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Department of Chemistry College of Liberal Arts and Sciences

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University of Florida

Reaction scheme showing the chemical structures of variediene and phomopsene with an arrow labeled "PsVSF86L" indicating that that mutation changes the function of the terpene synthase.

75. Wei, X.; Ning, W.; Huang, P.-S.; Nafie, J.; Ghiviriga, I.;Rudolf, J. D.* Sequence-guided engineering of a bacterial diterpene synthase induces further cyclization. ACS. Catal. 2026, doi: 10.1021/acscatal.6c04391.

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74. Ning, W.; Kong, W.-Y.; Li, Z.; Wei, X.; Nafie, J.; Xu, B.; Cavassa, F. G.; Huang, P.-S.; Tantillo, D. J.; Rudolf, J. D.* Biosynthetic formation of the 6/7/5-odyverdiene diterpenes via a 6/10-trans-eunicellanyl intermediate. ACS. Catal. 2026, 16, 7572–7581.

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73. Ahmed, M. M. A.; Nafie, J.; Rudolf, J. D.* A single residue switch controls isomer selectivity in the myxobacterial isobonnadiene synthase. Org. Lett. 2026, 28, 2342–2436.

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72. Alsup, T. A.; Łomowska-Keehner, D. P.; Osei Opoku, M.; Li, Z.; McCadden, C. A.; Qu, T.;  Gillia, G. R.; Nafie, J.; Rudolf, J. D.* Discovery of UbiA-type cyathane synthases in bacteria. ACS Catal. 2025, 15, 16873–16881.

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Chemical reaction diagram titled "bacterial tridomain bifunctional diterpene synthase" shows the enzyme bAbS (γβα) catalyzing the conversion of GGPP to syn-CPP (OPP) and then to syn-abieta-7,13-diene, set against a background of the enzyme's protein structure.

71. McCadden, C. A.; Łomowska-Keehner, D. P.; Qu, T.;  Nafie, J.; Alsup, T. A.; Rudolf, J. D.* Discovery of a plant-like tridomain bifunctional syn-abieta-7,13-diene synthase in Streptomyces. Org. Biomol. Chem. 2025, 23, 9845–9850.

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A chemical scheme showing geranylgeranyl diphosphate as a substrate. The enzyme AriE (PDB ID: 9LPB), depicted as a protein structure, converts it to (2E)-cis-6/10-fused benditerpe-2,6,15-triene, while the mutant AriE^W73A converts it to isocembrene C.

70. Li, F.-R.; Yang, Q.; He, J.; Sun, X.; Pan, X.; Xu, H.-M.; Rudolf, J. D.; Dong, L.-B.*  Structural insights into the catalytic mechanism of cis-eunicellane cyclase AriE. Chem. Eur. J. 2025, 31, e202500012.

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Chemical mechanism depicting Myxobacterial terpene synthase (TiqS) converting GGPP to a tetraisohinane skeleton via deprotonation/reprotonation and a non-classical carbocation. An F81L mutation leads to a mutation-induced bifurcation product.

69. Wei, X.; DeSnoo, W.; Li, Z.; Ning, W.; Kong, W.-Y.; Nafie, J.; Tantillo, D. J.;* Rudolf, J. D.*  Avoidance of secondary carbocations, unusual deprotonation, and non-statistical dynamic effects in the cyclization mechanism of the 5/5/5/5-tetracyclic tetraisoquinane skeleton. J. Am. Chem. Soc. 2025, 147, 16293–16300.

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Pie chart titled "TS Library (diterpene active/total number)" showing diterpene activity across bacterial phyla, a bar chart comparing diterpene counts from literature and this study for selected phyla, and two diterpene chemical structures.

68. Wei, X.; Ning, W.; McCadden, C.; Alsup, T. A.; Li, Z.; Łomowska-Keehner, D. P.; Nafie, J.; Qu, T.; Osei Opoku, M.; Gillia, G. R.; Xu, B.; Icenhour, D. G.; Rudolf, J. D.*  Exploring and expanding the natural chemical space of bacterial diterpenes. Nat. Commun. 2025, 16, 3721.

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Workflow illustrating genome mining using tools like MIBiG, antiSMASH, UniProt, EFI-GNT, and NCBI to identify novel terpene synthases (TSs) or biosynthetic gene clusters (BGCs), which ultimately leads to the discovery of new terpene skeletons or terpenoids.

67. Ning, W.; Rudolf, J. D.* Discovery of bacterial terpenoids by genome mining. Meth. Enzymol. 2025, 717, pp 349–385.

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Graphical abstract showing the biotransformation of a tetracyclic compound by Streptomyces, as indicated by the text "Biotransformation in Streptomyces" and images of microbial cultures. The starting material is on the left, leading to three different product structures with modifications on the right.

66. McCadden, C. A.; Alsup, T. A.; Ghiviriga, I.; Rudolf, J. D.* Biocatalytic diversification of abietic acid in Streptomyces. J. Ind. Microbiol. Biotechnol. 2025, 52, kuaf003.

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Biosynthetic pathway for atolypenes, showing the enzymatic conversion of GFPP through epoxidation (AtoF), prenylation (AtoD), transamination (AtoB), cyclization (AtoE with Glu314), and oxidation steps to form Atolypene E and Atolypene A.

