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Dissertations / Theses on the topic 'Polyketides'

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Published: 4 June 2021
Last updated: 31 July 2024

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1

Wang, Siyuan. "Engineering of polyketide biosynthetic pathways for bioactive molecules." DigitalCommons@USU, 2016. https://digitalcommons.usu.edu/etd/4684.

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Polyketides are a large group of structurally diverse natural products that have shown a variety of biological activities. These molecules are synthesized by polyketide synthases (PKSs). PKSs are classified into three types based on their sequence, primary structure, and catalytic mechanism. Because of the bioactivities of polyketide natural products, this study is focused on the engineering of PKS pathways for efficient production of useful bioactive molecules or structural modification to create new molecules for drug development. One goal of this research is to create an efficient method to produce pharmaceutically important molecules. Seven biosynthetic genes from plants and bacteria were used to establish a variety of complete biosynthetic pathways in Escherichia coli to make valuable plant natural products, including four phenylpropanoid acids, three bioactive natural stilbenoids, and three natural curcuminoids. A curcumin analog dicafferolmethane was synthesized by removing a methyltransferase from the curcumin biosynthetic pathway. Furthermore, introduction of a fungal flavin-dependent halogenase into the resveratrol biosynthetic pathway yielded a novel chlorinated molecule 2-chloro-resveratrol. This demonstrated that biosynthetic enzymes from different sources can be recombined like legos to make various plant natural products, which is more efficient (2-3 days) than traditional extraction from plants (months to years). Phenylalanine ammonia-lyase (PAL) is a key enzyme involved in the first biosynthetic step of some plant phenylpropanoids. Based on the biosynthetic pathway of curcuminoids, a novel and efficient visible reporter assay was established for screening of phenylalanine ammonia-lyase (PAL) efficiency in Escherichia coli. The other goal of this research is to characterize and engineer natural product biosynthetic pathways for new bioactive molecules. The biosynthetic gene cluster of the antibacterial compound dutomycin was discovered from Streptomyces minoensis NRRL B-5482 through genome sequencing. Confirmation of the involvement of this gene cluster in dutomycin biosynthesis and creation of a series of new molecules were successfully conducted by rationally modifying the biosynthetic pathway. More importantly, a new demethylated analog of dutomycin was found to have much higher antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.
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2

Hager, Dominik. "From nucleosides to alkaloids and polyketides." Diss., Ludwig-Maximilians-Universität München, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-153975.

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This dissertation describes the synthetic work on several natural products including nucleosides, alkaloids, and polyketides. The first and main part of this thesis focuses on the total synthesis of the nucleoside antibiotics herbicidin C and its hydrolysis product aureonuclemycin. Due to their diverse biological activity, the herbicidins are considered as promising herbicides for agricultural application. In cooperation with Bayer CropScience AG, a flexible and efficient access to the herbicidins was developed and the challenges and successes of this synthesis are described in detail. More specifically, the route to the undecose moiety integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations. The nucleobase was introduced by a surprisingly facile and highly diastereoselective late-stage N-glycosylation. In addition to that, natural herbicidin A was transformed into promising derivatives and all compounds, including the intermediates of the total synthesis, were provided to Bayer CropScience AG for a structure activity relationship study (SAR). A list of all provided derivatives is given at the end of the thesis. The progress toward the synthesis of stephadiamine is described in the second chapter of this thesis. The natural product is the first example of a C-norhasubanan alkaloid natural product and despite its structural beauty, no total synthesis of stephadiamine has been reported to date. The proposed racemic retrosynthetic analysis of stephadiamine makes use of a Curtius rearrangement and a late lactonization. The propellane skeleton of this alkaloid was envisioned to be made by means of a homoconjugated addition/Mannich cascade of the key enamine in an extremely efficient manner. An alternative strategy is proposed for future work, which includes a Tsuji-Trost allylation arising the potential for an enantioselective synthesis of stephadiamine. In chapter III, the progress toward the divergolides C and D is presented. Attention was focused on the large scale preparation of the volatile side chain, and its unusual isolation method is pointed out in detail. In addition, the assembly of the three main building blocks is discussed. The preparation of Legionella autoinducer 1 (LAI-1) is described in chapter IV. The bacterial signaling molecule LAI-1 belongs to the class of alpha-hydroxyketones (AHKs). Given the effects of LAI-1 on virulence and motility of the bacteria L. pneumophila, this signaling molecule has the potential for clinical or technical applications. For a deeper understanding of the signaling circuit in L. pneumophila and in order to gain more insight in the mechanism of cell-cell communication, synthetic LAI-1 was prepared and provided to the research group of H. Hilbi, who investigates the gene regulation by AHK-mediated signaling. Chapter V includes the experimental procedures for the preparation of all compounds, backed up by full analytical characterization. In addition, 1H- and 13C-NMR spectra as well as crystallographic details are given.
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3

Zhang, Wenjun. "Engineered biosynthesis of bacterial aromatic polyketides." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1905657321&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.

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4

Macpherson, Gordon R. "Biosynthesis of polyketides produced by marine microbes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ66668.pdf.

