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51. Small-molecule mimicry hunting strategy in the imperial cone snail, Conus imperialis

Author

Torres, Joshua P., primary, Lin, Zhenjian, additional, Watkins, Maren, additional, Salcedo, Paula Flórez, additional, Baskin, Robert P., additional, Elhabian, Shireen, additional, Safavi-Hemami, Helena, additional, Taylor, Dylan, additional, Tun, Jortan, additional, Concepcion, Gisela P., additional, Saguil, Noel, additional, Yanagihara, Angel A., additional, Fang, Yixin, additional, McArthur, Jeffrey R., additional, Tae, Han-Shen, additional, Finol-Urdaneta, Rocio K., additional, Özpolat, B. Duygu, additional, Olivera, Baldomero M., additional, and Schmidt, Eric W., additional

Published
2021
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53. A symbiotic bacterium of shipworms produces a compound with broad spectrum anti-apicomplexan activity.

Author

O'Connor, Roberta M., Striepen, Boris1, O'Connor, Roberta M, Nepveux V, Felix J, Abenoja, Jaypee, Bowden, Gregory, Reis, Patricia, Beaushaw, Josiah, Bone Relat, Rachel M, Driskell, Iwona, Gimenez, Fernanda, Riggs, Michael W, Schaefer, Deborah A, Schmidt, Eric W, Lin, Zhenjian, Distel, Daniel L, Clardy, Jon, Ramadhar, Timothy R, Allred, David R, Fritz, Heather M, Rathod, Pradipsinh, Chery, Laura, White, John, O'Connor, Roberta M., Striepen, Boris1, O'Connor, Roberta M, Nepveux V, Felix J, Abenoja, Jaypee, Bowden, Gregory, Reis, Patricia, Beaushaw, Josiah, Bone Relat, Rachel M, Driskell, Iwona, Gimenez, Fernanda, Riggs, Michael W, Schaefer, Deborah A, Schmidt, Eric W, Lin, Zhenjian, Distel, Daniel L, Clardy, Jon, Ramadhar, Timothy R, Allred, David R, Fritz, Heather M, Rathod, Pradipsinh, Chery, Laura, and White, John

Abstract

Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.

Published
2020

54. Genetic and Biochemical Reconstitution of Bromoform Biosynthesis in Asparagopsis Lends Insights into Seaweed Reactive Oxygen Species Enzymology

Author

Thapa, Hem R., Lin, Zhenjian, Yi, Dongqi, Smith, Jennifer E., Schmidt, Eric W., Agarwal, Vinayak, Thapa, Hem R., Lin, Zhenjian, Yi, Dongqi, Smith, Jennifer E., Schmidt, Eric W., and Agarwal, Vinayak

Abstract

Marine macroalgae, seaweeds, are exceptionally prolific producers of halogenated natural products. Biosynthesis of halogenated molecules in seaweeds is inextricably linked to reactive oxygen species (ROS) signaling as hydrogen peroxide serves as a substrate for haloperoxidase enzymes that participate in the construction these halogenated molecules. Here, using red macroalga Asparagopsis taxiformis, a prolific producer of the ozone depleting molecule bromoform, we provide the discovery and biochemical characterization of a ROS-producing NAD(P)H oxidase from seaweeds. This discovery was enabled by our sequencing of Asparagopsis genomes, in which we find the gene encoding the ROS-producing enzyme to be clustered with genes encoding bromoform-producing haloperoxidases. Biochemical reconstitution of haloperoxidase activities establishes that fatty acid biosynthesis can provide viable hydrocarbon substrates for bromoform production. The ROS production haloperoxidase enzymology that we describe here advances seaweed biology and biochemistry by providing the molecular basis for decades worth of physiological observations in ROS and halogenated natural product biosyntheses.

Published
2020
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55. Structure of trichamide, a cyclic peptide from the bloom-forming cyanobacterium Trichodesmium erythraeum, predicted from the genome sequence

Author

Sudek, Sebastian, Haygood, Margo G., Youssef, Diaa T.A., and Schmidt, Eric W.

