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  1. Article ; Online: Engineering Orthogonal Methyltransferases to Create Alternative Bioalkylation Pathways.

    Herbert, Abigail J / Shepherd, Sarah A / Cronin, Victoria A / Bennett, Matthew R / Sung, Rehana / Micklefield, Jason

    Angewandte Chemie (International ed. in English)

    2020  Volume 59, Issue 35, Page(s) 14950–14956

    Abstract: S-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) catalyse the methylation of a vast array of small metabolites and biomacromolecules. Recently, rare carboxymethylation pathways have been discovered, including carboxymethyltransferase ... ...

    Abstract S-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) catalyse the methylation of a vast array of small metabolites and biomacromolecules. Recently, rare carboxymethylation pathways have been discovered, including carboxymethyltransferase enzymes that utilise a carboxy-SAM (cxSAM) cofactor generated from SAM by a cxSAM synthase (CmoA). We show how MT enzymes can utilise cxSAM to catalyse carboxymethylation of tetrahydroisoquinoline (THIQ) and catechol substrates. Site-directed mutagenesis was used to create orthogonal MTs possessing improved catalytic activity and selectivity for cxSAM, with subsequent coupling to CmoA resulting in more efficient and selective carboxymethylation. An enzymatic approach was also developed to generate a previously undescribed co-factor, carboxy-S-adenosyl-l-ethionine (cxSAE), thereby enabling the stereoselective transfer of a chiral 1-carboxyethyl group to the substrate.
    MeSH term(s) Crystallography, X-Ray/methods ; Humans ; Methyltransferases/chemistry
    Chemical Substances Methyltransferases (EC 2.1.1.-)
    Language English
    Publishing date 2020-06-22
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202004963
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Recent advances in methyltransferase biocatalysis.

    Bennett, Matthew R / Shepherd, Sarah A / Cronin, Victoria A / Micklefield, Jason

    Current opinion in chemical biology

    2017  Volume 37, Page(s) 97–106

    Abstract: S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review covers the recent advances in the development of methyltransferase enzymes for ... ...

    Abstract S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review covers the recent advances in the development of methyltransferase enzymes for synthetic applications, focusing on the methyltransferase catalyzed transformations with S-adenosyl methionine analogs, as well as non-native substrates. We discuss how metabolic engineering approaches have been used to enhance S-adenosyl methionine production in vivo. Enzymatic approaches that enable the more efficient generation of S-adenosyl methionine analogs, including more stable analogs, will also be described; this has expanded the biocatalytic repertoire of methyltransferases from methylation to a broader range of alkylation reactions. The review also examines how the selectivity of the methyltransferase enzymes can be improved through structure guided mutagenesis approaches. Finally, we will discuss how methyltransferases can be deployed in multi-enzyme cascade reactions and suggest future challenges and avenues for further investigation.
    MeSH term(s) Animals ; Biocatalysis ; Biotransformation ; Coenzymes/metabolism ; Humans ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Substrate Specificity
    Chemical Substances Coenzymes ; Methyltransferases (EC 2.1.1.-)
    Language English
    Publishing date 2017-03-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1439176-4
    ISSN 1879-0402 ; 1367-5931
    ISSN (online) 1879-0402
    ISSN 1367-5931
    DOI 10.1016/j.cbpa.2017.01.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.

    Rosenblat, Joshua D / Meshkat, Shakila / Doyle, Zoe / Kaczmarek, Erica / Brudner, Ryan M / Kratiuk, Kevin / Mansur, Rodrigo B / Schulz-Quach, Christian / Sethi, Rickinder / Abate, Amanda / Ali, Shaun / Bawks, Jordan / Blainey, Marc G / Brietzke, Elisa / Cronin, Victoria / Danilewitz, Jessica / Dhawan, Shalini / Di Fonzo, Anthony / Di Fonzo, Melissa /
    Drzadzewski, Pawel / Dunlop, William / Fiszter, Hajnalka / Gomes, Fabiano A / Grewal, Smrita / Leon-Carlyle, Marisa / McCallum, Marilyn / Mofidi, Niki / Offman, Hilary / Riva-Cambrin, Jeremy / Schmidt, Joel / Smolkin, Mark / Quinn, Joan M / Zumrova, Andrea / Marlborough, Michelle / McIntyre, Roger S

    Med (New York, N.Y.)

    2024  Volume 5, Issue 3, Page(s) 190–200.e5

    Abstract: Background: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, ...

    Abstract Background: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period.
    Methods: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466).
    Findings: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline.
    Conclusions: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity.
    Funding: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.
    MeSH term(s) Adult ; Humans ; Psilocybin/adverse effects ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Major/chemically induced ; Depressive Disorder, Treatment-Resistant/drug therapy ; Antidepressive Agents/adverse effects ; Psychotherapy
    Chemical Substances Psilocybin (2RV7212BP0) ; Antidepressive Agents
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ISSN 2666-6340
    ISSN (online) 2666-6340
    DOI 10.1016/j.medj.2024.01.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Structure and Biocatalytic Scope of Coclaurine N-Methyltransferase.

    Bennett, Matthew R / Thompson, Mark L / Shepherd, Sarah A / Dunstan, Mark S / Herbert, Abigail J / Smith, Duncan R M / Cronin, Victoria A / Menon, Binuraj R K / Levy, Colin / Micklefield, Jason

    Angewandte Chemie (International ed. in English)

    2018  Volume 57, Issue 33, Page(s) 10600–10604

    Abstract: Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common ...

    Abstract Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)-reticulene at which point the pathway diverges. Coclaurine N-methyltransferase (CNMT) is a key enzyme in the pathway to (S)-reticulene, installing the N-methyl substituent that is essential for the bioactivity of many BIAs. In this paper, we describe the first crystal structure of CNMT which, along with mutagenesis studies, defines the enzymes active site architecture. The specificity of CNMT was also explored with a range of natural and synthetic substrates as well as co-factor analogues. Knowledge from this study could be used to generate improved CNMT variants required to produce BIAs or synthetic derivatives.
    MeSH term(s) Alkaloids/biosynthesis ; Alkaloids/chemistry ; Benzylisoquinolines/chemistry ; Benzylisoquinolines/metabolism ; Biocatalysis ; Catalytic Domain ; Coptis/enzymology ; Crystallography, X-Ray ; Kinetics ; Methyltransferases/chemistry ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Mutagenesis, Site-Directed ; Plant Proteins/chemistry ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Substrate Specificity
    Chemical Substances Alkaloids ; Benzylisoquinolines ; Plant Proteins ; Methyltransferases (EC 2.1.1.-) ; S-adenosyl-L-methionine coclaurine N-methyltransferase (EC 2.1.1.-) ; reticuline (X35Z551WT4)
    Language English
    Publishing date 2018-06-28
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201805060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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