65. Wang, Z.; Alsup, T. A.; Pan, X.; Li, L.; Tian, J.; Yang, Z.; Lin, X.; Xu, H.-M.; Rudolf, J. D.; Dong, L.-B.* Biosynthesis of a bacterial meroterpenoid reveals a non-canonical class II meroterpenoid cyclase. Chem. Sci. 2025, 16, 310–317.

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Radial phylogenetic tree illustrating evolutionary relationships between Acariformes (magenta), Collembola (green), Bacteria (blue), and Fungi (light blue), with specific clades S1 and S2 marked.

64. Chen, X.; Urban, J. M.; Wurlitzer, J.; Wei, X.; Han, J.; O’Connor, S. E.; Rudolf, J. D.; Köllner, T. G.; Chen, F. Canonical terpene synthases in arthropods: Intraphylum gene transfer. Proc. Natl. Acad. Sci. 2024, 121, e2413007121.

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Experiment for *A. alliaceus* showing fungal cultures grown in No Salt, Instant Ocean®, NaBr, and NaI media, with a PCA plot displaying metabolic profiles and structures of the resulting brominated anthraquinone natural products.

63. Mandelare, P. E.; Tee, S. S.; Icenhour, D. G.; Kaweesa, E. N.; McCauley, M.; Risinger, A. L.; Rudolf, J. D.; Loesgen, S.* Chemical diversity of Aspergillus alliaceus phenotypes: discovery of brominated bianthrones with activity against triple-negative breast cancer cell lines. ChemBioChem. 2024, 25, e202400398.

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A network diagram displays six distinct complex chemical structures alongside pathways of researcher names, including Rudolf, Skellam, Parkinson, Tao, and Caranto, likely representing research collaborations or synthetic routes.

62. Rudolf, J. D.*; Barra, L.;* Awakawa, T.* Young investigators in natural products chemistry, biosynthesis, and enzymology. Beilstein J. Org. Chem. 2024, 20, 2720–2721. Special Issue Editorial.

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Chemical reaction scheme illustrating the Cope rearrangement of atropisomeric Cope products to the eunicellane skeleton, followed by C6 electrophilic addition and C2-C7 cyclization to form the gersemiane skeleton.

61. Li, Z.; Jindani, S.; Kojasoy, V.; Ortega, T.; Marshall, E.; Aboudd, K. A.; Loesgen, S.; Tantillo, D.;* Rudolf, J. D.* Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis eunicellanes. Beilstein J. Org. Chem. 2024, 20, 1320–1326.

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Diagram showing the heterologous expression of *pla* genes in *Streptomyces*, detailing *plaT4* (GGPP synthase), *plaT3* (UbiA prenyltransferase), *plaT2* (Type II terpene synthase), and *plaT1* (Flavin-dependent monooxygenase) in the fungal meroterpenoid-like scaffold assembly from GGPP.

60. Alsup, T. A.; Li, Z.; McCadden, C.; Jagels, A.; Łomowska-Keehner, D. P.; Marshall, E. M.; Dong, L.-B.; Loesgen, S.; Rudolf, J. D.* Early-stage biosynthesis of phenalinolactone diterpenoids involves sequential prenylation, epoxidation, and cyclization. RSC Chem. Biol. 2024, 5, 1010–1016.

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A cycle diagram illustrating how bacteria produce a compound via CorA (NRPS-PKS) that leads to increased extracellular matrix and cellular aggregation, while also inhibiting CorB (protease) which causes extracellular matrix degradation.

59. Rudolf, J. D.*; Loesgen, S.* Pyrazinone biosynthesis and signaling – myxostyle. ACS Cent. Sci. 2024, 10, 511–513. Invited First Reaction.

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Book cover for "Methods in Enzymology, Volume 699: Terpene Synthases," edited by Jeffrey D. Rudolf.

58. Rudolf, J. D.* Preface to Terpene Synthases. Meth. Enzymol. 2024, 699, xxi–xxiii.

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Diagram illustrating the biosynthesis of lydicene from isoprenol, showing the conversion to IPP, DMAPP, and GGPP via enzymes ThiM, IPK, IDI, and GGPPS, followed by conversion to lydicene by StlTC, all within a cellular environment.

57. Alsup, T. A.; Osei Opoku, M.; Rudolf, J. D.* Characterization of UbiA terpene synthases with a precursor overproduction system in Escherichia coli. Meth. Enzymol. 2024, 699, 395–417.

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Graphical abstract featuring a central protein complex labeled 'β' and 'γ' next to the text 'Class II TCs', encircled by various chemical structures, many with a common polycyclic core highlighted in red.

55. Pan, X.; Rudolf, J. D.;* Dong, L.-B.* Class II terpene cyclases: structures, mechanisms, and engineering. Nat. Prod. Rep. 2024, 41, 402–433.

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The *Streptomyces albireticuli* alb gene cluster (albG-albP2) is depicted, along with a biosynthetic pathway showing sequential enzymatic transformations. AlbU catalyzes eunicellane isomerization, AlbP1 performs an innate P450 reaction, and AlbP2* performs a restored P450 reaction followed by oxy-Cope and reduction.