Subjects
Cyanobacteria -- Genetic aspects, Nucleotide sequence -- Research, Marine bacteria -- Genetic aspects, Biological sciences
Abstract

A gene cluster for the biosynthesis of a new small cyclic peptide, dubbed trichamide, was discovered in the genome of the global, bloom-forming cyanobacterium Trichodesmium erythraeum ISM 101 because of striking similarities to the previously characterized patellamide biosynthesis cluster. Based upon detailed sequence analysis, a structure was predicted for trichamide and confirmed by Fourier transform mass spectrometry.

Published
2006

56. New developments in RiPP discovery, enzymology and engineering

Author

Montalbán-López, Manuel, primary, Scott, Thomas A., additional, Ramesh, Sangeetha, additional, Rahman, Imran R., additional, van Heel, Auke J., additional, Viel, Jakob H., additional, Bandarian, Vahe, additional, Dittmann, Elke, additional, Genilloud, Olga, additional, Goto, Yuki, additional, Grande Burgos, María José, additional, Hill, Colin, additional, Kim, Seokhee, additional, Koehnke, Jesko, additional, Latham, John A., additional, Link, A. James, additional, Martínez, Beatriz, additional, Nair, Satish K., additional, Nicolet, Yvain, additional, Rebuffat, Sylvie, additional, Sahl, Hans-Georg, additional, Sareen, Dipti, additional, Schmidt, Eric W., additional, Schmitt, Lutz, additional, Severinov, Konstantin, additional, Süssmuth, Roderich D., additional, Truman, Andrew W., additional, Wang, Huan, additional, Weng, Jing-Ke, additional, van Wezel, Gilles P., additional, Zhang, Qi, additional, Zhong, Jin, additional, Piel, Jörn, additional, Mitchell, Douglas A., additional, Kuipers, Oscar P., additional, and van der Donk, Wilfred A., additional

Published
2021
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62. Secondary Metabolism in the Gill Microbiota of Shipworms (Teredinidae) as Revealed by Comparison of Metagenomes and Nearly Complete Symbiont Genomes

Author

Altamia, Marvin A., primary, Lin, Zhenjian, additional, Trindade-Silva, Amaro E., additional, Uy, Iris Diana, additional, Shipway, J. Reuben, additional, Wilke, Diego Veras, additional, Concepcion, Gisela P., additional, Distel, Daniel L., additional, Schmidt, Eric W., additional, and Haygood, Margo G., additional

Published
2020
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67. Boholamide A, an APD-Class, Hypoxia-Selective Cyclodepsipeptide

Author

Torres, Joshua P., primary, Lin, Zhenjian, additional, Fenton, David S., additional, Leavitt, Lee U., additional, Niu, Changshan, additional, Lam, Pui-Ying, additional, Robes, Jose Miguel, additional, Peterson, Randall T., additional, Concepcion, Gisela P., additional, Haygood, Margo G., additional, Olivera, Baldomero M., additional, and Schmidt, Eric W., additional

Published
2020
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69. Secondary metabolic symbiosis in shipworms (Teredinidae)

Author

Altamia, Marvin A., Lin, Zhenjian, Trindade-Silva, Amaro E., Uy, Iris Diana, Shipway, J. Reuben, Wilke, Diego Veras, Concepcion, Gisela P., Distel, Daniel L., Schmidt, Eric W., and Haygood, Margo G.