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5

Iqbal, Zafar. "Biosynthetic studies of strobilurin & mupirocin polyketides." Thesis, University of Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535223.

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6

Loughran, Mark Stephen. "The biosynthesis of erythromycin." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307943.

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7

Tam, Wan-ting, and 譚韻婷. "Characterization of polyketide synthases in penicillium marneffei." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/197137.

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Penicillium marneffei is a thermal dimorphic fungus that causes systemic mycosis in HIV-positive patients. The fungus displays unique phenotypic properties, including the yellow and black pigments on its conidia as well as the secretion of a diffusible red pigment during growth in mycelial phase. However, all these pigments have not been characterized. Investigation into the pigment production of the fungus can provide insights into the functions of the respective pigment to the fungus as well as their roles in fungal pathogenesis. This study reports the identification and characterization of 23 polyketide synthase (PKS) and 2 polyketide synthase non-ribosomal peptide synthase hybrid (PKS-NRPS) genes in the genome of P. marneffei. Systematic knockdown of the PKS genes showed a loss of black pigment on the conidia of the pks4 (alb1) knockdown mutant, a loss of yellow pigment in the mycelial form of pks11 and pks12 knockdown mutants and a loss of red pigment production in the pks3 knockdown mutant. PKS4 in P. marneffei is responsible for melanin production. Knockdown of pks4 resulted in the loss of melanin production and reduced ornamentation on the conidial surface. Mice that were challenged with the pks4 knockdown mutant survived significantly better than those challenged with wild type conidia (P<0.005). The sterilizing doses of hydrogen peroxide giving a 50% survival reduction of the fungal conidia were 11 minutes and 6 minutes for wild type and the pks4 knockdown mutant, respectively. These together suggested that melanin in P. marneffei contributed to its pathogenesis by reducing its susceptibility to killing by hydrogen peroxide. HPLC-MS analysis revealed the identity of the yellow pigment of P. marneffei to be mitorubrinic acid and mitorubrinol. Mice that were challenged with the pks11and pks12 knockdown mutants survived significantly better than those challenged with wild type conidia (P<0.05). The survival of the pks11and pks12 knockdown mutants in J774 and THP1 macrophages were also both significantly lower than the wild type, suggesting mitorubrinic acid and mitorubrinol contribute to fungal pathogenesis by improving its survival in macrophages. The red pigment secreted by P. marneffei was found to compose of monascorubrin, rubropunctatin, ankaflavin, citrinin and different amino acid conjugated with monascorubrin/rubropunctatin. The biosynthetic pathway of the red pigment involved a polyketide synthase (pks3), a transcription activator (rp1), a fatty acid synthase subunit beta (rp2), a 3-oxoacyl-[acyl-carrier-protein] synthase (rp3) and an oxidoreductase (rp4). RP2, PR3 and RP4 are responsible for fatty acid production. PKS3 is responsible for the biosynthesis of an intermediate polyketide, and RP1 is responsible for the biosynthetic activation. Through esterification, the fatty acid attaches to the intermediate polyketide to form monascorubin, an orange pigment, which is secreted out of the cell. Amino acids in the culture medium were found to conjugate with monascorubrin to form pigments ranging from orange to red in color. Ankaflavin is synthesized by the reduction of monascorubrin. PKS3 and RP1 are also responsible for the biosynthesis of citrinin. In conclusion, the chemical composition, biosynthetic pathways and potential roles in virulence of the black, yellow and red pigments in P. marneffei were characterized.
published_or_final_version
Microbiology
Doctoral
Doctor of Philosophy
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8

König, Ariane. "Genes for macrolide formation in rapamycin biosynthesis from Streptomyces hygroscopicus." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264158.

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9

Hill, Alison Margaret. "The biosynthesis of aspyrone." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319492.

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10

He, Weiguo. "Biochemical analysis of polyketide synthases domains and modules." View abstract/electronic edition; access limited to Brown University users, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3318326.

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11

Findlay, A. D. "Total synthesis and structural assignment of antimitotic polyketides." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599022.

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The first part of this dissertation describes the revised stereochemical assignment of the cytotoxic marine macrolide dolastain 19, isolated from the sea hare Dolabella auricularia, which was proposed and subsequently validated by completion of the first total synthesis. Based upon molecular modelling and common biogenetic considerations, four of the twelve stereocentres of the originally proposed structure 50 were inverted in configuration. The carbon backbone 56 of this stereochemically reassigned 14-membered macrolide 54 was assembled using an asymmetric vinylogous Mukaiyama aldol reaction, in combination with boron aldol methodology. A Mukaiyama glycosylation was employed to append the required L-rhamose-derived sugar unit 44. Overall the synthesis was completed in 23 steps and 1.7% overall yield. The second part of this dissertation focuses on the myxobacterium-derived natural product, spirangien A (124). Initial work centred on the preparation of an advanced diene degradation fragment 134, and the subsequent assignment of absolute configuration. The use of a common stereotetrad intermediate 149 was crucial in the development of a convergent and step-economic synthetic strategy. Two series of reactions were performed to access 234 and 148, before recombination via aldol coupling. Elaboration of linear spiroacetalisation precursor 244 provided synthetic spirangien diene 134. Measurement of the optical rotation and comparison with available literature data for natural 134 then enabled the confident assignment of the complete stereochemistry of spirangien A. Laterally, studies focussed on the extension of this synthetic strategy to enable the completion of the total synthesis of spirangien A.
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12

Lou, Samuel. "Stereochemical Control of Polyketides through Asymmetric Aldol Reaction." Master's thesis, Virginia Tech, 2000. http://hdl.handle.net/10919/37095.

