2010 – 2019 Publications
75
Precord, T.W.; Mahanta, N.; Mitchell, D.A. “Reconstitution and substrate specificity of the thioether-forming radical S-adenosylmethionine enzyme in freyrasin biosynthesis.” ACS Chem. Biol., 14: 1981-1989 (2019). doi:10.1021/acschembio.9b00457
Freyrasin, a thioether-containing RiPP from Paenibacillus polymyxa, was characterized in vivo and reconstituted in vitro, yielding the first in-depth characterization of a ranthipeptide.
74
Hudson, G.A.; Burkhart, B.J.; DiCaprio, A.J.; Schwalen, C.; Kille, B.; Pogorelov, T.V.; Mitchell, D.A. “Bioinformatic mapping of radical S-adenosylmethionine-dependent ribosomally synthesized and post-translationally modified peptides identifies new Cα, Cβ, and Cγ-linked thioether-containing peptides.” J. Am. Chem. Soc., 141: 8228-8238 (2019). doi:10.1021/jacs.9b01519
RODEO 2.0 was utilized to map thioether rSAMs, revealing a novel sactipeptide as well as a new class of non-Cα-linked thioether RiPPs, now termed ranthipeptides, including the enigmatic “SCIFFs.”
73
Dong, S.H.; Liu, A.; Mahanta, N.; Mitchell, D.A.; Nair, S.K. “Mechanistic basis for ribosomal peptide backbone modifications.” ACS Cent. Sci., 5: 842-851 (2019). doi:10.1021/acscentsci.9b00124
The first crystal structure of a substrate-bound YcaO illuminate mechanistic conservation across all YcaOs.
72
Mahanta, N.; Szantai-Kis, D.M.; Petersson, E.J.; Mitchell, D.A. “Biosynthesis and chemical applications of thioamides.” ACS Chem. Biol., 14: 142-163 (2019). doi:10.1021/acschembio.8b01022
Both synthetic and biosynthetic mechanisms of thioamide installation are discussed in the context of physiochemical implications of this rare modification.
71
DiCaprio, A.J.; Firouzbakht, A.; Hudson, G.H.; Mitchell, D.A. “Enzymatic reconstitution and biosynthetic investigation of the lasso peptide fusilassin.” J. Am. Chem. Soc., 141: 290-297 (2019). doi:10.1021/jacs.8b09928
Reconstitution of the fusilassin biosynthetic enzymes allowed unprecedented access to mechanisms governing lasso peptide biosynthesis.
70
Hegemann, J.D.; Schwalen, C.J.; Mitchell, D.A.; van der Donk, W.A. “Elucidation of the roles of conserved residues in the biosynthesis of the lasso peptide paeninodin.” Chem. Commun., 54: 9007-9010 (2018). doi:10.1039/C8CC04411B
Mutagenesis of critical residues conserved in lasso peptide biosynthesis reveal specific roles in substrate recognition and enzymatic processing.
69
Schwalen, C.J.; Hudson, G.A.; Kille, B.; Mitchell, D.A. “Bioinformatic expansion and discovery of thiopeptide antibiotics.” J. Am. Chem. Soc., 140: 9494-9501 (2018). doi:10.1021/jacs.8b03896
Large-scale genome mining reveals a wealth of untapped thiopeptide scaffolds which was leveraged to identify the source of thioamides in ribosomal natural products.
68
Hudson, G.A.; Mitchell, D.A. “RiPP antibiotics: biosynthesis and engineering potential.” Curr. Opin. Microbiol., 45: 61-69 (2018). doi.org/10.1016/j.mib.2018.02.010
Prominent antibiotic RiPP classes are examined from the standpoint of their defining structural features, mode of action, and biosynthetic malleability.
67
Mahanta, N.; Liu, A.; Dong, S.; Nair, S.K.; Mitchell, D.A. “Enzymatic reconstitution of ribosomal peptide backbone thioamidation.” Proc. Natl. Acad. Sci. USA, 115: 3030-3035 (2018). doi.org/10.1073/pnas.1722324115
YcaO proteins are shown to catalyze regiospecific thioglycine formation in methyl coenzyme M-reductase in an ATP and sulfide dependent manner.