Subjects
animal structures, fungi
Abstract

Shipworms, assisted by intracellular γ-proteobacteria in their gills, are the principal degraders of wood in the sea. Shipworm symbionts have been cultivated in the laboratory. The genomes of these symbionts, in addition to being replete with lytic enzymes capable of degrading wood and/or enzymes of thioautotrophic metabolism, are among the bacterial genomes richest in secondary metabolite genes. These cultivated symbionts represent the dominant species in the gills in diverse shipworm species. We investigated how the isolate secondary metabolites might impact the host animals: which bacterial pathways are present, how widely distributed they are, and how they vary. Focusing on 14 wood-eating shipworm specimens, we found between one to three major bacterial species in each gill, with each species comprising a complex mixture of closely related strains. The mixture allows the shipworm host to access a much more complex metabolism than can be afforded by a single symbiont strain. We analyzed sequences from 22 shipworm gill metagenomes from seven shipworm species and compared them with the genomes of 23 cultivated bacterial isolates from shipworm gills. Limiting our analyses to well-characterized biosynthetic gene families, we found more than 400 polyketide, nonribosomal peptide, and related biosynthetic gene clusters, only a handful of which resemble known ones, comprising over 100 gene cluster families (GCFs). Only four GCFs are found in all specimens investigated. Several GCFs exhibited a host species-specific distribution, but most occurred stochastically. Shipworms and their symbionts thus provide a model system for understanding the role of secondary metabolism in symbioses. Significance Shipworms play critical roles in recycling wood in the sea and in shaping mangrove habitats. Symbiotic bacteria supply the enzymes that they need for nutrition and wood degradation. Here, we show that the same nutritional symbionts also have an immense capacity to produce a multitude of diverse and likely novel bioactive secondary metabolites. The compounds likely support the ability of shipworms to degrade wood in marine environments and include a compound under investigation for its therapeutic potential. Because many of the symbionts can be cultivated, they provide a model for understanding how secondary metabolism impacts microbial symbiosis in animals.

Published
2019
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70. Theopalauamide, a bicyclic glycopeptide from filamentous bacterial symbionts of the lithistid sponge Theonella swinhoei from Palau and Mozambique

Author

Schmidt, Eric W., Bewley, Carole A., and Faulkner, D. John

Subjects
Peptides -- Research, Stereochemistry -- Research, Biological sciences, Chemistry
Abstract

Symbiotic filamentous bacteria of the sponge Theonella swinhoei contain a major bicyclic peptide called theopalauamide. Proton nuclear magnetic resonance studies, gas chromatographic analysis and mass spectrometry were undertaken to determine its stereochemistry. The analysis of the degradation products of theopalauamide by chiral GC-MS helped in establishing the stereochemical characteristics of this compound.

Published
1998

71. A Single Amino Acid Switch Alters the Isoprene Donor Specificity in RiPP Prenyltransferases

Author

Estrada, Paola, Morita, Maho, Hao, Yue, Schmidt, Eric W., and Nair, Satish K.

Subjects
Models, Molecular, Hemiterpenes, Butadienes, Molecular Conformation, Amino Acids, Dimethylallyltranstransferase, Peptides, Protein Processing, Post-Translational, Ribosomes, Article
Abstract

Mutation at a single amino acid alters the isoprene donor specificity of prenyltransferases involved in the modification of ribosomally synthesized and post-translationally modified peptides (RiPPs). While most characterized RiPP prenyltransferases carry out the regiospecific transfer of C(5) dimethylallyl donor to the side chain atoms on macrocyclic acceptor substrates, the elucidation of the cyanobactin natural product piricyclamide 70005E1 identifies an O-geranyl modification on Tyr, a reaction with little prior biochemical precedence. Reconstitution and kinetic studies of the presumptive geranyltransferase PirF shows that the enzyme utilizes a C(10) donor, with no C(5) transferase activity. The crystal structure of PirF reveals a single amino acid difference in the vicinity of the isoprene-binding pocket, relative to the C(5) utilizing enzymes. Remarkably, only a single amino acid mutation is necessary to completely switch the donor specificity from a C(5) to a C(10) prenyltransferase, and vice versa. Lastly, we demonstrate that these enzymes may be used for the chemospecific attachment of C(5) or C(10) lipid groups on lanthipeptides, an unrelated class of RiPP natural products. These studies represent a rare example where prenyl donor specificity can be discretely altered, which expands the arsenal of synthetic biology tools for tuning biological activities of peptide natural products.

