Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3098
Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Attempt to read property "Count" on bool
Filename: helpers/my_audit_helper.php
Line Number: 3100
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3100
Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Polycyclic tetramate macrolactams (PoTeMs) represent a growing class of bioactive natural products that are derived from a common tetramate polyene precursor, lysobacterene A, produced by an unusual bacterial iterative polyketide synthase (PKS) / non-ribosomal peptide synthetase (NRPS). The structural and functional diversity of PoTeMs is biosynthetically elaborated from lysobacterene A by pathway-specific cyclizing and modifying enzymes. This results in diverse core structure decoration and cyclization patterns. However, approaches to directly edit the PoTeM carbon skeleton are currently not existing. We thus set out to modify the PoTeM core structure by exchanging the natural L-ornithine-derived building block by L-lysine, hence extending macrocycle size by an additional CH2 group. We developed streamlined synthetic access to lysobacterene A and the corresponding extended analog and achieved cyclization of both precursors by the cognate PoTeM cyclases IkaBC in vitro. This chemo-enzymatic approach corroborated the catalytic competence of IkaBC to produce a larger macrolactam yielding homo-ikarugamycin. We thus engineered the adenylation domain active site of IkaA to directly accept L-lysine, which upon co-expression with IkaBC delivered a recombinant bacterial homo-ikarugamycin producer. Our work establishes an entirely new PoTeM structural framework and sets the stage for the biotechnological diversification of the PoTeM natural product class in general.
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Source |
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http://dx.doi.org/10.1002/anie.202420335 | DOI Listing |
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