66
Schwalen, C.J.; Hudson, G.A.; Kosol, S.; Mahanta, N.; Challis, G.L.; Mitchell, D.A. “In vitro biosynthetic studies of bottromycin expand the enzymatic capabilities of the YcaO superfamily.” J. Am. Chem. Soc., 139: 18154-18157 (2017). doi:10.1021/jacs.7b09899
YcaO proteins are demonstrated to biosynthesize the unique lactamidine macrocycle in the antibiotic bottromycin.
65
Zhang, Z.; Mahanta, N.; Hudson, G.A.; Mitchell, D.A.; van der Donk, W.A. “Mechanism of a class C radical SAM thiazole methyl transferase.” J. Am. Chem. Soc., 139: 18623-18631 (2017). doi:10.1021/jacs.7b10203
Mechanistic enzymology of a novel radical SAM thiazole C-methyltransferase involved in thiomuracin biosynthesis.
64
Cogan, D.P.; Hudson, G.A.; Zhang, Z.; Pogorelov, T.V.; van der Donk, W.A.; Mitchell, D.A.; Nair, S.K. “Structural insights into enzymatic [4+2] aza-cycloaddition in thiopeptide antibiotic biosynthesis.” Proc. Natl. Acad. Sci. USA, 114: 12928–12933 (2017). doi:10.1073/pnas.1716035114
Biophysical, structural and computational methods are used to gain mechanistic understanding of thiopeptide [4+2] cycloaddition.
63
Mahanta, N.; Hudson, G.A.; Mitchell, D.A. “Radical SAM enzymes involved in RiPP biosynthesis.” Biochemistry, 56: 5229-5244 (2017). doi:10.1021/acs.biochem.7b00771
Focusing on the past decade, this review covers six distinct reaction types for radical SAM enzymes involved in RiPP biosynthesis.
62
Nayak, D.D.; Mahanta, N.; Mitchell, D.A.; Metcalf, W.W. “Post-translational thioamidation of methyl-coenzyme M reductase, a key enzyme in methanogenic and methanotrophic Archaea.” eLife, e29218 (2017). doi:10.7554/eLife.29218
YcaO and TfuA are implicated in the thioamidation of methyl-coenzyme M reductase, a key player in the global carbon cycle.
61
Si, T.; Li, B.; Comi, T.J.; Wo, Y.; Hu, P.; Wu, Y.; Min, Y.; Mitchell, D.A.; Zhao, H.; Sweedler, J.V. “Profiling of microbial colonies for high-throughput engineering of multi-step enzymatic reactions via optically guided MALDI MS.” J. Am. Chem. Soc., 139: 12466-12473 (2017). doi:10.1021/jacs.7b04641
A high-throughput MALDI MS method for monitoring the formation of microbial secondary metabolites.
60
Burkhart, B.J.; Kakkar, N.; Hudson, G.A.; van der Donk, W.A.; Mitchell, D.A. “Chimeric leader peptides for the generation of non-natural hybrid RiPP products” ACS Cent. Sci., 6: 629-638 (2017). doi:10.1021/acscentsci.7b00141
A “chimeric leader peptide” strategy enables combination of different RiPP enzymes to rationally design novel hybrid posttranslationally modified peptides.
59
Blin, K.; Wolf, T.; Chevrette, M.G.; Lu,X.; Schwalen, C.J.; Kautsar, S.A.; Suarez Duran, H.G.; de los Santos, E.L.C.; Kim, H.U.; Nave, M.; Dickschat, J.S.; Mitchell, D.A.; Shelest, E.; Breitling, R.; Takano, E.; Lee, S.Y.; Weber, T.; Medema, M. “antiSMASH 4.0 – improvements in chemistry prediction and gene cluster boundary identification” Nucleic Acids Res., 45: W36-41 (web server issue) (2017). doi:10.1093/nar/gkx319
The latest version of antiSMASH, the premier natural products genome-mining tool, is updated with RODEO’s RiPP detection algorithms.
58
Schwalen, C.J.; Feng, X.; Liu, W.; O-Dowd, B.; Ko, T.P.; Shin, C.J.; Guo, R.T.; Mitchell, D.A.; Oldfield, E. “”Head-to-head” prenyl synthases in some pathogenic bacteria.” ChemBioChem, 18: 985-991 (2017). doi:10.1002/cbic.201700099
Genome mining of pathogens was used to guide enzymatic characterization of new prenyltransferases.