54. Li, Z.; Xu, B.; Alsup, T. A.; Wei, X.; Ning, W.; Icenhour, D. G.; Ehrenberger, M. A.; Ghiviriga, I.; Giang, B.-D.; Rudolf, J. D.* Cryptic isomerization in diterpene biosynthesis and the restoration of an evolutionarily defunct P450. J. Am. Chem. Soc. 2023, 145, 22361–22365.

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Diagram of the ari gene cluster and the Aridacins biosynthetic pathway, showing the conversion of GGPP via enzymes AriA-C, AriE (Class I TC), and AriF (P450) through Benditerpe-2,6,15-triene and Arida-3,6,15-triene intermediates.

53. Wang, Z.; Yang, Q.; He, J.; Li, H.; Pan, X.; Li, Z.; Xu, H.-M.; Rudolf, J. D.; Tantillo, D. J.*; Dong, L.-B.* Cytochrome P450-mediated cyclization in eunicellane-derived diterpenoid biosynthesis. Angew. Chem. Int. Ed. 2023, 62, e202312490.

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A biochemical pathway diagram illustrates how the precursor GGPP is converted by coral enzymes (BaTC-2 or EcTPS1) into polycyclic natural products, and by bacterial enzymes (AlbS or Bnd4) into different bicyclic and polycyclic structures.

52. Li, Z.; Rudolf, J. D.* Biosynthesis, enzymology, and future of eunicellane diterpenoids. J. Ind. Microbiol. Biotechnol. 2023, 50, kuad027.

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Diagram showing the enzyme AlbS (diterpene synthase) forming two products. Albireticule is shown with "Mechanism via" indicated, and prenylgermacrene A is associated with "Mutagenesis Labeling DFT Calculations".

51. Li, Z.; Xu, B.; Kojasoy, V.; Ortega, T.; Adpressa, D.; Ning, W.; Wei, X.; Liu, J.; Tantillo, D. J.; Loesgen, S.; Rudolf, J. D.* First trans-eunicellane terpene synthase in bacteria. Chem 2023, 9, 698–708.

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Diagram illustrating the enzyme SsDMS, a βγ-didomain protein composed of β and γ domains, catalyzing the conversion of Farnesyl diphosphate to Drimenyl diphosphate. The enzyme features an Mg2+ binding site.

50. Pan, X.; Du, W.; Zhang, X.; Lin, X.; Li, F.-R.; Yang, Q.; Wang, H.; Rudolf, J. D.;* Zhang, B.;* Dong, L.-B.* Discovery, structure, and mechanism of a class II sesquiterpene cyclase. J. Am. Chem. Soc. 2022, 144, 22067–22074.

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49. Stowell, E. A.; Ehrenberger, M. E.; Lin, Y.-L.; Chang, C.-Y.;* Rudolf, J. D.* Structure-guided product determination of the bacterial type II diterpene synthase Tpn2. Commun. Chem. 2022, 5, 146.

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Diagram illustrating how the bacterial terpene synthase Bnd4 produces a specific chemical structure, and how enzyme mutations (Bnd4 W316A, Bnd4 Y197A, CotB2 W186A) result in an "Altered Product Profile" or products "Engineered for C15 Prenylation.

48. Xu, B.; Ning, W.; Wei, X.; Rudolf, J. D.* Mutation of the eunicellane synthase Bnd4 alters its product profile and expands its prenylation ability. Org. Biomol. Chem. 2022, 20, 8833–8837.

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Biochemical pathway illustrating the conversion of L-Arginine (L-Arg) to L-Cap by CmnC and CmnD, which is then processed by CmnG-A and NRPS machinery into CMN, alongside a structural view of an enzyme binding L-Cap.

47. Chen, I.-H.; Cheng, T.; Wang, Y.-L.; Huang, S.-J.; Hsiao, Y.-H.; Lai, Y.-T.; Rudolf, J. D.; Chang, C.-Y.* Characterization and structural determination of CmnG-A, the adenylation domain that activates the nonproteinogenic amino acid capreomycidine in capreomycin biosynthesis. ChemBioChem 2022, 23, e202200563.

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Journal cover for "DATABASE: The Journal of Biological Databases and Curation," with a network graph design on a blue background.

46. de Crecy-Lagard, V.;* […] Rudolf, J. D.; […] (58 total authors). A roadmap for the functional annotation of protein families: a community perspective. Database 2022, baac062.

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Diagram illustrating human bleomycin hydrolase (hBH) and its "conversion" between "Cysteine protease" (Cys, His) and "Serine protease" (Ser, His) functions. The chemical structure of "BLMs" is shown with scissors indicating the enzymatic cleavage site.

45. Zheng, Y.-Z.; Cui, J.; Wang, Y.-L.; Huang, S.-J.; Lin, E.-C.; Huang, S.-C.; Rudolf, J. D.; Yan, X.; Chang, C.-Y.* The structure-function relationship of human bleomycin hydrolase: mutation of a cysteine protease into a serine protease. ChemBioChem 2022, 23, e202200186.

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Logo for npatlas, displaying three spheres wrapped in blue, white, and orange bands.