Published
2018

72. The biochemistry and structural biology of cyanobactin biosynthetic enzymes

Author

Gu, Wenjia, Dong, Shi-Hui, Sarkar, Snigdha, Nair, Satish K., and Schmidt, Eric W.

Subjects
Tyrosine, Dimethylallyltranstransferase, Peptides, Cyclic, Article, Biosynthetic Pathways, Enzymes, Peptide Hydrolases
Abstract

Cyanobactin biosynthetic enzymes have exceptional versatility in the synthesis of natural and unnatural products. Cyanobactins are ribosomally synthesized and post-translationally modified peptides (RiPPs) synthesized by multistep pathways involving a broad suite of enzymes, including heterocyclases / cyclodehydratases, macrocyclases, proteases, prenyltransferases, methyltransferases, and others. Here, we describe the enzymology and structural biology of cyanobactin biosynthetic enzymes, aiming at the twin goals of understanding biochemical mechanisms and biosynthetic plasticity. We highlight how this common suite of enzymes may be utilized to generate a large array or structurally and chemically diverse compounds.

Published
2018

74. Secondary metabolism in the gill microbiota of shipworms (Teredinidae) as revealed by comparison of metagenomes and nearly complete symbiont genomes

Author

Altamia, Marvin A., primary, Lin, Zhenjian, additional, Trindade-Silva, Amaro E., additional, Uy, Iris Diana, additional, Shipway, J. Reuben, additional, Wilke, Diego Veras, additional, Concepcion, Gisela P., additional, Distel, Daniel L., additional, Schmidt, Eric W., additional, and Haygood, Margo G., additional

Published
2019
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77. Mindapyrroles A–C, Pyoluteorin Analogues from a Shipworm-Associated Bacterium

Author

Lacerna, Noel M., primary, Miller, Bailey W., additional, Lim, Albebson L., additional, Tun, Jortan O., additional, Robes, Jose Miguel D., additional, Cleofas, Mark Jeremiah B., additional, Lin, Zhenjian, additional, Salvador-Reyes, Lilibeth A., additional, Haygood, Margo G., additional, Schmidt, Eric W., additional, and Concepcion, Gisela P., additional

Published
2019
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79. The hidden diversity of ribosomal peptide natural products

Author

Schmidt Eric W

Subjects
Biology (General), QH301-705.5
Abstract

Abstract A recent report in BMC Biology on the discovery and analysis of biosynthetic genes for ribosomal peptide natural products confirms that these pathways are much more common and diverse than previously suspected, contributing substantially to the chemical arsenal employed by bacteria. See research article http://www.biomedcentral.com/1741-7007/8/70

Published
2010
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86. Chemical Metagenomics of an Anti-HIV Compound From Uncultivated Symbionts

Author

Smith, Thomas E., primary, Pond, Christopher D., additional, Pierce, Elizabeth, additional, Harmer, Zachary P., additional, Kwan, Jason, additional, Zachariah, Malcom M., additional, Harper, Mary Kay, additional, Wyche, Thomas P., additional, Matainaho, Teatulohi K., additional, Bugni, Tim S., additional, Barrows, Louis R., additional, Ireland, Chris M., additional, and Schmidt, Eric W., additional

Published
2018
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87. Accessing chemical diversity from the uncultivated symbionts of small marine animals

Author

Smith, Thomas E, primary, Pond, Christopher D, additional, Pierce, Elizabeth, additional, Harmer, Zachary P, additional, Kwan, Jason, additional, Zachariah, Malcolm M, additional, Harper, Mary Kay, additional, Wyche, Thomas P, additional, Matainaho, Teatulohi K, additional, Bugni, Tim S, additional, Barrows, Louis R, additional, Ireland, Chris M, additional, and Schmidt, Eric W, additional

Published
2018
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89. Cysteine-Free Intramolecular Ligation of N-Sulfanylethylanilide Peptide Using 4-Mercaptobenzylphosphonic Acid : Synthesis of Cyclic Peptide Trichamide

