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Moore, BS.  2018.  Asymmetric Alkene and Arene Halofunctionalization Reactions in Meroterpenoid Biosynthesis. Synlett. 29:401-409.   10.1055/s-0036-1590919   AbstractWebsite

Meroterpenoid natural products are important bioactive molecules with broad distribution throughout nature. In Streptomyces bacteria, naphthoquinone-based meroterpenoids comprise a simple yet structurally fascinating group of natural product antibiotics that are enzymatically constructed through a series of asymmetric alkene and arene halofunctionalization reactions. This account article highlights our discovery and characterization of a group of vanadium-dependent chloroperoxidase enzymes that catalyze halogen-assisted cyclization and rearrangement reactions and have inspired biomimetic syntheses of numerous meroterpenoid natural products. 1 Introduction 2 Early Biosynthetic Insights and the Characterization of Alkene Halofunctionalization in Napyradiomycin Biosynthesis 3 Discovery of the Merochlorin Natural Products and Enzymatic Aryl Halofunctionalization 4 Discovery and Development of Unifying THN-Based Meroterpenoid Biosynthesis and Synthesis Approaches 5 Insights into Naphterpin and Marinone Biosynthesis Involving Cryptic Aryl Halofunctionalization Reactions 6 Closing Thoughts

Larson, CB, Crusemann M, Moore BS.  2017.  PCR-independent method of transformation-associated recombination reveals the cosmomycin biosynthetic gene cluster in an ocean streptomycete. Journal of Natural Products. 80:1200-1204.   10.1021/acs.jnatprod.6b01121   AbstractWebsite

The transformation-associated recombination cloning methodology facilitates the genomic capture and heterologous expression of natural product biosynthetic gene clusters (BGCs). We have streamlined this procedure by introduction of synthetic DNA gene blocks for the efficient capture of BGCs. We show the successful capture and expression of the aromatic polyketide antitumor agent cosmomycin from streptomycete bacteria and the discovery of new cosmomycin analogues by mass spectral molecular networking.

Jordan, PA, Moore BS.  2016.  Biosynthetic pathway connects cryptic ribosomally synthesized posttranslationally modified peptide genes with pyrroloquinoline alkaloids. Cell Chemical Biology. 23:1504-1514.   10.1016/j.chembiol.2016.10.009   AbstractWebsite

In an era where natural product biosynthetic gene clusters can be rapidly identified from sequenced genomes, it is unusual for the biosynthesis of an entire natural product class to remain unknown. Yet, the genetic determinates for pyrroloquinoline alkaloid biosynthesis have remained obscure despite their abundance and deceptive structural simplicity. In this work, we have identified the biosynthetic gene cluster for ammosamides A-C, pyrroloquinoline alkaloids from Streptomyces sp. CNR-698. Through direct cloning, heterologous expression and gene deletions we have validated the ammosamide biosynthetic gene cluster and demonstrated that these seemingly simple molecules are derived from a surprisingly complex set of biosynthetic genes that are also found in the biosynthesis of lymphostin, a structurally related pyrroloquinoline alkaloid from Salinispora and Streptomyces. Our results implicate a conserved set of genes driving pyrroloquinoline biosynthesis that consist of genes frequently associated with ribosomal peptide natural product biosynthesis, and whose exact biochemical role remains enigmatic.

Teufel, R, Kaysser L, Villaume MT, Diethelm S, Carbullido MK, Baran PS, Moore BS.  2014.  One-pot enzymatic synthesis of merochlorin A and B. Angewandte Chemie-International Edition. 53:11019-11022.   10.1002/anie.201405694   AbstractWebsite

The polycycles merochlorinA and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH-189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis invitro. The interplay of a dedicated typeIII polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide-terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by invivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorinA and isomeric merochlorinB by a single vanadium-dependent haloperoxidase, thus completing the remarkably efficient pathway.

Kalaitzis, JA, Cheng Q, Meluzzi D, Xiang LK, Izumikawa M, Dorrestein PC, Moore BS.  2011.  Policing starter unit selection of the enterocin type II polyketide synthase by the type II thioesterase EncL. Bioorganic & Medicinal Chemistry. 19:6633-6638.   10.1016/j.bmc.2011.04.024   AbstractWebsite

Enterocin is an atypical type II polyketide synthase (PKS) product from the marine actinomycete 'Streptomyces maritimus'. The enterocin biosynthesis gene cluster (enc) codes for proteins involved in the assembly and attachment of the rare benzoate primer that initiates polyketide assembly with the addition of seven malonate molecules and culminates in a Favorskii-like rearrangement of the linear poly-beta-ketone to give its distinctive non-aromatic, caged core structure. Fundamental to enterocin biosynthesis, which utilizes a single acyl carrier protein (ACP), EncC, for both priming with benzoate and elongating with malonate, involves maintaining the correct balance of acyl-EncC substrates for efficient polyketide assembly. Here, we report the characterization of EncL as a type II thioesterase that functions to edit starter unit (mis)priming of EncC. We performed a series of in vivo mutational studies, heterologous expression experiments, in vitro reconstitution studies, and Fourier-transform mass spectrometry-monitored competitive enzyme assays that together support the proposed selective hydrolase activity of EncL toward misprimed acetyl-ACP over benzoyl-ACP to facilitate benzoyl priming of the enterocin PKS complex. While this system resembles the R1128 PKS that also utilizes an editing thioesterase (ZhuC) to purge acetate molecules from its initiation module ACP in favor of alkylacyl groups, the enterocin system is distinct in its usage of a single ACP for both priming and elongating reactions with different substrates. (C) 2011 Elsevier Ltd. All rights reserved.