57
Mahanta, N.; Zhang, Z.; Hudson, G.A.; van der Donk, W.; Mitchell, D.A. “Reconstitution and substrate specificity of the radical SAM thiazole C-methyltransferase in thiomuracin biosynthesis” J. Am. Chem. Soc., 139: 4310–4313 (2017). doi:10.1021/jacs.7b00693
Characterization of the substrate selectivity and regioselectivity of TbtI, a radical SAM methyltransferase that acts upon an unactivated sp2 thiazole carbon.
56
Burkhart, B.J.; Schwalen, C.J.; Mann, G.; Naismith, J.H.; Mitchell, D.A. “YcaO-dependent posttranslational amide activation: biosynthesis, structure, and function.” Chem. Rev., 117: 5389-5456 (2017). doi:10.1021/acs.chemrev.6b00623
A review of all biosynthetic pathways with a YcaO, the rules governing cyclodehydratases, and the possible role of YcaOs in thioamide and amidine formation.
55
Tietz, J.I.; Schwalen, C.J.; Patel, P.S.; Maxson, T.; Blair, P.M.; Tai, H.C.; Zakai, U.Z.; Mitchell, D.A. “A new genome mining tool redefines the lasso peptide biosynthetic landscape.” Nat. Chem. Biol., 13: 470-478 (2017). doi:10.1038/nchembio.2319
Design of a new genome mining tool guides mapping of a RiPP family and discovery of several new antimicrobial natural products.
54
Maxson, T.; Tietz, J.I.; Hudson, G.A.; Guo, X.R.; Tai, H.; Mitchell, D.A. “Targeting reactive carbonyls for identifying natural products and their biosynthetic origins.” J. Am. Chem. Soc., 138: 15157-15166 (2016). doi:10.1021/jacs.6b06848
Development and use of a new probe for reactivity-based screening to discover a novel natural product and its biosynthetic origin.
53
Zhang, Z.; Hudson, G.A.; Mahanta, N.; Tietz, J.I.; van der Donk, W.A.; Mitchell, D.A. “Biosynthetic timing and substrate specificity for the thiopeptide thiomuracin.” J. Am. Chem. Soc., 138: 15511–15514 (2016). doi:10.1021/jacs.6b08987
A study on the substrate specificity and order of modifications in the biosynthesis of thiomuracin.
52
Deane, C.D.; Burkhart, B.J.; Blair, P.M.; Tietz, J.I.; Lin, A.; Mitchell, D.A. “In vitro biosynthesis and substrate tolerance of the plantazolicin family of natural products.” ACS Chem. Biol., 11: 2232−2243 (2016). doi:10.1021/acschembio.6b00369
Characterization of the synthetase and new natural products from the plantazolicin family.
51
Molloy, E.M.; Tietz, J.I.; Blair, P.M.; Mitchell, D.A. “Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products.” Bioorg. Med. Chem., 24: 6276-6290 (2016). doi:10.1016/j.bmc.2016.05.021
Genomics and reactivity-based labeling were used to identify a hygrobafilomycin gene cluster, probe bioactivity, and elucidate structure.
50
Tietz, J.I.; Mitchell, D.A. “Using genomics for natural product structure elucidation.” Curr. Top. Med. Chem., 16: 1645-1694 (2016). doi:10.2174/1568026616666151012111439
A review discussing the use of genomic information to discover and elucidate or confirm the structure of novel natural products.
49
Molohon, K.; Blair, P.; Park, S.; Doroghazi, J.R.; Maxson, T.; Hershfield, J.; Flatt, K.; Schroeder, N.; Ha, T.; Mitchell, D.A. “Plantazolicin is an ultra-narrow spectrum antibiotic that targets the Bacillus anthracis membrane.” ACS Infect. Dis., 2: 207-220 (2016). doi:10.1021/acsinfecdis.5b00115
The scope of bioactivity and action of plantazolicin on the bacteria cell membrane is elucidated.
