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3. Interception of the Bycroft–Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides

Author

Bogart, Jonathan W, Kramer, Nicholas J, Turlik, Aneta, Bleich, Rachel M, Catlin, Daniel S, Schroeder, Frank C, Nair, Satish K, Williamson, R Thomas, Houk, KN, and Bowers, Albert A

Subjects
Organic Chemistry, Chemical Sciences, Biocatalysis, Cycloaddition Reaction, Lyases, Protein Conformation, Thiostrepton, General Chemistry, Chemical sciences, Engineering
Abstract

Thiopeptides are a broad class of macrocyclic, heavily modified peptide natural products that are unified by the presence of a substituted, nitrogen-containing heterocycle core. Early work indicated that this core might be fashioned from two dehydroalanines by an enzyme-catalyzed aza-[4 + 2] cycloaddition to give a cyclic-hemiaminal intermediate. This common intermediate could then follow a reductive path toward a dehydropiperidine, as in the thiopeptide thiostrepton, or an aromatization path to yield the pyridine groups observed in many other thiopeptides. Although several of the enzymes proposed to perform this cycloaddition have been reconstituted, only pyridine products have been isolated and any hemiaminal intermediates have yet to be observed. Here, we identify the conditions and substrates that decouple the cycloaddition from subsequent steps and allow interception and characterization of this long hypothesized intermediate. Transition state modeling indicates that the key amide-iminol tautomerization is the major hurdle in an otherwise energetically favorable cycloaddition. An anionic model suggests that deprotonation and polarization of this amide bond by TbtD removes this barrier and provides a sufficient driving force for facile (stepwise) cycloaddition. This work provides evidence for a mechanistic link between disparate cyclases in thiopeptide biosynthesis.

Published
2020

19. Discovery and Development of Cyclic Peptide Inhibitors of CIB1

Author

Haberman, Victoria A., primary, Fleming, Steven R., additional, Leisner, Tina M., additional, Puhl, Ana C., additional, Feng, Emerald, additional, Xie, Ling, additional, Chen, Xian, additional, Goto, Yuki, additional, Suga, Hiroaki, additional, Parise, Leslie V., additional, Kireev, Dmitri, additional, Pearce, Kenneth H., additional, and Bowers, Albert A., additional

Published
2021
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20. On the use of 3,5-O-benzylidene and 3,5-O-(di-tert-butylsilylene)-2-O-benzylarabinothiofuranosides and their sulfoxides as glycosyl donors for the synthesis of [beta]-arabinofuranosides: Importance of the activation method

Author

Crich, David, Pedersen, Christian Marcus, Bowers, Albert A., and Wink, Donald J.

Subjects
Toluene -- Chemical properties, Nuclear magnetic resonance -- Usage, Thiols -- Chemical properties, Biological sciences, Chemistry
Abstract

A 2-O-benzyl-3,5-O-benzylidene-[alpha]-D-thioarabinofuranoside which was obtained by reaction of the corresponding diol with [alpha],[alpha]-dibromotoluene under basic conditions is reviewed. The poor selectivity observed on activation of the thioglycosides with the 1-benzenesulfinyl piperidine, or diphenyl sulfoxide, and trifluoromethanesulfonic anhydride methods appears to be the result of the formation of a complex mixture of glycosyl donors, as determined by low-temperature NMR work.

Published
2007

21. 4,6-O-[1-cyano-2-(2-iodophenyl)ethylidene] acetals. Improved second-generation acetals for the stereoselective formation of beta-D-mannopyranosides and regioselective reductive radical fragmentation to beta-D-rhamnopyranosides. Scope and limitations

Author

Crich, David and Bowers, Albert A.

Subjects
Glycosides -- Atomic properties, Carbohydrates -- Atomic properties, Electron donor-acceptor complexes -- Research, Biological sciences, Chemistry
Abstract

The [1-cyano-2-(2-iodophenyl)]ethylidene group, an acetal protecting group for carbohydrate thioglycoside donors, is developed where the group is easily introduced under mild conditions, over short reaction times and in the presence of a wide variety of other protecting groups. It has conveyed a strong beta-selectivity with thiomannoside donors and has undergone a tin-mediated radical fragmentation to provide high yields of the synthetically challenging beta-rhamnopyranosides.

