in regioselectivity of H atom abstraction during the hydroxylation and cyclization reactions catalyzed by hyoscyamine 6β-hydroxylase. J Am Chem Soc 141:1062–1066 PubMedPubMedCentralCrossRef
38.
Kluza A, Wojdyla Z, Mrugala B, Kurpiewska K, Porebski PJ, Niedzialkowska E, Minor W, Weiss MS, Borowski T (2020) Regioselectivity of hyoscyamine 6β-hydroxylase-catalysed hydroxylation as revealed by high-resolution structural information and QM/MM calculations. Dalton Trans 49:4454–4469 PubMedCentralCrossRef
39.
Gama SR, Stankovic T, Hupp K, Al Hejami A, McClean M, Evans A, Beauchemin D, Hammerschmidt F, Pallitsch K, Zechel DL (2022) Biosynthesis of the fungal organophosphonate fosfonochlorin involves an iron (II) and 2-(oxo) glutarate dependent oxacyclase. ChemBioChem 23:e202100352 CrossRef
40.
Liu P, Murakami K, Seki T, He X, Yeung S-M, Kuzuyama T, Seto H, Liu H-w (2001) Protein purification and function assignment of the epoxidase catalyzing the formation of fosfomycin. J Am Chem Soc 123:4619–4620 PubMedCrossRef
41.
Wang C, Chang W-c, Guo Y, Huang H, Peck SC, Pandelia ME, Lin G-m, Liu H-w, Krebs C, Bollinger JM Jr (2013) Evidence that the fosfomycin-producing epoxidase, HppE, is a non–heme-iron peroxidase. Science 342:991–995 PubMedPubMedCentralCrossRef
42.
Zhou S, Pan J, Davis KM, Schaperdoth I, Wang B, Boal AK, Krebs C, Bollinger JM Jr (2019) Steric enforcement of cis-epoxide formation in the radical C-O-coupling reaction by which ( S)-2-hydroxypropylphosphonate epoxidase (HppE) produces Fosfomycin. J Am Chem Soc 141:20397–20406 PubMedPubMedCentralCrossRef
43.
Clardy J, Springer JP, Buechi G, Matsuo K, Wightman R (1975) Tryptoquivaline and tryptoquivalone, two tremorgenic metabolites of Aspergillus clavatus. J Am Chem Soc 97:663–665 PubMedCrossRef
44.
Ariza MR, Larsen TO, Petersen BO, Duus JØ, Barrero AF (2002) Penicillium digitatum metabolites on synthetic media and citrus fruits. J Agric Food Chem 50:6361–6365 PubMedCrossRef
45.
Gao X, Haynes SW, Ames BD, Wang P, Vien LP, Walsh CT, Tang Y (2012) Cyclization of fungal nonribosomal peptides by a terminal condensation-like domain. Nat Chem Biol 8:823–830 PubMedPubMedCentralCrossRef
46.
Haynes SW, Ames BD, Gao X, Tang Y, Walsh CT (2011) Unraveling terminal C-domain-mediated condensation in fungal biosynthesis of imidazoindolone metabolites. Biochemistry 50:5668–5679 PubMedCrossRef
47.
Gao X, Chooi Y-H, Ames BD, Wang P, Walsh CT, Tang Y (2011) Fungal indole alkaloid biosynthesis: genetic and biochemical investigation of the tryptoquialanine pathway in Penicillium aethiopicum. J Am Chem Soc 133:2729–2741 PubMedPubMedCentralCrossRef
48.
Leitgeb B, Szekeres A, Manczinger L, Vagvolgyi C, Kredics L (2007) The history of alamethicin: a review of the most extensively studied peptaibol. Chem Biodivers 4:1027–1051 PubMedCrossRef
49.
50.
Fox RO Jr, Richards FM (1982) A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-Å resolution. Nature 300:325–330 PubMedCrossRef
51.
Rinehart KL Jr, Gaudioso LA, Moore ML, Pandey RC, Cook JC Jr, Barber M, Sedgwick RD, Bordoli RS, Tyler AN, Green BN (1981) Structures of eleven zervamicin and two emerimicin peptide antibiotics studied by fast atom bombardment mass spectrometry. J Am Chem Soc 103:6517–6520 CrossRef
52.
Karle IL, Flippen-Anderson J, Sukumar M, Balaram P (1987) Conformation of a 16-residue zervamicin IIA analog peptide containing three different structural features: 3 (10)-helix, alpha-helix, and beta-bend ribbon. Proc Natl Acad Sci USA 84:5087–5091 PubMedPubMedCentralCrossRef
53.
Rogozhin EA, Sadykova VS, Baranova AA, Vasilchenko AS, Lushpa VA, Mineev KS, Georgieva ML, Kul’ko AB, Krasheninnikov ME, Lyundup AV (2018) A novel lipopeptaibol emericellipsin A with antimicrobial and antitumor activity produced by the extremophilic fungus Emericellopsis alkalina. Molecules 23:2785 PubMedPubMedCentralCrossRef
54.