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Polyketides are a group of complex natural products that can inhibit the growth of bacteria, viruses, fungi, and tumor cells. Most polyketides are very difficult to extract from bacteria. Therefore, numerous syntheses of polyketide-related synthons have been attempted.

However, controlling the stereochemistry of the polyketide poses the most challenging task for researchers. The aim of this report is to discuss control of the stereochemistry of the polyketide-related synthons in asymmetric aldol reactions. Several important methodologies for stereochemical control in the aldol reaction exist. The first approach is to control the enolate geometry and the aldehyde (or ketone) geometry. The second approach is to use a chiral auxiliary and chiral ligands. The third approach is to use a chiral catalyst, which is the most efficient method if the catalyst operates with complete efficiency. Proposed transition states are also described to explain the resulting stereochemistry of the aldol adduct.
Master of Science

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13

Ackrill, Thomas. "Synthetic and biosynthetic studies on polyketides and diarylheptanoids." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682231.

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This thesis describes the synthesis of putative intermediates to investigate the biosynthesis of the polyketide bacillaene and the development of a novel cyclisation reaction and its application towards the total synthesis of calyxin I. Chapter one describes the design and synthesis of a variety of analogues required for the investigation of the biosynthesis of bacillaene, a natural product isolated from extracts of Bacillus subtilis Chapter two describes the development of a new cyclisation reaction using y,δ-unsaturated alcohols with a pendant phenol and an electrophile. After much investigation a robust route was developed to y,δ-unsaturated alcohol 203 from 2-hydroxycinnamaldehyde via a asymmetric 1 ,4-conjugate addition followed by a Grignard reaction. Cyclisation of 203 with panisaldehyde in the presence of TMSOTf gave a tricyclic product 209 in 75% yield with two rings and three new stereocenters formed in one step. The final chapter describes the application of our new methodology towards the total synthesis of natural product calyxin I.
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14

Jacobs, Adam. "Aspyrone biosynthesis." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241064.

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15

Bhatia, Mohamed. "Synthetic studies towards the solanapyrones." Thesis, University of Salford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365966.

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16

Schicker, Susanna Heidi. "Synthesis of intermediates for chalcone and 6-MSA biosynthesis." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336910.

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17

Less, Simon. "Biosynthetic studies on tetronasin." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364530.

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18

Marimo, Patience. "Steps Towards Deciphering the Post-Polyketide Synthase Tailoring Steps in the Phoslactomycin Biosynthesis Pathway." PDXScholar, 2015. https://pdxscholar.library.pdx.edu/open_access_etds/2408.

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Phoslactomycins (PLMs) are a group of natural products belonging to a polyketides class. These polyketides are synthesized by sequential reaction catalyzed by a collection of enzymes activities called polyketide synthases. A polyketide is a large class of diverse compounds that are characterized by more than two carbonyl groups connected by single intervening carbon atoms. In other words, a polyketide is a polymer whose monomer is a ketide. The PLMs are also known as phosphazomycins or phospholines. These compounds were isolated based on antifungal and antitumor activities. This array of promising biological activities has stimulated research into the field of PLMs for treatment of various diseases such as aspergillosis. A significant success has been reported in understanding and manipulating PLM biosynthesis. However, its post-polyketide biosynthetic mechanism remains to be elucidated. In this study, we established steps needed to pave the way for the elucidation of the post-polyketide synthase tailoring steps in the phoslactomycin biosynthetic pathway. Various, biological activities of polyketide natural products are often linked with specific structural motifs, biosynthetically introduced after construction of the polyketide core. Therefore, investigation of such "post-polyketide synthase (PKS)" modifications is important, and the accumulated knowledge on these processes can be applied for combinatorial biosynthesis to generate new polyketide derivatives with enhanced biological activity. In this study, the enzymes and genes responsible for the modification of the phoslactomycin moiety have been investigated to verify their functions and to study how they are coordinated to achieve the desired phoslactomycin. The proposed modification steps in the PLM biosynthesis pathway involves, PlmT4 a cytochrome P450 monooxygenase, PlmT5, a kinase, and PlmT8 an oxidoreductase. These enzymes were successfully cloned, overexpressed, and purified from an overexpression vector. Mutant strains for two genes plmT4 and plmT8 were either constructed or studied. The function of PlmT4 tailoring enzyme was characterized, by gene disruption and an in vitro enzyme activity assay. The isolation of PLM 1 an intermediate analog from plmT4 mutant strain and the observation of a malonylated PLMs, suggests that the malonyl side chain is introduced during polyketide chain formation These results, will pave the way to delineate the intermediary steps between the PLM PKS product(s) that is released from the PLM PKS and the formation of the final phoslactomycin.
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19

Oldfield, Mark F. "Biosynthesis of fungal polyketides : compactin and 6-methylsalicylic acid." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261336.