44. van Santen, J. A.; Poynton, E. F.; Iskakova, D.; McMann, E.; Alsup, T. A.; Clark, T. N.; Fergusson, C. H.; Fewer, D. P.; Hughes, A. H.; McCadden, C. A.; Parra, J.; Soldatou, S.; Rudolf, J. D.; Janssen, E. M-L.; Duncan, K. R.; Linington, R. G.* The Natural Products Atlas 2.0: a database of microbially-derived natural products. Nucl. Acids Res. 2022, 50, D1317–D1323.

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Diagram illustrating the dual catalytic activity of bacterial diterpene synthase Bnd4 (D94NxxxD, E169), showing the formation of FPP-derived products and the proposed mechanism for eunicellane skeleton biosynthesis from GGPP via 1,10-ring closure, 1,3-hydride shift, 1,14-ring closure, and deprotonation.

43. Xu, B.; Tantillo, D. J.; Rudolf, J. D.* Mechanistic insights into the formation of the 6,10-bicyclic eunicellane skeleton by the bacterial diterpene synthase Bnd4. Angew. Chem. Int. Ed. 2021, 60, 23159–23163.

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Diagram showing a Bacterial Diterpene Synthase catalyzing two reactions: "Cyclization of Native Substrate" (GGPP to Diterpenes) and "Prenylation via Substrate 'Decoy'" (Shorter R-PP & Nucleophile to Prenylated products).

42. Xu, B.; Li, Z.; Alsup, T. A.; Ehrenberger, M. A.; Rudolf, J. D.* Bacterial diterpene synthases prenylate small molecules. ACS Catal. 2021, 11, 5906–5915.

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Biosynthetic pathway of benditerpenoic acid from Streptomyces sp. (CL12-4), showing the bnd gene cluster and the conversion of GGPP to benditerpe-2,6,15-triene by Bnd4, and then to benditerpenoic acid by P450s.

41. Zhu, C.; Xu, B.; Address, D. A.; Rudolf, J. D.;* Loesgen, S.* Discovery and biosynthesis of a structurally dynamic antibacterial diterpenoid. Angew. Chem. Int. Ed. 2021, 60, 14163–14170.

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Eight petri dishes show different microbial cultures, each featuring an overlaid chemical structure, illustrating various natural products from microorganisms.

40. Rudolf, J. D.;* Alsup, T. A.; Xu, B.; Li, Z. Bacterial terpenome. Nat. Prod. Rep. 2021, 38, 905–980.

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Diagram illustrating canonical terpene synthases (type I, type II) and non-canonical terpene synthases (cis-PT, MT, P450, VHPO), showing associated chemical structures and protein models (NEPS, Stig, FMO, 'large' TS).

38. Rudolf, J. D.;* Chang, C.-Y. Terpene synthases in disguise: enzymology, structure, and opportunities of non-canonical terpene synthases. Nat. Prod. Rep. 2020, 37, 425–463.

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Scripps Florida – Postdoc

Bar chart displaying average titers (mg L⁻¹) for S. p. strains SB12051, SB12053, and SB12052 across conditions PTM, PTN, PTL, PTM-MS, PTM-SS, and PTMM, with accompanying petri dish images illustrating bacterial growth of each strain.

56. Fluegel, L. L.; Deng, M.-R.; Su, P.; Kalkreuter, E.; Yang, D.; Rudolf, J. D.; Dong, L.-B.; Shen, B.* Development of platensimycin, platencin, and platensilin overproducers by biosynthetic pathway engineering and fermentation medium optimization. J. Ind. Microbiol. Biotechnology. 2024, 51, kuae003.

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Reaction scheme illustrating the synthesis of natural products fischericin B (2), rosthornin B (3), mitrephorone A (7), and mitrephorone C (8). The synthesis involves an oxidative approach using both chemical and enzymatic methods, alongside skeletal reorganization via carbocationic intermediates.

39. Zhang, X.; King-Smith, E.; Dong, L.-B.; Yang, L.-C.; Rudolf, J. D.; Shen, B.; Renata, H.* Divergent synthesis of complex diterpenes through a hybrid oxidative approach. Science 2020, 369, 799–806.

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Chemical reaction scheme and protein structure showing PtmU3, A TIM-barrel fold diiron monooxygenase, catalyzing the Fe2+ and O2-dependent hydroxylation of two complex organic substrates, followed by retro-aldol cleavage to form keto-CoA products.

37. Dong, L.-B.; Liu, Y.-C.; Cepeda, A.; Kalkreuter, E.; Deng, M.-R.; Rudolf, J. D.; Chang, C.; Joachimiak, A.; Phillips Jr., G. N.;  Shen, B.* Characterization and crystal structure of a nonheme diiron monooxygenase involved in platensimycin and platencin biosynthesis. J. Am. Chem. Soc. 2019, 141, 12406–12412.

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Chemical structures illustrate PTM-2t undergoing β-elimination to form Platensimycin (PTM). PTM-2t shows improved pharmacokinetics and inhibits MRSA in a mouse peritonitis model, while PTM inhibits MRSA in a mouse wound burn model.