Bunno R, Awakawa T, Mori T, Abe I (2021) Aziridine formation by a Fe II/α-ketoglutarate dependent oxygenase and 2-aminoisobutyrate biosynthesis in fungi. Angew Chem Int Ed 60:15847–15831 CrossRef
55.
Tao H, Ushimaru R, Awakawa T, Mori T, Uchiyama M, Abe I (2022) Stereoselectivity and substrate specificity of the Fe (II)/α-ketoglutarate-dependent oxygenase TqaL. J Am Chem Soc 144:21512–21520 PubMedCrossRef
56.
Oh S-U, Lee S-J, Kim J-H, Yoo I-D (2000) Structural elucidation of new antibiotic peptides, atroviridins A, B and C from trichoderma atroviride. Tetrahedron Lett 41:61–64 CrossRef
57.
Abrahams JP, Buchanan SK, Van Raaij MJ, Fearnley IM, Leslie A, Walker JE (1996) The structure of bovine F1-ATPase complexed with the peptide antibiotic efrapeptin. Proc Natl Acad Sci USA 93:9420–9424 PubMedCentralCrossRef
58.
Cross RL, Kohlbrenner W (1978) The mode of inhibition of oxidative phosphorylation by efrapeptin (A23871). Evidence for an alternating site mechanism for ATP synthesis. J Biol Chem 253:4865–4873 PubMedCrossRef
59.
Cha L, Paris JC, Zanella B, Spletzer M, Yao A, Guo Y, Chang W-c (2023) Mechanistic studies of aziridine formation catalyzed by mononuclear non-heme iron enzymes. J Am Chem Soc 145:6240–6246 PubMedCrossRef
60.
Davis KA, Jones AM, Panaccione DG (2023) Two satellite gene clusters enhance ergot alkaloid biosynthesis capacity of Aspergillus leporis. Appl Environ Microbiol 89:e00793-e723 PubMedCrossRef
61.
Pařenicová L, Skouboe P, Frisvad J, Samson RA, Rossen L, Mt H-S, Visser J (2001) Combined molecular and biochemical approach identifies Aspergillus japonicus and Aspergillus aculeatus as two species. Appl Environ Microbiol 67:521–527 PubMedPubMedCentralCrossRef
62.
Stauffacher D, Niklaus P, Tscherter H, Weber H, Hofmann A (1969) Cycloclavin, ein neues alkaloid aus Ipomoea hildebrandtii vatke—71: Mutterkornalkaloide. Tetrahedron 25:5879–5887 PubMedCrossRef
63.
Incze M, Dörnyei G, Moldvai I, Temesvári-Major E, Egyed O, Szántay C (2008) New routes to clavine-type ergot alkaloids. Part 2: Synthesis of the last, so far not yet synthesized member of the clavine alkaloid family, (±)-cycloclavine. Tetrahedron 64:2924–2929 CrossRef
64.
Wallwey C, Li S-M (2011) Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat Prod Rep 28:496–510 PubMedCrossRef
65.
Jakubczyk D, Caputi L, Hatsch A, Nielsen CA, Diefenbacher M, Klein J, Molt A, Schröder H, Cheng JZ, Naesby M (2015) Discovery and reconstitution of the cycloclavine biosynthetic pathway—enzymatic formation of a cyclopropyl group. Angew Chem Int Ed 54:5117–5121 CrossRef
66.
Havemann J, Vogel D, Loll B, Keller U (2014) Cyclolization of d-lysergic acid alkaloid peptides. Chem Biol 21:146–155 PubMedCrossRef
67.
Robinson SL, Panaccione DG (2014) Heterologous expression of lysergic acid and novel ergot alkaloids in Aspergillus fumigatus. Appl Environ Microbiol 80:6465–6472 PubMedPubMedCentralCrossRef
68.
Jakubczyk D, Caputi L, Stevenson CE, Lawson DM, O’Connor SE (2016) Structural characterization of EasH ( Aspergillus japonicus)—an oxidase involved in cycloclavine biosynthesis. Chem Commun 52:14306–14309 CrossRef
69.
Yan L, Liu Y (2019) Insights into the mechanism and enantioselectivity in the biosynthesis of ergot alkaloid cycloclavine catalyzed by Aj_EasH from Aspergillus japonicus. Inorg Chem 58:13771–13781 PubMedCrossRef
70.
Asai A, Hasegawa A, Ochiai K, Yamashita Y, Mizukami T (2000) Belactosin A, a novel antituor antibiotic acting on cyclin/CDK mediated cell cycle regulation, produced by Streptomyces sp. J Antibiot 53:81–83 CrossRef
71.
Groll M, Larionov OV, Huber R, de Meijere A (2006) Inhibitor-binding mode of homobelactosin C to proteasomes: new insights into class I MHC ligand generation. Proc Natl Acad Sci USA 103:4576–4579 PubMedPubMedCentralCrossRef
72.
