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12
this point by swapping the KS domain of fumonisin with that of lovastatin, which resulted in a product of shorter chain length.[3, 6]
These findings give us a structural basis for the different chain lengths we observe in the polyketides. It also gives us a tool to control the chain length by mutagenesis of active sites to control the number of iterations
The minimal NR-PKS from the bikaverin biosynthesis produced a polyketide of the correct length but lacked the ability to control cyclization. It was seen that starter units with different chain lengths caused an alteration in the number of ketide extensions to reflect the natural chain length of the polyketide as dictated by the KS cavity volume. When a PT domain was added to the minimal PKS, there was a decrease in the linear intermediate and increase in the correct cyclization product indicating the role of PT domain in aromatization and cyclization of the linear intermediate. When the full complement of all six domains was present, the correct final cyclization outcome was observed. The TE-CLC domain catalyzed the C-C bond formation, assisting the PT domain in cyclization of the product. A recent study on the TE domain of PKS13 showed that the TE domain acts as a gatekeeper to the release of the polyketides ensuring that only appropriately functionalized and
Object Description
| Title | Fungal polyketides -- Review of recent findings |
| Author | Jain, Sofina M. |
| Author email | sofinaja@usc.edu; sofinajain27@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Pharmacy / Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2011-05-04 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-05-05 |
| Advisor (committee chair) | Wang, Clay C. C. |
| Advisor (committee member) |
Okamoto, Curtis Toshio Shen, Wei-Chiang |
| Abstract | Fungal polyketides are a group of bioactive compounds which have found use in humans as anti-cholesterol, anti-cancer and antibiotic agents. These are synthesized by a group of enzymes called the polyketide synthases (PKSs) which are found in fungi as well as bacteria. PKSs are classified as type I, II and III. All fungal PKSs are type I iterative polyketide synthases which means they use a set of catalytic functions by a group of active domains in repetitive cycles to give the end product. Type I enzymes contain multidomains that catalyze a set of reactions.; The minimal PKS contains the domains ketosynthase (KS), acyltransferase (AT) and acyl carrier protein (ACP). The three types of PKSs are non-reduced polyketide synthases (NR-PKSs), highly-reduced polyketide synthases (HR-PKSs) and partially-reduced polyketide synthases (PR-PKSs). This classification is another form separate from type I, II and III. This paper discusses the recent research into further details of the SAT, PT and TE domain of the NR-PKSs and also recent advances in the HR-PKSs. This paper will also discuss the role of NADPH, SAM and CON domain in the HR-PKSs. We will also discuss the two off-loading mechanism of HR-PKSs that were seen in recent papers. While little research is done on PR-PKSs, NR-PKS and HR-PKS are extensively being worked on.Recent findings have brought us a step closer to the domains of the PKSs and promise us a better clearer understanding of this complex multidomain entity. |
| Keyword | fungal polyketides; HR-PKS; NR-PKS; PT domain; SAT domain; TE domain |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3914 |
| Contributing entity | University of Southern California |
| Rights | Jain, Sofina M. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-jain-4552 |
| Archival file | uscthesesreloadpub_Volume40/etd-jain-4552.pdf |
Description
| Title | Page 18 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 12 this point by swapping the KS domain of fumonisin with that of lovastatin, which resulted in a product of shorter chain length.[3, 6] These findings give us a structural basis for the different chain lengths we observe in the polyketides. It also gives us a tool to control the chain length by mutagenesis of active sites to control the number of iterations The minimal NR-PKS from the bikaverin biosynthesis produced a polyketide of the correct length but lacked the ability to control cyclization. It was seen that starter units with different chain lengths caused an alteration in the number of ketide extensions to reflect the natural chain length of the polyketide as dictated by the KS cavity volume. When a PT domain was added to the minimal PKS, there was a decrease in the linear intermediate and increase in the correct cyclization product indicating the role of PT domain in aromatization and cyclization of the linear intermediate. When the full complement of all six domains was present, the correct final cyclization outcome was observed. The TE-CLC domain catalyzed the C-C bond formation, assisting the PT domain in cyclization of the product. A recent study on the TE domain of PKS13 showed that the TE domain acts as a gatekeeper to the release of the polyketides ensuring that only appropriately functionalized and |