36. Su, M.; Qiu, L.; Deng, Y.; Ruiz, C. H.; Rudolf, J. D.; Dong, L.-B.; Feng, X.; Cameron, M. D.; Shen, B.; Duan, Y.; Huang, Y.* Evaluation of platensimycin and platensimycin-inspired thioether analogues against methicillin-resistant Staphylococcus aureus in topical and systemic infection mouse models. Mol. Pharm. 2019, 16, 3065–3071.

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Diagram showing the ptm gene cluster with PTM cassette genes O1-O8, illustrating the biosynthesis of Platensimycin and Platencin. The pathway converts ent-Kauranol and ent-Atiserene scaffolds via intermediates, catalyzed by PtmO3, PtmO6, PtmO8, and PtmO1 enzymes.

35. Dong, L.-B.; Zhang, X.; Rudolf, J. D.; Deng, M.-R.; Kalkreuter, E.; Cepeda, A. J.; Renata, H.; Shen, B.* Cryptic and stereospecific hydroxylation, oxidation, and reduction in platensimycin and platencin biosynthesis. J. Am. Chem. Soc. 2019, 141, 4043–4050.

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Reaction scheme showing PtmO5-catalyzed hydroxylation (HO) of a precursor, followed by acid (H+)-catalyzed dehydration (H2O) to form an epoxide (between C11 and C16), ultimately leading to platensimycin.

34. Rudolf, J. D.; Dong, L.-B.; Zhang, X.; Renata, H.; Shen, B.* Cytochrome P450-catalyzed hydroxylation initiating ether formation in platensimycin biosynthesis. J. Am. Chem. Soc. 2018, 140, 12349–12353.

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Molecular illustration of the TtnD enzyme with its prenylated FMN cofactor and the reaction it catalyzes: decarboxylation of TTN D-1 (an R-substituted acrylic acid) to form TTN I-1 (an R-substituted alkene) and CO2, with R defined as a complex polyketide structure.

33. Annaval, T.; Han, L.; Rudolf, J. D.; Xie G.; Yang, D.; Chang, C.-Y.; Ma, M.; Crnovcic, I.; Miller, M. D.; Soman, J.; Xu, W.; Phillips Jr., G. N.; Shen, B.* Biochemical and structural characterization of TtnD, a prenylated FMN-dependent decarboxylase from the tautomycetin biosynthetic pathway. ACS Chem. Biol. 2018, 13, 2728–2738.

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Chemical reaction scheme illustrating the enzymatic conversion of LNM E1 to LNM, catalyzed by LnmA, LnmZ, and other enzymes, featuring hydroxylation at C8 and formation of a 4'-hydroxy-dithiolactone ring.

32. Kwong, T.; Ma, M.; Pan, G.; Hindra; Yang, D.; Lohman, J. R..; Rudolf, J. D.; Cleveland, J. L.; Shen, B.* P450-catalyzed tailoring steps in leinamycin biosynthesis featuring regio- and stereoselectivity hydroxylations and substrate promiscuities. Biochemistry 2018, 57, 5005–5013.

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A molecular graphic shows a green protein binding two purple and orange enediyne molecules. The caption reads: "TnmS1, TnmS2, and TnmS3 confer enediyne resistance by sequestration.

31. Chang, C.-Y.; Yan, X.; Crnovcic, I.; Annaval, T.; Chang, C.; Nocek, B.; Rudolf, J. D.; Yang, D.; Hindra; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.;  Shen, B.* Resistance to enediyne antitumor antibiotics by sequestration. Cell Chem. Biol. 2018, 25, 1075–1085.

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Diagram of a biosynthetic pathway showing Atypical Bacterial Diterpene Synthases converting Oxo-GGPP into 66 Gene Clusters, which then yield Unknowns, Diterpenes (TNLs/PLAs/BRAs) with a tricyclic structure, and Tetraterpenes (LON).

30. Dong, L.-B.; Rudolf, J. D.; Deng, M.-R.; Yan, Y.;  Shen, B.* Discovery of the tiancilactone antibiotics by genome mining of atypical bacterial type II diterpene synthases. ChemBioChem 2018, 19, 1727–1733.

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Biosynthesis pathway for thioPTM (1), thioPTN (2), PTM (3), and PTN (4). It illustrates the formation of ADHBHS (5-SH) from PtmS2-GGMV, ASA, and DHAP, and its subsequent condensation with Platensicyl-CoA or Platencinyl-CoA derived from diterpenoid precursors.

29. Dong, L.-B.; Rudolf, J. D.; Kang, D.; Wang, N.;  He, C. Q.; Deng, Y.; Huang, Y.; Houk, K. N.; Duan, Y.; Shen, B.* Biosynthesis of thiocarboxylic acid-containing natural products. Nat. Commun. 2018, 9, 2362.

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A two-step enzymatic pathway is shown, with adenylation (PtmA2 A497K) of CO2H to CO-AMP, then thioesterification (PtmA2) to CO-SCoA, next to a 3D ribbon diagram of the multi-domain PtmA2 protein.

28. Wang, N.; Rudolf, J. D.; Dong, L.-B.; Osipiuk, J.; Hatzos-Skintges, C.; Endres, M.; Chang, C.-Y.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.;  Shen, B.* Natural separation of the acyl-CoA ligase reaction results in a non-adenylating enzyme. Nat. Chem. Biol. 2018, 14, 730–737.