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20

McGaw, Oliver. "Studies towards the novel synthesis of benzoisochromane quinone polyketides." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/58538/.

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Granaticin is a structurally unique member of the benzoisochromane quinone (BIQ) family of antibiotics. The molecule and its derivative exhibit a sugar moiety fusted to the naphthazarin core, only exhibited by one other natural compound, by a C-C glycosidic bond and an aldol like bond. The mechanism of enzymatic attachment of this substituent is currently unknown. This project aimed to devise a novel and elegant synthesis towards the granaticin aglycone and other benzoisochromane quinone natural compounds with the long term aim of discerning the mechanism of glycosylation. This thesis shows a novel route for the synthesis of highly substituted isochromane and isochromane quinone compounds towards the eventual synthesis of the desired natural molecules.
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21

Yin, Sen [Verfasser]. "Biosynthesis of fungal alkyl citrates and polyketides / Sen Yin." Hannover : Gottfried Wilhelm Leibniz Universität Hannover, 2020. http://d-nb.info/1220422126/34.

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22

Stössel, Daniel. "Chemistry of 1,3,5-tris (trimethylsiloxy) -1-methoxyhexa-1,3,5-triene." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75352.

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The title compound was synthesized and its chemistry studied for the first time. It reacts with carbon electrophiles initially at its $ epsilon$-position. The condensation with aliphatic imidazolides or similar acylating agents furnished methyl 6-alkyl-2,4-dihydroxy benzoates in a 5C + 1C fashion. Reaction with aromatic imidazolides, also in a 5C + 1C manner, gave unsymmetrical biphenyls with the 2-carbomethoxy-3,5-dihydroxyphenyl moiety. A regiocontrolled synthesis of naphthalene derivatives was developed by reaction with the appropriate 1,3,5-tris-electrophiles in a 5C + 5C fashion.
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23

Bhogal, Pamela. "The incorporation of substrate analogues and proposed intermediates into tetraketide products by 6-methylsalicylic acid synthase." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307098.

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24

Donlevy, Philip James. "The biosynthesis of pseudomonic acid." Thesis, University of Bristol, 1996. http://hdl.handle.net/1983/981be1e9-5a9a-4c42-ab3f-055a64319aad.

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25

Razzak, Mina. "Synthetic studies of bioactive polyketides : the saliniketals, pelorusides and bafilomycins." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/252198.

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26

Zormpaides, Vassilios. "The utilisation of oils in Saccharopolyspora erythraea cultures producing polyketides." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367757.

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27

Le, Sann Christine. "Enantioselective synthesis of N-Acetylcysteamine thioester putative intermediates to polyketides." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340274.

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28

Bayazeed, Abrar Ahmad Ali. "Studies towards the total synthesis of DEM30355/A and related polyketides." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3746.

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DEM30355/A 1 is a novel bioactive natural product polyketide isolated from an Amycolatopsis bacteria. 1 shows antibacterial activity against several pathogenic Gram positive bacteria, including methicillin-resistant Staphylococcus aureus. Thus we have explored the total synthesis of 1 and a number of related polyketide natural products (Figure 1). Figure 1: Structure of DEM30355A 1. In our first attempts towards the synthesis of target molecule 1 we examined several synthetic routes towards a key intermediate 2. These routes included: (a) the synthesis of Wittig product 3, followed by an unsuccessful attempt at a sterically challenging Baylis- Hillman reaction with diethyl ketomalonate 4; (b) following the synthesis of 5, an attempted Lewis acid catalysed Friedel-Crafts reaction between 1,4-dimethoxybenzene 6 and 5; and (c) Heck coupling of 2-bromo-1,4-dimethoxybenzene 8 with 5. The best results were obtained via route (c) although the yields from the Heck coupling were low, prompting us to examine an alternative route (Scheme 1). Scheme 1: Examined routes to key synthetic intermediate 2. Abstract iii We then examined alternative synthetic approaches towards the aromatic ring A of target molecule 1, based on the formation of the synthetic intermediate 9. Compound 11, which contains the core substitution pattern needed to create ring A, was successfully produced via an unusual bromination of 2,5-dihydroxybenzaldehdye 10. After considerable optimisation we developed a method for the di-methylation of 11. Reduction of aldehyde 12 into corresponding alcohol 13 and subsequent protection of 13 with TBDMSCl gave 14 in a high yield. The synthesis of 9 was completed via a halogen-metal exchange reaction of 14 followed by trapping with DMF (Scheme 2). Scheme 2: Synthesis of ring A. Alongside our work towards the synthesis of 1, we have examined the total synthesis of the polyketide natural product (-)-(3R)-5-hydroxymellein 15, starting from the previously synthesised common intermediate 13. We have successfully synthesised 18, the deoxy-analogue of 15, via a halogen-metal exchange reaction of 16 followed by ring opening of propylene oxide and followed by deprotection and cyclisation.
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29

Chen, Hao Harrison Paul H. M. "A biomimetic decarboxylative condensation on a glycoluril scaffold and biosynthesis of streptolydigin." *McMaster only, 2004.

