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Hauptverfasser:	Noella Younan, Felice A. Dacpano, Eli Frazer, Angeline Dauz, Areli Tlatelpa, Gönül Vardar‐Schara
Format:	Artículo Open Access
Veröffentlicht:	Wiley 2025
Schlagworte:	Biotechnology and Bioengineering
Online-Zugang:	https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/bit.70117
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Inhaltsangabe:

Drug Metabolism by Engineered Toluene o ‐Xylene Monooxygenases of Pseudomonas sp. OX1 Noella Younan Felice A. Dacpano Eli Frazer Angeline Dauz Areli Tlatelpa Gönül Vardar‐Schara Biotechnology and Bioengineering ABSTRACT Toluene o ‐xylene monooxygenase (ToMO) of Pseudomonas sp. OX1 was investigated as a drug‐metabolizing enzyme for the first time and was found to metabolize chlorzoxazone and resveratrol to form human metabolites 6‐chlorzoxazone (0.045 ± 0.016 nmol/hr/mg protein) and piceatannol (0.014 ± 0.009 nmol/hr/mg protein), respectively, though at low rates. ToMO also forms 2‐acetamidophenol (2‐AAP, 27%), 3‐AAP (42%), and 4‐AAP (31%) from acetanilide at 3.6 ± 0.3 nmol/hr/mg protein. Multiple‐site saturation mutagenesis at positions I100/E103/A107 of the alpha‐subunit along with site‐directed mutagenesis approaches were used to isolate thirty‐seven different ToMO variants with enhanced activities and/or fine‐tuned specificities. Specifically, variant I100V/E103T was identified with 2.1‐ and 49‐fold higher activities towards acetanilide and chlorzoxazone, respectively, compared to native ToMO. Variant I100V/E103T also had the regiospecificity of acetanilide change from 31% to 100% 4‐AAP, mimicking human liver enzyme behavior. In addition, several variants showed up to 3.7‐, 1.6‐, and 3.2‐fold improved selectivity for 2‐, 3‐, and 4‐AAP formation, respectively. For resveratrol, variant I100T/E103L was a better catalyst than native ToMO, exhibiting 34‐fold higher activity. The results presented here demonstrate the potential of nonhuman ToMO variants in drug metabolism and contribute to the list of research on probing this promising enzyme. 10.1002/bit.70117 http://onlinelibrary.wiley.com/termsAndConditions#vor

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// Anecdotal testing Today and Yesterday seems to indicate destroy() // is called by the garbage collector and everything is good. // Something to keep in mind though. return 0; } /** * Write function that is called when session data is to be saved. * * @param string $sessId The current session ID * @param string $data The session data to write * * @return bool */ public function write($sessId, $data): bool { if ($this->writesDisabled) { return true; } return $this->saveSession($sessId, $data); } /** * A function that is called internally when session data is to be saved. * * @param string $sessId The current session ID * @param string $data The session data to write * * @return bool */ abstract protected function saveSession($sessId, $data): bool; }

* * @return void */ public function writeClose() { // The assumption is that we're using PHP's ext/session. // session_write_close() will actually overwrite $_SESSION with an // empty array on completion -- which leads to a mismatch between what // is in the storage object and $_SESSION. To get around this, we // temporarily reset $_SESSION to an array, and then re-link it to // the storage object. // // Additionally, while you _can_ write to $_SESSION following a // session_write_close() operation, no changes made to it will be // flushed to the session handler. As such, we now mark the storage // object isImmutable. $storage = $this->getStorage(); if (! $storage->isImmutable()) { $_SESSION = $storage->toArray(true); session_write_close(); $storage->fromArray($_SESSION); $storage->markImmutable(); } } /** * Attempt to set the session name * * If the session has already been started, or if the name provided fails * validation, an exception will be raised. * * @param string $name * @return SessionManager * @throws Exception\InvalidArgumentException */ public function setName($name) { if ($this->sessionExists()) { throw new Exception\InvalidArgumentException( 'Cannot set session name after a session has already started'

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