48
Hudson, G.A.; Zhang, Z.; Tietz, J.I.; Mitchell, D.A.; van der Donk, W.A. “In vitro biosynthesis of the core scaffold of the thiopeptide thiomuracin.” J. Am. Chem. Soc., 137: 16012-16015 (2015). doi:10.1021/jacs.5b10194
The total enzymatic synthesis of a thiomuracin antibiotic.
47
Maxson, T.; Bertke, J.A.; Gray, D.L.; Mitchell, D.A. “Crystal structure and absolute configuration of (3S,4aS,8aS)-N-tert-butyl-2-[(S)-3-(2-chloro-4-nitrobenzamido)-2-hydroxy-propyl]decahydroisoquinoline-3-carboxamide and (3S,4aS,8aS)-N-tert-butyl-2-{(S)-2-[(S)-1-(2-chloro-4-nitrobenzoyl)pyrrolidin-2-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxamide.” Acta Cryst., E17: 1401-1407 (2015). doi:10.1107/S2056989015020046
Description of the crystal structures for two nelfinavir analogs, establishing the absolute configuration and intra- and inter-molecular interactions.
46
Cox, C.L.; Doroghazi, J.R.; Mitchell, D.A. “The genomic landscape of ribosomal peptides containing thiazole and oxazole heterocycles.” BMC Genomics, 16: 778 (2015). doi:10.1186/s12864-015-2008-0
A comprehensive mining effort reveals the genomic landscape of linear azol(in)e-containing peptide biosynthetic gene clusters.
45
Maxson, T.; Mitchell, D.A. “Targeted treatment for bacterial infections: Prospects for pathogen-specific antibiotics coupled with rapid diagnostics.” Tetrahedron (Special Issue on Natural Product-Inspired Approaches to Combat Bacteria), 72: 3609-3624 (2016). doi:10.1016/j.tet.2015.09.069
A review discussing the benefits and drawbacks of narrow-spectrum antibiotics and the diagnostics needed to employ them.
44
Medema, M.H.; et al. “Minimum information about a biosynthetic gene cluster.” Nat. Chem. Biol., 11: 625-631 (2015). doi:10.1038/nchembio.1890
The MIBIG specification and database provide a community standard for description and annotation of biosynthetic gene clusters.
43
Molloy, E.M.; Casjens, S.R.; Cox, C.L.; Maxson, T.; Ethridge, N.A.; Margos, G.; Fingerle, V.; Mitchell, D.A. “Identification of the minimal cytolytic unit for streptolysin S and an expansion of the toxin family.” BMC Microbiol., 15: 141 (2015). doi:10.1186/s12866-015-0464-y
Newly-identified truncated SLS-like precursor peptides facilitate a greater understanding of SLS structure-activity relationship.
42
Burkhart, B.J.; Hudson, G.A.; Dunbar, K.L.; Mitchell, D.A. “A prevalent peptide-binding domain guides ribosomal natural product biosynthesis” Nat. Chem. Biol., 11: 564-570 (2015). doi:10.1038/nchembio.1856
A conserved peptide binding domain recruits precursor peptides to enzymes in diverse RiPP biosynthetic pathways.
41
Dunbar, K.L.; Tietz, J.I.; Cox, C.L.; Burkhart, B.J.; Mitchell, D.A. “Identification of an auxiliary leader peptide-binding protein required for azoline formation in ribosomal natural products” J. Am. Chem. Soc., 137: 7672-7677 (2015). doi:10.1021/jacs.5b04682
A novel linear azol(in)e-containing peptide biosynthetic protein is shown to be involved in substrate binding and cyclodehydratase activation.
40
Maxson, T.; Deane, C.D.; Molloy, E.M.; Cox, C.L.; Markley, A.L.; Lee, S.W.; Mitchell, D.A. “HIV protease inhibitors block streptolysin S production” ACS Chem. Biol., 10: 1217–1226 (2015). doi:10.1021/cb500843r
An HIV protease inhibitor is repurposed to block the production of the virulence factor streptolysin S from S. pyogenes.
39
Hao, Y.; Blair, P.M.; Sharma, A.; Mitchell, D.A.; Nair, S.K. “Insights into methyltransferase specificity and bioactivity of derivatives of the antibiotic plantazolicin” ACS Chem. Biol., 10: 1209–1216 (2015). doi:10.1021/cb501042a
Plantazolicin substructures are used to probe methyltransferase activity and antibacterial specificity.