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30

Westaway, Susan Marie. "Squalestatin biosynthesis : synthesis and incorporation of assembly intermediates." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296602.

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Crump, Matthew Philip. "NMR studies on type II polyketide acyl carrier proteins." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294958.

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32

Goode, Ann Marie Liles Mark Russell. "Polyketide synthase pathway discovery from soil metagenomic libraries." Auburn, Ala., 2009. http://hdl.handle.net/10415/1805.

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33

Yan, John Kam. "Functional Separation of Multimodular Type I PKS Polypeptides by Utilizing Matched Docking Domains From a Heterologous PKS System." PDXScholar, 2010. https://pdxscholar.library.pdx.edu/open_access_etds/135.

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Bacterial type I modular polyketide synthases (PKS) are large multifunctional enzyme systems responsible for the biosynthesis of complex polyketide natural products such as erythromycin, pikromycin, and borrelidin. Type I systems are comprised of a loading module which generally selects an appropriate acyl group starter unit, and multiple discrete extension modules, responsible for each single round of acyl group incorporation into the final polyketide core structure. These modules can exist naturally as either single discrete polypeptides, such as modules 5 and 6 from the pikromycin PKS (PikA3 and PikA4 respectively), or as multimodular polypeptides fused together by short intrapolypeptide linkers such as the loading module and the first and second extension modules of the erythromycin and pikromycin PKSs (DEBS1 and PikAI respectively). While short peptide linkers between modules on the same polypeptide facilitate the transfer of polyketide intermediates from one module to the next via their close proximity to one another, docking domains found at the C-terminus of one module and the N-terminus of the next subsequent module facilitate the needed protein-protein interactions for the passage of biosynthetic intermediates between modules on separate polypeptides. The ability to utilize docking domains in place of intrapolypeptide linkers was explored in the pikromycin and erythromycin PKSs by dissecting the tri-modular PikAI and DEBS1 polypeptides with matched docking domains. It has been shown that PikAI can be separated into two proteins at either of these linkers, only when matched pairs of docking domains from a heterologous modular phoslactomycin PKS are used in place of the intrapolypeptide linker. In both cases the yields of pikromycin produced by the S. venezuelae host mutant, which is a PikAI deletion strain were 50% of that of an S. venezuelae strain expressing the native trimodular PikAI. Additionally, expression of module 2 as a monomodular protein fused to a heterologous N-terminal docking domain was also observed to give almost a 10-fold improvement in the in vivo generation of pikromycin from a synthetic diketide intermediate. The utilization of docking domains to separate linked modules was also demonstrated in the erythromycin PKS. Expression of the first protein involved in erythromycin biosynthesis (DEBS1) with the DEBS thioesterase fused to the C-terminal (DEBS1-TE) in S. venezuelae results in the production of triketide lactone products. Separation of DEBS1-TE resulted in 50% triketide lactone production, consistent with the observations in the pikromycin system. Published work has shown that the DEBS loading module has relaxed substrate specificity, and is capable of incorporating acetate, butyrate and isobutyrate in addition to the normally observed propionate starter unit, which typically predominates. However, in the current study when the DEBS loading module is separated from module 1 with matched docking domains, a dramatic shift in the starter unit, favoring the isobutyrate derived tri-ketide lactone is observed. This apparent shift in starter unit preference for a dissected PKS system has resulted in insights into the kinetics of acyl group loading, off loading, as well as the hydrolysis and transfer from the AT to ACP domains. In addition to the separation of multimodular PKS polypeptides with docking domains, it has also been shown that the individual catalytic domains of single discrete module, BorA5 from the borrelidin PKS can be expressed as stand alone proteins while retaining catalytic functionality in vitro. This work has provided a basis for future studies of this module, which has been proposed to function iteratively, catalyzing three rounds of chain elongation.
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34

Stevens, David Cole. "Developing Heterologous Expression Platforms for the Production of Polyketides from Microbial Hosts." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20220.

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Bacterial polyketides possess an enormous range of chemical diversity and biological function. Many polyketides such as tetracycline, epothilone, and rapamycin have been developed into key clinical pharmaceuticals in a broad range of therapeutic areas. Sequencing of bacterial genomes has shown that there are many more polyketide biosynthetic pathways than there are polyketides isolated from standard cultivation techniques. These genetically encoded polyketide natural products from cultivatable and uncultivatable bacteria represent one of the greatest remaining untapped reservoirs of new natural product diversity. To access this untapped diversity of polyketide products, a general method for heterologous expression of these pathways is needed. Heterologous expression has proven to be a valuable asset in the discovery, production, engineering, and characterization of bacterial secondary metabolites and the complex enzymology involved in their biosynthesis. Herein we discuss the development and investigation of two unique heterologous expression platforms utilizing host strains of Myxococcus xanthus and Escherichia coli. Using our developed heterologous hosts, we were able to produce the Streptomyces rimosus polyketide oxytetracycline. Through production of oxytetracycline in E .coli we have identified the potential of alternative transcription factors as regulators of secondary metabolism. Further investigation and development of alternative transcription factors as regulators of secondary metabolism in heterologous hosts could benefit the development of robust general methodology for the heterologous expression of polyketides.
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35

Shang, Shiying. "A unified synthetic approach to polyketides having both skeletal and stereochemical diversity /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528359411&sid=7&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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36

Harris, Jonathan Peter. "The biosynthesis of ochratoxin A and other structurally related polyketides by Aspergillus ochraceus." Thesis, Imperial College London, 1996. http://hdl.handle.net/10044/1/7972.