Lane, AL, Moore BS.  2011.  A sea of biosynthesis: marine natural products meet the molecular age. Natural Product Reports. 28:411-428.   10.1039/c0np90032j   AbstractWebsite

The years 2000 through mid-2010 marked a transformational period in understanding of the biosynthesis of marine natural products. During this decade the field emerged from one largely dominated by chemical approaches to understanding biosynthetic pathways to one incorporating the full force of modern molecular biology and bioinformatics. Fusion of chemical and biological approaches yielded great advances in understanding the genetic and enzymatic basis for marine natural product biosynthesis. Progress was particularly pronounced for marine microbes, especially actinomycetes and cyanobacteria. During this single decade, both the first complete marine microbial natural product biosynthetic gene cluster sequence was released as well as the first entire genome sequence for a secondary metabolite-rich marinemicrobe. The decade also saw tremendous progress in recognizing the key role of marine microbial symbionts of invertebrates in natural product biosynthesis. Application of genetic and enzymatic knowledge led to genetic engineering of novel "unnatural'' natural products during this time, as well as opportunities for discovery of novel natural products through genome mining. The current review highlights selected seminal studies from 2000 through to June 2010 that illustrate breakthroughs in understanding of marine natural product biosynthesis at the genetic, enzymatic, and small-molecule natural product levels. A total of 154 references are cited.

Louie, GV, Bowman ME, Moffitt MC, Baiga TJ, Moore BS, Noel JP.  2006.  Structural determinants and modulation of substrate specificity in phenylalanine-tyrosine ammonia-lyases. Chemistry & Biology. 13:1327-1338.   10.1016/j.chembiol.2006.11.011   AbstractWebsite

Aromatic amino acid ammonia-lyases catalyze the deamination of L-His, L-Phe, and L-Tyr, yielding ammonia plus aryl acids bearing an alpha, beta-unsaturated propenoic acid. We report crystallographic analyses of unliganded Rhodobacter sphaeroides tyrosine ammonia-tyase (RsTAL) and RsTAL bound to p-coumarate and caffeate. His 89 of RsTAL forms a hydrogen bond with the p-hydroxyl moieties of coumarate and caffeate. His 89 is conserved in TALs but replaced in phenylalanine ammonia-tyases (PALs) and histidine ammonia-tyases (HALs). Substitution of His 89 by Phe, a characteristic residue of PALs, yields a mutant with a switch in kinetic preference from L-Tyr to L-Phe. Structures of the H89F mutant in complex with the PAL product, cinnamate, or the PAL-specific inhibitor, 2-aminoindan-2-phosphonate (AIP), support the role of position 89 as a specificity determinant in the family of aromatic amino acid ammonia-lyases and amino-mutases responsible for beta-amino acid biosynthesis.

Xiang, L, Kalaitzis JA, Moore BS.  2004.  EncM, a versatile enterocin biosynthetic enzyme involved in Favorskii oxidative rearrangement, aldol condensation, and heterocycle-forming reactions. Proceedings of the National Academy of Sciences of the United States of America. 101:15609-15614.   10.1073/pnas.0405508101   AbstractWebsite

The bacteriostatic natural product enterocin from the marine microbe "Streptomyces maritimus" has an unprecedented carbon skeleton that is derived from an aromatic polyketide biosynthetic pathway. Its caged tricyclic, nonaromatic core is derived from a linear poly-beta-ketide precursor that formally undergoes a Favorskii-like oxidative rearrangement. In vivo characterization of the gene encM through mutagenesis and heterologous biosynthesis demonstrated that its protein product not only is solely responsible for the oxidative C-C rearrangement, but also facilitates two aldol condensations plus two heterocycle forming reactions. In total, at least five chiral centers and four rings are generated by this multifaceted flavoprotein. Heterologous expression of the enterocin biosynthesis genes encABCDLMN in Streptomyces lividans resulted in the formation of the rearranged metabolite desmethyl-5-deoxyenterocin and the shunt products wailupemycins D-G. Addition of the methyltransferase gene encK, which was previously proposed through mutagenesis to additionally assist EncM in the Favorskii rearrangement, shifted the production to the O-methyl derivative 5-deoxyenterocin. The O-methyltransferase EncK seems to be specific for the pyrone ring of enterocin, because bicyclic polyketides bearing pyrone rings are not methylated in vivo. Expression of encM with different combinations of homologous actinorhodin biosynthesis genes did not result in the production of oxidatively rearranged enterocin-actinorhodin hybrid compounds as anticipated, suggesting that wild-type EncM may be specific for its endogenous type II polyketide synthase or for benzoyl-primed polyketide precursors.

Kalaitzis, JA, Hamano Y, Nilsen G, Moore BS.  2003.  Biosynthesis and structural revision of neomarinone. Organic Letters. 5:4449-4452.   10.1021/ol035748b   AbstractWebsite

The biosynthesis of the meroterpenoid neomarinone from a marine actinomycete was probed through feeding experiments with C-13-labeled precursors. NMR characterization of [U-C-13(6)]glucose-enriched neomarinone led to the structural revision of structure 4a to 4b, which was confirmed by extensive 2D NMR spectrometry with unlabeled compound.