38
Metelev, M.; Tietz, J.I.; Melby, J.O.; Blair, P.M.; Zhu, L.; Livnat, I.; Severinov, K.; Mitchell, D.A. “Structure, bioactivity, and resistance mechanism of streptomonomicin, an unusual lasso peptide from an understudied halophilic actinomycete” Chem. Biol., 22: 241-250 (2015). doi:10.1016/j.chembiol.2014.11.017
An unusual lasso peptide antibiotic is characterized, and genome sequencing predicts biosynthetic potential in an overlooked genus.
37
Dunbar, K.L.; Chekan, J.R.; Cox, C.L.; Burkhart, B.J.; Nair, S.K.; Mitchell, D.A. “Discovery of a new ATP-binding motif involved in peptidic azoline biosynthesis” Nat. Chem. Biol., 10: 823-829 (2014). doi:10.1038/nchembio.1608
X-ray structure of a YcaO family member resolves the linear azol(in)e-containing peptide cyclodehydratase ATP-binding pocket and active site.
36
Zhang, Q.; Ortega, M; Shi, Y.; Wang, H.; Melby, J.O.; Tang, W.; Mitchell, D.A.; van der Donk, W.A. “Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS” Proc. Natl. Acad. Sci. USA USA, 111: 12031-12036 (2014). doi:10.1073/pnas.1406418111
An algorithm-based method uses tandem mass spectra for automatic RiPP structure assignment.
35
Cox, C.L.; Tietz, J.I.; Sokolowski, K.; Melby, J.O.; Doroghazi, J.R.; Mitchell, D.A. “Nucleophilic 1,4-additions for natural product discovery” ACS Chem. Biol., 9: 2014-2022 (2014). doi:10.1021/cb500324n
Bioinformatics-prioritized reactivity-based screening identifies a new thiopeptide antibiotic.
34
Sinko, W.; Wang, Y.; Zhu, W.; Zhang, Y.; Feixas, F.; Cox, C.; Mitchell, D.A.; Oldfield, E.; McCammon, J.A. “Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads” J. Med. Chem., 57: 5693–5701 (2014). doi:10.1021/jm5004649
Computer-identified inhibitors of undecaprenyl disphosphate synthase, a novel target in cell wall biosynthesis, kill drug-resistant pathogens.
33
Li, K.; Schurig-Briccio, L.A.; Feng, X.; Upadhyay, A.; Pujari, V.; Lechartier, B.; Fontes, F.L.; Yang, H.; Rao, G.; Zhu, W.; Gulati, A.; No, J.H.; Cintra, G.; Bogue, S.; Liu, Y.-L.; Molohon, K.; Orlean, P.; Mitchell, D.A.; Freitas-Junior, L.; Ren, F.; Sun, H.; Jiang, T.; Li, Y.; Guo, R.-T.; Cole, S.T.; Gennis, R.B.; Crick, D.C.; Oldfield, E. “Multitarget drug discovery for tuberculosis and other infectious diseases.” J. Med. Chem., 57: 3126-3139 (2014). doi:10.1021/jm500131s
Establishment of antibacterial, antifungal, and antimalarial SAR, as well as mammalian cell toxicity, for a panel of M. tuberculosis drug analogs.
32
Deane, C.D.; Mitchell, D.A. “Lessons learned from the transformation of natural product discovery to a genome-driven endeavor.” J. Ind. Microbiol. Biot., 41: 315-331 (2014). doi:10.1007/s10295-013-1361-8
A review on “reverse” discovery of natural products, including lessons learned and recommendations for the future of the field.
31
Melby, J.O.; Li, X.; Mitchell, D.A. “Orchestration of enzymatic processing by thiazole/oxazole-modified microcin dehydrogenases.” Biochemistry, 53: 413-422 (2014). doi:10.1021/bi401529y
By separating cyclodehydratase and dehydrogenase activity, dehydrogenase promiscuity and selectivity was investigated.
30
Sharma, A.; Blair, P.M.; and Mitchell, D.A. “Synthesis of plantazolicin analogues enables dissection of ligand binding interactions of a highly selective methyltransferase.” Org. Lett., 15: 5076-5079 (2013). doi:10.1021/ol402444a
PZN truncations were synthesized to study binding requirements of its methyltransferase.