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37

Koopmans, Kyra Romy Mariette Verfasser], Frank [Gutachter] Schuz, and Robert [Gutachter] [Kourist. "Extension of nascent polyketides / Kyra Romy Mariette Koopmans. Gutachter: Frank Schuz ; Robert Kourist." Bochum : Ruhr-Universität Bochum, 2016. http://d-nb.info/111232674X/34.

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38

Koopmans, Kyra Romy Mariette [Verfasser], Frank Gutachter] Schuz, and Robert [Gutachter] [Kourist. "Extension of nascent polyketides / Kyra Romy Mariette Koopmans. Gutachter: Frank Schuz ; Robert Kourist." Bochum : Ruhr-Universität Bochum, 2016. http://d-nb.info/111232674X/34.

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39

Chang, Shuh-Kuen. "Studies toward the total synthesis of amphidinol 3." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150261354.

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40

Hariprakasha, H. K. "Synthesis Of Natural Products Based On Cyclohexadienes." Thesis, Indian Institute of Science, 1996. https://etd.iisc.ac.in/handle/2005/118.

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The thesis entitled "Synthesis of Natural Products Based on Cyclohexadienes" consists of two chapters. Chapter 1 is divided into two parts. Part I gives a brief introduction to the structure, synthesis, biosynthesis and biological activities of some naturally occurring phthalides (eg. mycophenolic acid 1, zinniol2, phthalides 3 & 4). A general strategy for the preparation of highly substituted phthalides is also described. Cycloaddition of 1,s-dimethoxycoclohexa-1, 4-diene with dimethylacetylenedicarboxylate(DMAD) followed by an Alder-Rickert reaction gave the diester 5 which upon hydrolysis with KOH and refluxing with acetic anhydride gave the phthalic anhydride 6. Regioselective reductions of the anhydride 6 gave the phthalides 7 and 8. Using a similar strategy the phthalides 11 & 12 were prepared from 2,6dimethoxytoluene through the intermediates 9 & 10. The aromatic ethers 13 & 14 upon Birch reduction followed by Diels-Alder reaction with maleic anhydride gave the bicyclic anhydrides 15 & 16 respectively. Attempts to dehydrogenate 15 using variety of conditions failed. But refluxing 15 in nitrobenzene gave a poor yield of 17 which is an important intermediate in the synthesis of mycophenolic acid. Part II describes the first total synthesis of zinniol 2, phthalide-1 3 & phthalide-2 4. Thus the diene 18, obtained from 2-methylcyclohexane-1,3dione, upon Diels-Alder and Alder-Rickert with DMAD gave the diester 19. Prenylation of 19 afforded the diester 20 which was convened into 21 upon hydrolysis and DCC treatment. DIBAL reduction of 20 gave Zinniol 2 which on oxidation provided the phthalides 3 & 4 (7:3 ratio respectively). The anhydride 21, on selective reduction, gave the same phthalides in 2:8 ratio which could be readily separated and characterized.
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41

Hariprakasha, H. K. "Synthesis Of Natural Products Based On Cyclohexadienes." Thesis, Indian Institute of Science, 1996. http://hdl.handle.net/2005/118.

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The thesis entitled "Synthesis of Natural Products Based on Cyclohexadienes" consists of two chapters. Chapter 1 is divided into two parts. Part I gives a brief introduction to the structure, synthesis, biosynthesis and biological activities of some naturally occurring phthalides (eg. mycophenolic acid 1, zinniol2, phthalides 3 & 4). A general strategy for the preparation of highly substituted phthalides is also described. Cycloaddition of 1,s-dimethoxycoclohexa-1, 4-diene with dimethylacetylenedicarboxylate(DMAD) followed by an Alder-Rickert reaction gave the diester 5 which upon hydrolysis with KOH and refluxing with acetic anhydride gave the phthalic anhydride 6. Regioselective reductions of the anhydride 6 gave the phthalides 7 and 8. Using a similar strategy the phthalides 11 & 12 were prepared from 2,6dimethoxytoluene through the intermediates 9 & 10. The aromatic ethers 13 & 14 upon Birch reduction followed by Diels-Alder reaction with maleic anhydride gave the bicyclic anhydrides 15 & 16 respectively. Attempts to dehydrogenate 15 using variety of conditions failed. But refluxing 15 in nitrobenzene gave a poor yield of 17 which is an important intermediate in the synthesis of mycophenolic acid. Part II describes the first total synthesis of zinniol 2, phthalide-1 3 & phthalide-2 4. Thus the diene 18, obtained from 2-methylcyclohexane-1,3dione, upon Diels-Alder and Alder-Rickert with DMAD gave the diester 19. Prenylation of 19 afforded the diester 20 which was convened into 21 upon hydrolysis and DCC treatment. DIBAL reduction of 20 gave Zinniol 2 which on oxidation provided the phthalides 3 & 4 (7:3 ratio respectively). The anhydride 21, on selective reduction, gave the same phthalides in 2:8 ratio which could be readily separated and characterized.
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42