Published
2006

25. Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1

Author

Puhl, Ana C., primary, Bogart, Jonathan W., additional, Haberman, Victoria A., additional, Larson, Jacob E., additional, Godoy, Andre S., additional, Norris-Drouin, Jacqueline L., additional, Cholensky, Stephanie H., additional, Leisner, Tina M., additional, Frye, Stephen V., additional, Parise, Leslie V., additional, Bowers, Albert A., additional, and Pearce, Kenneth H., additional

Published
2020
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29. Flexizyme-Enabled Benchtop Biosynthesis of Thiopeptides

Author

Fleming, Steven R., primary, Bartges, Tessa E., additional, Vinogradov, Alexander A., additional, Kirkpatrick, Christine L., additional, Goto, Yuki, additional, Suga, Hiroaki, additional, Hicks, Leslie M., additional, and Bowers, Albert A., additional

Published
2019
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31. Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology

Author

Farag, Sherif, Shank, Elizabeth A., Bleich, Rachel M., Maria, Kevin C. Santa, Grubbs, Kirk J., Bowers, Albert A., and Allen, Scott E.

Abstract

Bacteria possess an amazing capacity to synthesize a diverse range of structurally complex, bioactive natural products known as specialized (or secondary) metabolites. Many of these specialized metabolites are used as clinical therapeutics, while others have important ecological roles in microbial communities. The biosynthetic gene clusters (BGCs) that generate these metabolites can be identified in bacterial genome sequences using their highly conserved genetic features. We analyzed an unprecedented 1,566 bacterial genomes from Bacillus species and identified nearly 20,000 BGCs. By comparing these BGCs to one another as well as a curated set of known specialized metabolite BGCs, we discovered that the majority of Bacillus natural products are comprised of a small set of highly conserved, well-distributed, known natural product compounds. Most of these metabolites have important roles influencing the physiology and development of Bacillus species. We identified, in addition to these characterized compounds, many unique, weakly conserved BGCs scattered across the genus that are predicted to encode unknown natural products. Many of these “singleton” BGCs appear to have been acquired via horizontal gene transfer. Based on this large-scale characterization of metabolite production in the Bacilli , we go on to connect the alkylpyrones, natural products that are highly conserved but previously biologically uncharacterized, to a role in Bacillus physiology: inhibiting spore development. IMPORTANCE Bacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus’s metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation.

Published
2017
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32. Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus

Author

Bowers, Albert A., Walsh, Christopher T., and Acker, Michael G.

Subjects
Bacillus cereus -- Genetic aspects, Bacillus cereus -- Physiological aspects, Ring formation (Chemistry) -- Analysis, Organosulfur compounds -- Structure, Organosulfur compounds -- Chemical properties, Peptides -- Structure, Peptides -- Chemical properties, Chemistry
Abstract

G enetic i nterception and s tructural c haracterization of t hiopeptide c yclization p recursors for thiocillins (tclM) from Bacillus cereus is described. The studies provide insight into the TclM and its homologues in other thiazolyl peptide producing strains as the enzymes reponsible for the trans-annular heteroannulation at core of this class of molecules.

Published
2010

33. Manipulation of thiocillin variants by prepeptide gene replacement: structure, conformation, and activity of heterocycle substitution mutants

Author

Bowers, Albert A., Acker, Michael G., Koglin, Alexander, and Walsh, Christopher T.

Subjects
Alanine -- Chemical properties, Bacillus cereus -- Physiological aspects, Cysteine -- Chemical properties, Gene mutations -- Analysis, Organosulfur compounds -- Chemical properties, Organosulfur compounds -- Structure, Peptides -- Chemical properties, Peptides -- Structure, Chemistry
Abstract

Prepeptide gene variants were introduced into a knockout strain to conduct an alanine scan C-terminal 14 residues of a 52-mer prepeptide which is converted by Bacillus cereus ATCC 14579 as well as a serine scan of the six cysteine residues that are converted to thiazoles in the mature natural product. The tight conformational rigidity of the natural product which is severely disrupted by loss of even a single heterocycle accounted for the attendant loss of activity in such mutants.