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Diagram depicting the SgcC5-catalyzed biosynthesis of the C-1027 chromophore from a donor substrate (linked to SgcC2) and an enediyne acceptor substrate.

27. Chang, C.-Y.; Lohman, J. R.; Huang T.; Michalska, K.; Bigelow, L.; Rudolf, J. D.; Jedrzejczak, R.; Yan, Y.; Ma, M.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.;  Shen, B.* Structural insights into the free-standing condensation enzyme SgcC5 catalyzing ester-bond formation in the biosynthesis of the enediyne antitumor antibiotic C-1027. Biochemistry 2018, 57, 3278–3288.

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A reaction scheme showing SgcE and SgcE10 (represented by a protein structure) catalyzing the conversion of Acetyl-SCoA and 7x Malonyl-SCoA into an ACP-bound intermediate, which is then transformed into a polyene (depicted as a chain with 6 double bonds) and CO2 + H2O.

26. Annaval, T.; Rudolf, J. D.; Chang, C.-Y.; Lohman, J. R.; Kim, Y.; Bigelow, L.; Jedrzejczak, R.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.;  Shen, B.* Crystal structure of the thioesterase SgcE10 supporting common polyene intermediates in 9- and 10-membered enediyne core biosynthesis. ACS Omega. 2017, 2, 5159–5169.

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A sequence logo featuring "HLFG G HCL" followed by arrows pointing to a rainbow-colored protein ribbon structure with a bound ligand, which then points to three complex chemical structures. This illustrates a scientific process, likely a biosynthetic pathway or enzymatic mechanism.

25. Rudolf, J. D.; Chang, C.-Y.; Ma, M.; Shen, B.* Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function. Nat. Prod. Rep. 2017, 34, 1141–1172.

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Complex chemical structures are overlaid on various fungi and molds, illustrating the connection between natural organisms and derived chemical compounds.

24. Rudolf, J. D.; Crnovcic, I.; Shen, B.* The role of combinatorial biosynthesis in natural products discovery. In Chemical Biology of Natural Products. Newman, D.J.; Cragg, G.M.; Grothaus, P.G.; Eds. 2017, pp. 87–125.

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Line graph showing the Zone Diameter (mm) over 3 days for PM7 control, PM7+aspartic acid, and PM7+glycine, indicating PM7+aspartic acid produces the largest zone.

23. Falzone, M.; Crespo, E.; Jones, K.; Khan, G.; Korn, V.; Patel, A.; Patel, M.; Patel, K.; Perkins, C.; Siddiqui, S.; Stenger, A.; Yu, E.; Gelber, M.; Scheffler, R.; Nayda, V.; Ravin, A.; Komal, R.; Rudolf, J. D.; Shen, B.; Gullo, V.; Demain, A.* Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of L-aspartic acid. J. Antibiot. 2017, 70, 828–831.

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The image displays the chemical structures of Platensimycin and Platenicin in the center, encircled by illustrations and labels for "Chemistry," "Biology," "Enzymology," and "Medicine," indicating the interdisciplinary study of these compounds.

22. Rudolf, J. D.; Dong, L.-B.; Shen, B.* Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine. Biochem. Pharm. 2017, 133, 139–151.

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Chemical structures of germicidin A (1), germicidin C (2), germicidin D (3), germicidin H (4), germicidin I (5), and germicidin J (6), showing variations in their alkyl side chains.

21. Ma, M.; Rateb, M. E.; Yang, D.; Rudolf, J. D.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Duan, Y.; Shen, B.* Germicidins H–J from Streptomyces sp. CB00361. J. Antibiotic. 2017, 70, 200–203.

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Chemical structures of PTM illustrating 3 sites of metabolic liabilities (glucuronidation, hydrolysis, oxidation), alongside analogues 6, 7, and 8 with improved hydrolytic stability, showing modifications at the X and R groups.

20. Dong, L.-B.; Rudolf, J. D.; Lin, L.; Ruiz, C.; Cameron, M .D.; Shen, B.* In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin. Bioorg. Med. Chem. 2017, 25, 1990–1996.

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A gene cluster diagram of the "Platensimycin Cassette" shows ORFs including T3 and O5. Below, a biosynthetic pathway illustrates the conversion of ent-CPP by PtmT3 to an alcohol, followed by PtmO5 to a polycyclic ether carboxylic acid, linking gene functions to chemical transformations.

19. Rudolf, J. D.; Dong, L.-B.; Manoogian, K.; Shen, B.* Biosynthetic origin of the ether ring in platensimycin. J. Am. Chem. Soc. 2016, 138, 16711–16721.

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Chemical structures of TNM A, TNM C, and UCM, with carbon numbering shown for TNM A and TNM C.

18. Yan, X.; Ge, H.; Huang, T.; Hindra; Yang, D.; Teng, Q.; Crnovcic, I.; Li, X.; Rudolf, J. D.; Lohman, J. R.; Gansemans, Y.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Van Nieuwerburgh, F.; Rader, C.; Duan, Y.; Shen, B.* Strain prioritization and genome mining for enediyne natural products. mBio 2016, 7, e02104-16.