Eichenberger, Michael [Verfasser], Beatrix [Akademischer Betreuer] Süß, Heribert [Akademischer Betreuer] Warzecha, and Michael [Akademischer Betreuer] Næsby. "Biosynthesis of plant polyketides in yeast / Michael Eichenberger ; Beatrix Süß, Heribert Warzecha, Michael Næsby." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2019. http://d-nb.info/1182537529/34.

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43

Cadou, Romain F. "Studies in cyclic ether synthesis : Part one: Domino cyclisations to cyclic ethers -- Part two: Synthetic studies towards neopeltolide." Thesis, University of St Andrews, 2010. http://hdl.handle.net/10023/1025.

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Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).
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Vanga, Raghava Reddy. "Studies toward the synthesis and structural elucidation of chamuvarinin." Thesis, University of St Andrews, 2009. http://hdl.handle.net/10023/953.

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Chamuvarinin (22) is a unique annoanceaeous acetogenin isolated from the roots of Senegalese medicinal plant Uvaria chamae by Laurens and co-workers in 2004. It displays highly potent cytotoxicity towards the cervical cancer cell lines (KB 3-1, IC₅₀= 0.8 nM). Structurally, chamuvarinin is the first reported acetogenin to contain an adjacently linked bis-THF-THP ring system spanning the C15-C28 carbon backbone. However, initial efforts to assign the relative and absolute configuration within this stereochemical array, on the basis of ¹H and ¹³C NMR analysis, provided only partial information pertaining to the relative configuration of C15-C19 region. As a consequence, 32 diastereomeric structural possibilities exist for the highly unusual structure of chamuvarinin; an unrealistic target for total synthesis. The synthesis of the central core tricyclic (BCD) intermediate represents the most challenging aspect in the entire synthesis, which in turn will aid ultimate structural proof. At the outset of the project the stereochemical configuration of C15-C28 (BCD) of chamuvarinin was uncertain and a library approach was proposed to enable structure elucidation (Scheme A-1). Chapter 2 and Chapter 3 detail the synthesis of possible diastereomers of the C9-C21 (51) and C22-C34 fragments (52). Chapter 4 details the intial strategy to couple the key diastereomeric fragments in a series of model studies. Chapter 5 describes the successful coupling strategy via an revised synthetic approach to reach the advanced C9-C34 intermediate 251 (Scheme A-2).
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Ellerbrock, Pascal [Verfasser], and Dirk [Akademischer Betreuer] Trauner. "Biomimetic synthesis of polyketides : dibefurin and epicolactone and synthetic studies toward gracilin terpenoids / Pascal Ellerbrock. Betreuer: Dirk Trauner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1090785569/34.

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46

Ali, Ahmed Faisal Ahmed Ismail [Verfasser], Frank [Akademischer Betreuer] Schulz, and Alfred [Akademischer Betreuer] Wittinghofer. "Fermentation and biological profiling of non-natural polyketides / Ahmed Faisal Ahmed Ismail Ali. Gutachter: Frank Schulz ; Alfred Wittinghofer." Bochum : Ruhr-Universität Bochum, 2016. http://d-nb.info/1095884786/34.

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47

Cummings, Matthew. "Harnessing synthetic biology for the bioprospecting and engineering of aromatic polyketide synthases." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/harnessing-synthetic-biology-for-the-bioprospecting-and-engineering-of-aromatic-polyketide-synthases(e2317dbb-c1b7-4e6e-83d5-03a1453848b2).html.

