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21
The starter unit specificity of Pks4 was examined by incubating Pks4 with [2-14C] malonyl CoA with various alkylacyl-CoAs and then carrying out assays to detect the products by radio TLC. It was seen that Pks4 did not utilize short chain acyl-CoAs (C2-C6) as a starter unit and gave SMA76a (Fig. 6). While it did not accept short chain acyl groups, on addition of octanoyl as a starter unit, Pks4 gave two new peaks and synthesis of SMA76a decreased.
Hence it is seen that Pks4 selectively accepts octanoylCoA instead of malonylCoA in vitro to give products 3 and 4 when normally it is primed by malonylCoA and gives product SMA76a to finally product bikaverin. So there is a yet unknown mechanism by which Pks4 selects a C8 acyl chain. This phenomenon has been observed in bacterial type II minimal PKS where increase in the starter unit size leads to a decrease in the number of chain extension cycles to maintain the length of the polyketide backbone.[12] Hence, the overall size of the polyketide product and the number of iterative condensations are likely controlled by the cavity volume of the PKS4 KS active site. It was also shown that if the polyketide backbone composition is changed, it can stall certain programmed cyclization steps in the synthesis of certain products. It was maintained that the TE domain could not perform its cyclization step
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 27 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 21 The starter unit specificity of Pks4 was examined by incubating Pks4 with [2-14C] malonyl CoA with various alkylacyl-CoAs and then carrying out assays to detect the products by radio TLC. It was seen that Pks4 did not utilize short chain acyl-CoAs (C2-C6) as a starter unit and gave SMA76a (Fig. 6). While it did not accept short chain acyl groups, on addition of octanoyl as a starter unit, Pks4 gave two new peaks and synthesis of SMA76a decreased. Hence it is seen that Pks4 selectively accepts octanoylCoA instead of malonylCoA in vitro to give products 3 and 4 when normally it is primed by malonylCoA and gives product SMA76a to finally product bikaverin. So there is a yet unknown mechanism by which Pks4 selects a C8 acyl chain. This phenomenon has been observed in bacterial type II minimal PKS where increase in the starter unit size leads to a decrease in the number of chain extension cycles to maintain the length of the polyketide backbone.[12] Hence, the overall size of the polyketide product and the number of iterative condensations are likely controlled by the cavity volume of the PKS4 KS active site. It was also shown that if the polyketide backbone composition is changed, it can stall certain programmed cyclization steps in the synthesis of certain products. It was maintained that the TE domain could not perform its cyclization step |