Author

Aihara, Keisuke, Inokuma, Tsubasa, Jichu, Takahisa, Lin, Zhenjian, Fu, Feixue, Yamaoka, Kosuke, Shigenaga, Akira, Hutchins, David A., Schmidt, Eric W., Otaka, Akira, Aihara, Keisuke, Inokuma, Tsubasa, Jichu, Takahisa, Lin, Zhenjian, Fu, Feixue, Yamaoka, Kosuke, Shigenaga, Akira, Hutchins, David A., Schmidt, Eric W., and Otaka, Akira

Abstract

An N-sulfanylethylanilide (SEAlide)-based ligation was developed for the preparation of trichamide, a thiazole-containing cyclic peptide isolated from bloom-forming cyanobacterium Trichodesmium erythraeum. In this cysteine-free ligation, 4-mercaptobenzylphosphonic acid (MBPA) functions as a dual promoter both for the N–S acyl-transfer-mediated activation of the SEAlide unit and for subsequent ligation. Furthermore, we established a high-yielding route to enantiomerically pure thiazole amino acids using a one-pot Hantzsch process.

Published
2017

90. Linking neuroethology to the chemical biology of natural products:interactions between cone snails and their fish prey, a case study

Author

Olivera, Baldomero M., Raghuraman, Shrinivasan, Schmidt, Eric W., Safavi-Hemami, Helena, Olivera, Baldomero M., Raghuraman, Shrinivasan, Schmidt, Eric W., and Safavi-Hemami, Helena

Abstract

From a biological perspective, a natural product can be defined as a compound evolved by an organism for chemical interactions with another organism including prey, predator, competitor, pathogen, symbiont or host. Natural products hold tremendous potential as drug leads and have been extensively studied by chemists and biochemists in the pharmaceutical industry. However, the biological purpose for which a natural product evolved is rarely addressed. By focusing on a well-studied group of natural products—venom components from predatory marine cone snails—this review provides a rationale for why a better understanding of the evolution, biology and biochemistry of natural products will facilitate both neuroscience and the potential for drug leads. The larger goal is to establish a new sub-discipline in the broader field of neuroethology that we refer to as “Chemical Neuroethology”, linking the substantial work carried out by chemists on natural products with accelerating advances in neuroethology.

Published
2017

91. Circular logic: nonribosomal peptide-like macrocyclization with a ribosomal peptide catalyst

Author

McIntosh, John A., Robertson, Charles R., Agarwal, Vinayak, Nair, Satish K., Bulaj, Grzegorz W., and Schmidt, Eric W.

Subjects
Peptides -- Structure, Peptides -- Chemical properties, Polyketides -- Chemical properties, Proteases -- Structure, Proteases -- Chemical properties, Ribosomes -- Structure, Ribosomes -- Chemical properties, Thioesters -- Chemical properties, Chemistry
Abstract

A protease from ribosomal peptide biosynthesis with the ability to macrocyclize diverse substrates, including those resembling nonribosomal peptide and hybrid polyketide-peptide products is reported. The proposed mechanism is equivalent to thioesterase-catalyzed chemistry, but the substrates are amide bonds rather than thioesters.

Published
2010

92. Insights into heterocyclization from two highly similar enzymes

Author

McIntosh, John A., Donia, Mohamed S., and Schmidt, Eric W.

Subjects
Ring formation (Chemistry) -- Analysis, Chemistry
Abstract

The cyanobactin biosynthetic pathways pat and tru, isolated from metagenomes of marine animals, which gave diverse natural products containing heterocycles derived from Cys, Ser, and Thr are reported. The product chemistry in the hypervariable family of marine natural products is explained by the differences in the N-terminal putative catalytic domains and C-terminal putative substrate-binding.