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Antimicrobial resistant microorganisms are predicted to pose an existential threat to humanity inside of the next 3 decades. Characterisation of novel acting antimicrobial small molecules from microorganisms has historically counteracted this evolutionary arms race, however the bountiful source of pharmaceutically relevant bioactive specialised metabolites discovered in the Golden era of drug discovery has long since dried up. The clinicians' arsenal of useful antimicrobials is diminishing, and a fresh perspective on specialised metabolite discovery is necessary. This call to action is being answered, in part, through advances in genome sequencing, bioinformatics predictions and the development of next generation synthetic biology tools aiming to translate the biological sciences into an engineering discipline. To expedite our route to new pharmaceutically relevant specialised metabolites using the synthetic biology toolbox several bottlenecks need to be addressed, and are tackled here in. Biosynthetic gene clusters (BGCs) represent blueprints to pharmaceuticals, however to date the vast wealth of knowledge about biosynthetic gene clusters is inconsistently reported and sporadically disseminated throughout the literature and databases. To bring the reporting of BGCs in line with engineering principles we designed and built a community supported standard, the Minimum Information about a Biosynthetic Gene cluster (MIBiG), for reporting BGCs in a consistent manner, and centralised this information in an easy to operate and open access repository for rapid retrieval of information, an essential resource for the bioengineer. Prioritisation represents the next bottleneck in specialised metabolite discovery. Bioinformatics tools have predicted a cache of thousands of BGCs within publicly available genome sequences, however high experimental attrition rates drastically slows characterisation of the corresponding specialised metabolite. We designed and built an Output Ordering and Prioritisation System (OOPS), to rank thousands of BGCs in parallel against molecular biology relevant parameters, pairing BGCs with appropriate heterologous expression hosts and facilitating a judicious choice of BGCs for characterisation to reduce experimental attrition. To fully realise the potential of synthetic biology in specialised metabolite discovery a genetically amenable heterologous host, capable of completing rapid design-build-test-learn cycles, is necessary. This cannot be achieved for the pharmaceutically important type II polyketides, as their biosynthetic machinery is largely restricted to Actinobacteria. Using MIBiG datasets, antiSMASH and BLASTP we identify 5 sets of soluble type II polyketide synthases (PKS) in Escherichia coli for the first time. We construct and test the robustness of a plug-and-play scaffold for bioproduction of aromatic polyketides using one PKS in E. coli, yielding anthraquinones, dianthrones and benzoisochromanequinones intermediates. Through bioprospecting for biological 'parts' to expand the chemical diversity of our plug-and-play scaffold we describe a new lineage of type II PKSs predominantly from non-Actinobacteria. The standards, softwares, and plug-and-play scaffold and biosynthetic 'parts' described here-in will act as an engine for rapid and automated bioproduction of existing, and novel, pharmaceutically relevant aromatic polyketides in E. coli using the synthetic biology toolbox.
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48

Prince, Emily Katherine. "Chemically-mediated interactions in the plankton:." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/22701.

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Thesis (Ph. D.)--Biology, Georgia Institute of Technology, 2008.
Committee Chair: Kubanek, Julia; Committee Member: Hay, Mark; Committee Member: Jiang, Lin; Committee Member: Pavia, Henrik; Committee Member: Snell, Terry.
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49

Hager, Dominik [Verfasser]. "From Nucleosides to Alkaloids and Polyketides: Total Synthesis of Herbicidin C and Studies Toward Stephadiamine and Divergolides / Dominik Hager." München : Verlag Dr. Hut, 2013. http://d-nb.info/1031843728/34.

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50

Nybo, Stephen Eric. "ISOLATION AND ELUCIDATION OF THE CHRYSOMYCIN BIOSYNTHETIC GENE CLUSTER AND ALTERING THE GLYCOSYLATION PATTERNS OF TETRACENOMYCINS AND MITHRAMYCIN-PATHWAY MOLECULES." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/812.

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Natural products occupy a central role as the majority of currently used antibiotic and anticancer agents. Among these are type-II polyketide synthase (PKS)-derived molecules, or polyketides, which are produced by many representatives of the genus Streptomyces. Some type-II polyketides, such as the tetracyclines and the anthracycline doxorubicin, are currently employed as therapeutics. However, several polyketide molecules exhibit promising biological activity, but due to toxic side effects or solubility concerns, remain undeveloped as drugs. Gilvocarcin V (GV) (topoisomerase II inhibitor) has a novel mechanism of action: [2+2] cycloaddition to thymine residues by the 8-vinyl side chain and cross-linking of histone H. Mithramycin blocks transcription of proto-oncogenes c-myc and c-src by forming an Mg2+-coordinated homodimer in the GC-rich minor groove of DNA. The purpose of this research was to investigate the biosynthesis of several type II polyketide compounds (e.g. chrysomycin, elloramycin, and mithramycin) with the goal of improving the bioactivities of these drugs through combinatorial biosynthesis. Alteration of the glycosylation pattern of these molecules is one promising way to improve or alter the bioactivities of these molecules. To this end, an understanding of the glycosyltransferases and post-polyketide tailoring enzymatic steps involved in these biosynthetic pathways must be established. Four specific aims were established to meet these goals. In specific aim 1, the biosynthetic locus of chrysomycin A was successfully cloned and elucidated, which afforded novel biosynthetic tools. Chrysomycin monooxygenases were found to catalyze identical roles to their gilvocarcin counterparts. Cloning of deoxysugar constructs (plasmids) which could direct biosynthesis of ketosugars, NDP-D-virenose, and NDP-D-fucofuranose in foreign pathways was undertaken in specific aim 2. Finally, these “sugar” plasmids were introduced into producer organisms of elloramycin and mithramycin pathways in specific aims 3 and 4 to interrogate the endogenous glycosyltransferases in order to alter their glycosylation patterns. These experiments resulted in the successful generation of a newly glycosylated tetracenomycin, as well as premithramycin, and mithramycin analogues. In specific aim 4, a new mithramycin analogue with an altered sugar pattern rationally designed and improved structural features was generated and structurally elucidated.
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