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Reaction scheme illustrating the enzymatic synthesis of a library of PTM and PTN analogues. An acyl-CoA (CoAS-C(=O)R), where R is one of two bicyclic structures (one with an ether, one with an exocyclic alkene), reacts with X-C6H4-YH (Y = NH or O) catalyzed by S. platensis SB12032 (ΔptmR1/ΔptmB1) to yield X-C6H4-Y-C(=O)R.

17. Dong, L.-B.; Rudolf, J. D.; Shen, B.*  A mutasynthetic library of platensimycin and platencin analogues. Org. Lett. 2016, 18, 4606–4609.

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Enzymatic hydroxylation scheme: SgcC and SgcE6 catalyze the conversion of a SgcC2-bound chlorinated substrate and O2 to a dihydroxylated product and H2O, with FADH2/FAD and NADH + H+/NAD+ redox cycles.

16. Chang, C.-Y.; Lohman, J. R.; Cao, H.; Tan, K.; Rudolf, J. D.; Ma, M.; Xu, W.; Bingman, C. A.; Yennamalli, R. M.; Bigelow, L.; Babnigg, G.; Yan, X.; Joachimiak, A.; Phillips Jr., G.N.; Shen, B.*  Crystal structures of SgcE6 and SgcC, the two-component monooxygenase that catalyzes hydroxylation of a carrier protein-tethered substrate during the biosynthesis of the enediyne antitumor antibiotic C-1027 in Streptomyces globisporus. Biochemistry 2016, 55, 5142–5154.

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Biochemical pathway illustrating GGPP conversion to ent-CPP by PtmT2, which then equilibrates to PTM and PTN.

15. Rudolf, J. D.; Dong, L.-B.; Cao, H.; Hatzos-Skintges, C.; Osipiuk, J.; Endres, M.; Chang, C.-Y.; Ma, M.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G.N.; Shen, B.*  Structure of the ent-copalyl diphosphate synthase PtmT2 from Streptomyces platensis CB00739, a bacterial type II diterpene synthase. J. Am. Chem. Soc. 2016, 138, 10905–10915.

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Protein surface shown with electrostatic potential (left, red negative, blue positive) and a ribbon diagram (right) depicting ligand PG4 bound in a pocket with key residues Tyr72, Trp29, Phe37, Asp111, Tyr132, and Trp118 highlighted.

14. Huang, T.; Chang, C.-Y.; Lohman, J. R.; Rudolf, J. D.; Kim, Y.; Chang, C.; Yang, D.; Ma, M.; Yan, X.; Crnovcic, I.; Bigelow, L.; Clancy, S.; Bingman, C. A.; Yennamalli, R. M.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.; Shen, B.* Crystal structure of SgcJ, an NTF2-like superfamily protein involved in biosynthesis of the nine-membered enediyne antitumor antibiotic C-1027. J. Antibiot. 2016, 69, 731–740.

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Petri dish with SB12029 (ΔptmR1) bacteria overproducing PTM-PTN, showing structures of Platenisimicin, Platencin, and their S1 derivatives, plus Platenisimicin D1 (5) with MICs: 0.50 µg mL⁻¹ for S. aureus ATCC 25923 and 0.25 µg mL⁻¹ for M. luteus ATCC 9431.

13. Dong, L.-B.; Rudolf, J. D.; Shen, B.* Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029. Bioorg. Med. Chem. 2016, 24, 6348–6353.

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A network graph illustrates interconnected entities, with nodes colored by ORF distance from PksE (1-40), shaped by 9- or 10-membered classifications, and outlined to denote known function or database presence.

12. Rudolf, J. D.; Yan, X.; Shen, B.* Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery. J. Ind. Microbiol. Biotechnol. 2016, 43, 261–276.

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Diagram illustrating that ZBM forms M(II)-ZBM, which causes DNA Damage, but ZbmA prevents this by binding M(II)-ZBM to create a ZbmA•ZBM-M(II) complex, shown in a 3D molecular model.

11. Rudolf, J. D.; Bigelow, L.; Chang, C.; Cuff, M. E.; Lohman, J. R.; Chang, C.-Y.; Ma, M.; Yang, D.; Clancy, S.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.; Shen, B.* Crystal structure of the zorbamycin-binding protein ZbmA, the primary self-resistance element in Streptomycesflavoviridis ATCC21892. Biochemistry 2015, 54, 6842–6851.

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Streptomyces sp. CB01913 in a petri dish undergoes fermentation and isolation, yielding chemical structures 5, 7, 8 (7R, 12R or 7S, 12S), and 9-14, with varying R groups (CH3, CH2CH3, H) and stereochemistry (7S*, 12R* or 7S*, 12S*).

10. Ma, M.; Rateb, M.; Teng, Q.; Yang, D.; Rudolf, J. D.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Li, X.; Rader, C.; Duan Y.; Shen, B.* Angucyclines and angucyclinones from Streptomyces sp. CB01913 featuring C-ring cleavage and expansion. J. Nat. Prod. 2015, 78, 2471–2780.

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Petri dish showing "Dual PTM-PTN Overproducing Mutants" (SB12030 (ΔptmR1 ΔptmO4)) next to a chemical reaction where PtmO4 converts a substrate R1-C(=O)-CH(CH3)-CH2-R2 to R1-C(=O)-C(CH3)=CH-R2, with R1 = SCoA or OH, and R2 representing complex polycyclic structures M or N.