Published
2010

93. Microhabitats within venomous cone snails contain diverse actinobacteria

Author

Peraud, Olivier, Biggs, Jason S., Hughen, Ronald W., Light, Alan R., Concepcion, Gisela P., Olivera, Baldomero M., and Schmidt, Eric W.

Subjects
Actinomycetes -- Environmental aspects, Cone snails -- Environmental aspects, Cone snails -- Physiological aspects, Host-bacteria relationships -- Analysis, Biological sciences
Abstract

The study employs a microhabitat approach to analyze the different antimycetes and actinobacteria associated with the different venomous cone snails. The results prove that the various antimyocetes obtained from these cone snails can be widely used for the discovery of a large number of drugs.

Published
2009

94. Using marine natural products to discover a protease that catalyzes peptide macrocyclization of diverse substrates

Author

Jaeheon Lee, McIntosh, John, Hathaway, Brian J., and Schmidt, Eric W.

Subjects
Cyanobacteria -- Genetic aspects, Cyanobacteria -- Physiological aspects, Ring formation (Chemistry) -- Analysis, Peptides -- Chemical properties, Ribosomes -- Chemical properties, Chemistry
Abstract

The in vitro activity of enzymes is described by defining their role in cyclization of natural and artificial peptides and has also provided the first in vivo study of natural ribosomal peptide N-C cyclization. The close relative of cyanobactin gene cluster, PatG, has catalyzed the synthesis of additional known natural products and the wholly synthetic peptide, eptidemnamide, is cyclized by PatG in vivo and in vitro.

Published
2009

95. Characterization of SafC, catechol 4-O-methyltransferase involved in saframycin biosynthesis

Author

Nelson, James T., Jaeheon Lee, Sims, James W., and Schmidt, Eric W.

Subjects
Methyltransferases -- Analysis, Biosynthesis -- Analysis, Catechin -- Analysis, Biological sciences
Abstract

The study explains the synthesis and characterization of SafC, a catechol 4-O-methyltransferase protein, which is commonly used for the biosynthesis of various saframycin products. SafC has the ability to methylate a variety of catechols and hence can be used in many medical and biological applications.

Published
2007

99. Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis

Author

Zhang, Shuwei, primary, Qiu, Yixing, additional, Kakule, Thomas B., additional, Lu, Zhenyu, additional, Xu, Fuchao, additional, Lamb, John G., additional, Reilly, Christopher A., additional, Zheng, Yong, additional, Sham, Shing Wo Simon, additional, Wang, Wei, additional, Xuan, Lijiang, additional, Schmidt, Eric W., additional, and Zhan, Jixun, additional

Published
2017
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100. Genetic and Biochemical Reconstitution of Bromoform Biosynthesis in AsparagopsisLends Insights into Seaweed Reactive Oxygen Species Enzymology

Author

Thapa, Hem R., Lin, Zhenjian, Yi, Dongqi, Smith, Jennifer E., Schmidt, Eric W., and Agarwal, Vinayak

Abstract

Marine macroalgae, seaweeds, are exceptionally prolific producers of halogenated natural products. Biosynthesis of halogenated molecules in seaweeds is inextricably linked to reactive oxygen species (ROS) signaling as hydrogen peroxide serves as a substrate for haloperoxidase enzymes that participate in the construction these halogenated molecules. Here, using red macroalga Asparagopsis taxiformis, a prolific producer of the ozone depleting molecule bromoform, we provide the discovery and biochemical characterization of a ROS-producing NAD(P)H oxidase from seaweeds. This discovery was enabled by our sequencing of Asparagopsisgenomes, in which we find the gene encoding the ROS-producing enzyme to be clustered with genes encoding bromoform-producing haloperoxidases. Biochemical reconstitution of haloperoxidase activities establishes that fatty acid biosynthesis can provide viable hydrocarbon substrates for bromoform production. The ROS production haloperoxidase enzymology that we describe here advances seaweed biology and biochemistry by providing the molecular basis for decades worth of physiological observations in ROS and halogenated natural product biosyntheses.

Published
2020
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