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Structural and biochemical characterization of carrier proteins interacting with non-elongating ketosynthase from enacyloxin polyketide synthase
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Svatoš, Alma (2019) Structural and biochemical characterization of carrier proteins interacting with non-elongating ketosynthase from enacyloxin polyketide synthase. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3714385~S15
Abstract
Enacyloxin is an antibiotic synthesized inside bacterial cells by gigantic modular multienzyme complex called polyketide synthase (PKS), which is active against multidrug-resistant Acinetobacter baumannii that leads the World Health Organization ‘priority pathogens’ list. In spite of its promising physiological activity, enacyloxin IIa has not been used as a drug due its structural instability. The modular nature of enacyloxin and other PKSs makes them amenable to rational engineering to elucidating protein-protein interactions within PKSs will be crucial for their bioengineering to produce novel drugs. A key step in enacyloxin biosynthesis is the transfer of the polyketide chain from an acyl carrier protein (ACP) domain in the last PKS module to a standalone peptidyl carrier protein (PCP) by a non-elongating ketosynthase (KS^0) domain. It has been reported that this transfer is necessary for the condensation (C) domain to catalyse polyketide chain release via intermolecular esterification with 3, 4-dihydroxycyclo-hexane carboxylic acid (DHCCA). No esterification occurs when the substrate is attached to the ACP domain. Thus, the KS^0 transfers the substrate from a carrier protein that is unable to interact with the C domain to one that it is able to interact with.
An experimental approach combining NMR and biochemical techniques presented in the thesis suggests that the length of helix 1 and the lack of charged residues in the C-terminal part of ACP prevent it from establishing favourable interaction with C domain.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
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Library of Congress Subject Headings (LCSH): | Antibiotics -- Development, Antibiotics -- Synthesis, Carrier proteins, Polyketides, Biosynthesis, Natural products -- Biotechnology | ||||
Official Date: | 30 September 2019 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Lewandowski, Józef R. ; Challis, Gregory L. | ||||
Sponsors: | European Research Council | ||||
Format of File: | |||||
Extent: | viii, 160 leaves : illustrations (some colour) | ||||
Language: | eng |
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