9. Rudolf, J. D.; Dong, L.-B.; Huang, T.; Shen, B.* A genetically amenable platensimycin- and platencin-overproducer as a platform for biosynthetic explorations: a showcase of PtmO4, a long-chain acyl-CoA dehydrogenase. Mol. BioSyst. 2015, 11, 2717–2726.

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Diagram illustrating the process of identifying "Enediyne producers" from a "Strain collection" using "Genome mining" to find "Enediyne PKS cassettes," depicted as a phylogenetic tree.

8. Shen, B.;* Hindra; Yan, X.; Huang, T.; Ge, H.; Yang, D.; Qihui, T.; Rudolf, J. D.; Lohman, J. R. Enediynes: Exploration of microbial genomics to discover new anticancer drug leads. Bioorg. Med. Chem. 2015, 25, 9–15.

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Diagram illustrating Bleomycin (BLM) pathways: BLM-M(II) causes DNA Damage, but formation of Ac-BLM (via BlmB) or BlmA • BLM-M(II) (via BlmA) both prevent DNA Damage.

7. Coughlin, J. M.; Rudolf, J. D.; Wang, L.; Galm, U.; Wendt-Pienkowski, E.; Tao, M.; Shen, B.* BlmB and TlmB provide resistance to the bleomycin family of antitumor antibiotics by N-acetylating metal-free bleomycin, tallysomycin, phleomycin, and zorbamycin. Biochemistry 2014, 53, 6901–6909.

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Workflow from an Actinomycetes collection through strain prioritization and fermentation optimization of S. griseus CB00830, yielding the natural products Oxaloterpin C (3) and Grisechelin A (4).

6. Hindra; Huang, T.; Yang, D.; Rudolf, J. D.; Xie, P.; Xie, G.; Teng, Q.; Lohman, J. R.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Duan, Y.; Shen, B.* Strain prioritization for natural product discovery by a high-throughput real-time PCR method. J. Nat. Prod. 2014, 77, 2296–2303.

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Chemical reaction scheme showing the reduction of β-ketoacyl-SNACs (1-3) to β-D-hydroxyacyl-SNACs (4-6) catalyzed by KRs (PKSEs) with NADPH. Below the reaction, a diagram illustrates protein domains KS, AT, ACP, KR, DH, PPT, and lists PKSEs studied: SgcE, KedE, MdpE, NcsE, CalE8, DynE8, UcmE.

5. Ge, H.-M.; Huang, T.; Rudolf, J. D.; Lohman, J. R.; Huang, S.-X.; Guo, X.; Shen, B.* Enediyne polyketide synthases stereospecifically reduce the β-ketoacyl intermediates to β-D-hydroxyacyl intermediates in enediyne core biosynthesis. Org. Lett. 2014, 16, 3958–3961.

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Workflow diagram detailing natural product discovery: from strain collection, through qPCR strain prioritization and hit identification, to genome sequencing and mining for natural products, exemplified by a chemical structure.

4. Xie, P.; Ma, M.; Rateb, M.; Shaaban, K.; Yu, Z.; Huang, S.-X.; Zhao, L.-X.; Zhu, X.; Yan, Y.; Peterson, R. M.; Lohman, J. R.; Yang, D.; Yin, M.; Rudolf, J. D.; Jiang, Y.; Duan, Y.; Shen, B.* Biosynthetic potential-based strain prioritization for natural product discovery – a showcase for diterpenoid producing actinomycetes. J. Nat. Prod. 2014, 77, 377–387.

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Diagram illustrating the chemical structures of Platensimycin (PTM) and Platencin (PTN) and their inhibition of enzymes FabH and FabF/B in the FASII pathway, with PtmP3 also shown as an alternative pathway enzyme.

3. Peterson, R. M.; Huang, T.; Rudolf, J. D.; Smanski, M. J.; Shen B.* Mechanisms of self-resistance in the platensimycin and platencin producing Streptomyces platensis MA7327 and MA7339 strains. Chem. Biol. 2014, 21, 389–397.

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University of Utah – Graduate School

A reaction scheme illustrates SirD-catalyzed prenylation, where phenylalanine derivatives (X = OH, NH2, SH) and indole derivatives (R1 = H, CH3, OCH3; R2 = CH3) react with dimethylallyl pyrophosphate to yield a variety of prenylated aromatic amino acids shown within a protein scaffold.

2. Rudolf, J. D.; Poulter, C. D.* Tyrosine O-prenyltransferase SirD catalyzes S-, C-, and N-prenylations on tyrosine and tryptophan derivatives. ACS Chem. Biol. 2013, 8, 2707–2714.

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A protein ribbon diagram, featuring alpha-helices and beta-sheets, is connected to a magnified chemical mechanism. The mechanism depicts an indole (labeled R, NH) reacting with a positively charged carbon electrophile, showing multiple arrows for electron movement.

1. Rudolf, J. D.; Wang, H.; Poulter, C. D.* Multisite prenylation of 4-substituted tryptophans by dimethylallyltryptophan synthase. J. Am. Chem. Soc. 2013, 135, 1895–1902.

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