29
Lee, J.; Hao, Y.; Blair, P.M.; Melby, J.O.; Agarwal, V.; Burkhart, B.J.; Nair, S.K.; Mitchell, D.A. “Structural and functional insight into an unexpectedly selective N-methyltransferase involved in plantazolicin biosynthesis.” Proc. Natl. Acad. Sci. USA, 110: 12954-12959 (2013). doi:10.1073/pnas.1306101110
Studies in the biosynthesis of plantazolicin reveal a methyltransferase with unprecedented selectivity for its substrate.
28
Deane, C.D.; Melby, J.O.; Molohon, K.J.; Susarrey, A.R.; Mitchell, D.A. “Engineering unnatural variants of plantazolicin through codon reprogramming.” ACS Chem. Biol., 8: 1998-2008 (2013). doi:10.1021/cb4003392
Mutagenesis of the PZN precursor highlights the selectivity of its biosynthetic enyzmes.
27
Dunbar, K.L.; Mitchell, D.A. “Insights into the mechanism of peptide cyclodehydrations achieved through the chemoenzymatic generation of amide derivatives.” J. Am. Chem. Soc., 135: 8692-9701 (2013). doi:10.1021/ja4029507
The linear azol(in)e-containing peptide cyclodehydratase was used to install isotope labels into peptide backbones, and the resultant product was used as a mechanistic probe.
26
Hu, Y.; Jia, S.; Ren, F.; Huang, C.-H.; Ko, T.-P.; Mitchell, D.A.; Guo, R.-T.; Zheng, Y. “Crystallization and preliminary X-ray diffraction of YisP protein from Bacillus subtilissubsp. subtilis strain 168,” Acta Cryst., F69: 77-79 (2013). doi:10.1107/S1744309112049330
Crystals for structural studies of recombinant B. subtilis protein YisP were obtained, allowing insight into isoprenoid biosynthesis in this organism.
25
Dunbar, K.L.; Mitchell, D.A. “Revealing nature’s synthetic potential through the study of ribosomal natural product biosynthesis.” ACS Chem. Biol., 8: 473-487 (2013). doi:10.1021/cb3005325
A review focusing on the diverse biological chemistry discovered in the study of ribosomal natural product biosynthetic enzymes.
24
Zhu, W.; Zhang, Y.; Sinko, W.; Hensler, M.E.; Olson, J.; Molohon, K.J.; Lindert, S.; Cao, R.; Li, K.; Wang, K.; Wang, Y.; Liu, Y.-L.; Sankovsky, A.; de Oliveira, C.A.F.; Mitchell, D.A.; Nizet, V.; McCammon, J.A.; Oldfield, E. “Antibacterial drug leads targeting isoprenoid biosynthesis.” Proc. Natl. Acad. Sci. USA USA, 110: 123-128 (2013). doi:10.1073/pnas.1219899110
X-ray structures of ten antibacterial compounds reveal binding to the undecaprenyl diphosphate synthase, an essential cell wall biosynthesis enzyme.
23
Arnison, P.; et al. “Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature.” Nat. Prod. Rep., 30: 108-160 (2013). doi:10.1039/C2NP20085F
A comprehensive review on ribosomal natural products with a systematic naming system presented for the research community.
22
Zhang, Y.; Lin, F.-Y.; Li, K.; Zhu, W.; Liu, Y.-L.; Cao, R.; Pang, R.; Lee, E.; Axelson, J.; Hensler, M.; Wang, K.; Molohon, K.J.; Wang, Y.; Mitchell, D.A.; Nizet, V.; Oldfield, V. “HIV-1 integrase inhibitor-inspired antibacterials targeting isoprenoid biosynthesis.” ACS Med. Chem. Lett., 3: 402-406 (2012). doi:10.1021/ml300038t
Possessing a similar motif to HIV-1 integrase, prenyl transferases UPPS and CrtM are targeted by keto and diketo-acid compounds.
21
Dunbar, K.L.; Melby, J.O.; Mitchell, D.A. “YcaO domains use ATP to activate amide backbones during peptide cyclodehydrations.” Nat. Chem. Biol., 8: 569-575 (2012). doi:10.1038/nchembio.944
A biochemically novel mechanism for ATP use is demonstrated in the context of linear azol(in)e-containing peptide cyclodehydratases.