Kaysser L (2019) Built to bind: biosynthetic strategies for the formation of small-molecule protease inhibitors. Nat Prod Rep 36:1654–1686 PubMedCrossRef
73.
Omura S, Mamada H, Wang N-J, Imamura N, Oiwa R, Iwai Y, Muto N (1984) Takaokamycin, a new peptide antibiotic produced by Streptomyces sp. J Antibiot 37:700–705 CrossRef
74.
Andres N, Wolf H, Zähner H, Rössner E, Zeeck A, König WA, Sinnwell V (1989) Stoffwechselprodukte von Mikroorganismen. 253. Mitteilung. Hormaomycin, ein neues Peptid-lacton mit morphogener Aktivität auf Streptomyceten. Helv Chim Acta 72:426–437 CrossRef
75.
Rössner E, Zeeck A, König WA (1990) Elucidation of the structure of hormaomycin. Angew Chem Int Ed 29:64–65 CrossRef
76.
Zlatopolskiy BD, Loscha K, Alvermann P, Kozhushkov SI, Nikolaev SV, Zeeck A, de Meijere A (2004) Final elucidation of the absolute configuration of the signal metabolite hormaomycin. Chem Eur J 10:4708–4717 PubMedCrossRef
77.
Brandl M, Kozhushkov SI, Zlatopolskiy BD, Alvermann P, Geers B, Zeeck A, de Meijere A (2005) The biosynthesis of 3‐( trans‐2‐nitrocyclopropyl) alanine, a constituent of the signal metabolite hormaomycin. Eur J Org Chem 123–135
78.
Kozhushkov SI, Zlatopolskiy BD, Brandl M, Alvermann P, Radzom M, Geers B, de Meijere A, Zeeck A (2005) Hormaomycin analogues by precursor‐directed biosynthesis–synthesis of and feeding experiments with amino acids related to the unique 3-( trans‐2‐nitrocyclopropyl) alanine constituent. Eur J Org Chem 854–863
79.
Wolf F, Bauer JS, Bendel TM, Kulik A, Kalinowski J, Gross H, Kaysser L (2017) Biosynthesis of the β-lactone proteasome inhibitors belactosin and cystargolide. Angew Chem Int Ed 56:6665–6668 CrossRef
80.
Höfer I, Crüsemann M, Radzom M, Geers B, Flachshaar D, Cai X, Zeeck A, Piel J (2011) Insights into the biosynthesis of hormaomycin, an exceptionally complex bacterial signaling metabolite. Chem Biol 18:381–391 PubMedCrossRef
81.
Shimo S, Ushimaru R, Engelbrecht A, Harada M, Miyamoto K, Kulik A, Uchiyama M, Kaysser L, Abe I (2021) Stereodivergent nitrocyclopropane formation during biosynthesis of belactosins and hormaomycins. J Am Chem Soc 143:18413–18418 PubMedCrossRef
82.
Li X, Shimaya R, Dairi T, Wc C, Ogasawara Y (2022) Identification of cyclopropane formation in the biosyntheses of hormaomycins and belactosins: sequential nitration and cyclopropanation by metalloenzymes. Angew Chem Int Ed 61:e202113189 CrossRef
83.
Pang L, Niu W, Duan Y, Huo L, Li A, Wu J, Zhang Y, Bian X, Zhong G (2022) In vitro characterization of a nitro-forming oxygenase involved in 3-( trans-2′-aminocyclopropyl)alanine biosynthesis. Eng Microbiol 2:100007 CrossRef
84.
Engelbrecht A, Wolf F, Esch A, Kulik A, Kozhushkov SI, de Meijere A, Hughes CC, Kaysser L (2022) Discovery of a cryptic nitro intermediate in the biosynthesis of the 3-( trans-2′-aminocyclopropyl) alanine moiety of belactosin A. Org Lett 24:736–740 PubMedCrossRef
85.
86.
Yan D, Matsuda Y (2022) Biosynthetic elucidation and structural revision of brevione E: characterization of the key dioxygenase for pathway branching from setosusin biosynthesis. Angew Chem Int Ed 61:e202210938 CrossRef
87.
Macias FA, Varela RM, Simonet AM, Cutler HG, Cutler SJ, Dugan FM, Hill RA (2000) Novel bioactive breviane spiroditerpenoids from Penicillium brevicompactum Dierckx. J Org Chem 65:9039–9046 PubMedCrossRef
88.
Wei X, Matsuyama T, Sato H, Yan D, Chan PM, Miyamoto K, Uchiyama M, Matsuda Y (2021) Molecular and computational bases for spirofuranone formation in setosusin biosynthesis. J Am Chem Soc 143:17708–17715 PubMedCrossRef
Metadata
Title
Three-membered ring formation catalyzed by α-ketoglutarate-dependent nonheme iron enzymes
Author
Richiro Ushimaru
Publication date
19-11-2023
Publisher
Springer Nature Singapore
Published in
Journal of Natural Medicines
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI
https://doi.org/10.1007/s11418-023-01760-4