Published
2010

34. Generation of thiocillin variants by prepeptide gene replacement and in vivo processing by

Author

Bacillus cereus, Acker, Michael G., Bowers, Albert A., and Walsh, Christopher T.

Subjects
Antibiotics -- Research, Bacillus cereus -- Physiological aspects, Bacillus cereus -- Genetic aspects, Organosulfur compounds -- Chemical properties, Organosulfur compounds -- Structure, Chemistry
Abstract

Several studies are conducted to explain the application of prepeptide gene replacement and in vivo processing by Bacillus cereus in the generation of various thiocillin variants. The structure-activity relationships involved in the precursor peptide maturation and antibiotic activity are explained.

Published
2009

35. One-pot syntheses of dissymmetric diamides based on the chemistry of cyclic monothioanhydrides: scope and limitations and application to the synthesis of glycodipeptides

Author

Crich, David, Sasaki, Kaname, Rahaman, Md Yeajur, and Bowers, Albert A.

Subjects
Amines -- Chemical properties, Amines -- Structure, Amino compounds -- Chemical properties, Amino compounds -- Structure, Anhydrides -- Chemical properties, Anhydrides -- Structure, Biological sciences, Chemistry
Abstract

Opening cyclic monothioanhydrides by amines has provided an entry into amido thioacids that can be trapped in situ by 2,4-dinitrobenzenesulfonamides, by electron-deficient azides, or by amines in the presence of Sanger's reagent leading to dissymmetric diamindes. The reaction of N-benzyloxycarbonyl-L-aspartic monothioanhydride with unprotected glycosyl amines, followed by capture of the thioacid intermediate with N-sulfonyl amino acid derivatives has resulted in a three-component convergent synthesis of glycosylated peptides.

Published
2009

36. Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole

Author

Bowers, Albert A., Greshock, Thomas J., West, Nathan, Estiu, Guillermina, Schreiber, Stuart L., Wiest, Olaf, Williams, Robert M., and Bradner, James E.

Subjects
Azo compounds -- Structure, Azo compounds -- Chemical properties, Histones -- Chemical properties, Peptides -- Chemical properties, Chemistry
Abstract

The peptide isosteres of the naturally occurring and potent histone deacetylase (HDAC) inhibitors FK228 and largazole are prepared and analyzed along with FK228, largazole, and SAHA for inhibition of the class I HDACs.

Published
2009

37. Heterobivalent library expansion by 'living radical' processes: Thiocarbonyl addition/elimination, and nitroxide-based reactions with fluorous deconvolution

Author

Crich, David, Grant, Daniel, and Bowers, Albert A.

Subjects
Olefins -- Chemical properties, Chemical bonds -- Research, Polymerization -- Research, Chemistry
Abstract

The reversible fragmentation of hydroxylamine C-O bonds which gives a persistent nitroxide radical and a carbon-based radical is presented. This persistent radical effect could be applied in living radical polymerization of alkenes.

Published
2007

38. Electrochemical generation of glycosyl triflate pools

Author

Nokami, Toshiki, Shibuya, Akito, Tsuyama, Hiroaki, Suga, Seiji, Bowers, Albert A., Crich, David, and Yoshida, Jun-ichi

Subjects
Glycosylation -- Analysis, Electrochemical analysis, Chemistry
Abstract

Glycosyl triflates are generated and accumulated by the low-temperature electrochemical oxidation of thioglycosides like thioglucosides, thiogalactosides and thiomannosides in the presence of tetrabutylammonium triflate as a supporting electrolyte. The thermal stability of glycosyl triflates and their reactions with glycosyl acceptors are analyzed.

Published
2007

43. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Author

Lauinger, Linda, primary, Li, Jing, additional, Shostak, Anton, additional, Cemel, Ibrahim Avi, additional, Ha, Nati, additional, Zhang, Yaru, additional, Merkl, Philipp E, additional, Obermeyer, Simon, additional, Stankovic-Valentin, Nicolas, additional, Schafmeier, Tobias, additional, Wever, Walter J, additional, Bowers, Albert A, additional, Carter, Kyle P, additional, Palmer, Amy E, additional, Tschochner, Herbert, additional, Melchior, Frauke, additional, Deshaies, Raymond J, additional, Brunner, Michael, additional, and Diernfellner, Axel, additional

Published
2017
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