20
Melby, J.O.; Dunbar, K.L.; Trinh, N.Q.: Mitchell, D.A. “Selectivity, directionality, and promiscuity in peptide processing from a Bacillus sp. Al Hakam cyclodehydratase.” J. Am. Chem. Soc., 134: 5309-5316 (2012). doi:10.1021/ja211675n
The substrate processing of a Bacillus sp. Al Hakam cyclodehydratase was assessed using mass spectrometry and kinetics.
19
Molohon, K.J.; Melby, J.O.; Lee, J.; Evans, B.S.; Dunbar, K.L.; Bumpus, S.B.; Kelleher, N.L.; Mitchell, D.A. “Structure determination and interception of biosynthetic intermediates for the plantazolicin class of highly discriminating antibiotics.” ACS Chem. Biol., 6: 1307-1313 (2011). doi:10.1021/cb200339d
The structure of plantazolicin, a B. anthracis-specific antibiotic, is solved by MS and NMR.
18
Molloy, E.; Cotter, P.D.; Hill, C.; Mitchell, D.A.; Ross, R.P. “Streptolysin S-like virulence factors: the continuing SagA.” Nat. Rev. Microbiol., 9: 670-681 (2011). doi:10.1038/nrmicro2624
Review of the genetics, biochemistry, and biological functions of Streptolysin S, a virulence-associated cytolytic linear azol(in)e-containing peptide produced by Streptococcus pyogenes.
17
Pei, J.; Mitchell, D.A.; Dixon, J.E.; Grishin, N.V. “Expansion of type II CAAX proteases reveals evolutionary origin of γ-secretase subunit APH-1.” J Mol. Biol., 410: 18-26 (2011). doi:10.1016/j.jmb.2011.04.066
The discovery that the predicted protease within many linear azol(in)e-containing peptide clusters shares ancestry with a seemingly unrelated eukaryotic protease, gamma-secretase.
16
Melby, J.O.; Nard, N.J.; Mitchell, D.A. “Thiazole/oxazole-modified microcins: Complex natural products from ribosomal templates.” Curr. Op. Chem. Biol., 15: 369-378 (2011). doi:10.1016/j.cbpa.2011.02.027
Review of the linear azol(in)e-containing peptide natural product family with an emphasis on the evolution of novel natural products.
15
Scholz, R.; Molohon, K.J.; Nachtigall, J.; Vater, J.; Markley, A.L.; Sussmuth, R.D.; Mitchell, D.A.; Borriss, R. “Plantazolicin, a novel microcin B17/streptolysin S-like natural product from Bacillus amyloliquefaciens FZB42.” J. Bacteriol., 193: 215-224 (2011). doi:10.1128/JB.00784-10
Discovery of plantazolicin, a posttranslationally modified metabolite which shows specific antimicrobial activity.
14
Gonzalez, D.J.; Lee, S.W.; Hensler, M.E.; Dahesh, S.; Markley, A.L.; Mitchell, D.A.; Banderia, N.; Nizet, V.; Dixon, J.E.; Dorrestein, P.C. “Clostridiolysin S: a post-translationally modified biotoxin from Clostridium botulinum.” J. Biol. Chem., 285: 28220-28228 (2010). doi:10.1074/jbc.M110.118554
13
Mitchell, D.A.; Ryabov, A.D.; Kundu, S.; Chanda, A,; Collins, T.J. “Oxidation of pinacyanol chloride by H2O2 catalyzed by FeIII complexed to tetraamidomacrocyclic ligand: unusual kinetics and product identification.” J. Coord. Chem., 63 :2605-2618 (2010). doi:10.1080/00958972.2010.492426
12
Haft, D.; Basu, M.; Mitchell, D.A. “Expansion of ribosomally produced natural products: a nitrile hydratase- and Nif11-related precursor family.” BMC Biol., 8: 70 (2010). doi:10.1186/1741-7007-8-70
A bioinformatics-based discovery of novel linear azol(in)e-containing peptide natural products with uncharacteristically long leader peptides that derive from known enzymes.