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2. Transaminase mediated cascade reactions

Author

Slabu, Iustina, Flitsch, Sabine, and Turner, Nicholas

Subjects
540, equilibrium-shifting techniques, cadaverine, putrescine, biocatalysis, polyamines, PLP dependent enzymes, transaminases, chiral amines
Abstract

In all its forms, catalysis accounts for 80% of all chemical processes worldwide, with biocatalysis playing a major part, as a 'white biotechnological' tool in sustainable industrial production. Biocatalysis complements the traditional chemical synthetic methods and offers a distinct approach to the synthesis of high-value chiral molecules. Chiral amine units are highly common in both the pharmaceutical and agrochemical industries. Biocatalytic strategies for the synthesis of chiral amines rely heavily on the use of ω-transaminases, enzymes impeded by their thermodynamic limitations in the synthetic direction, amongst others. This thesis describes an attractive alternative strategy to both the equilibrium-shifting problem and the low-cost availability amine donor, by employing biogenic polyamines, which are ubiquitous in all types of living cells. Moreover, they can be used in biomimetic enzymatic cascades for the synthesis of simple heterocyclic scaffolds of more complex alkaloids. The present thesis shows the research carried out as part of this PhD and it is formatted as a series of manuscripts, part of which have either been published or recently accepted for publication, together with a manuscript which is planned to be submitted to a peer-review journal in the near future.

Published
2018

6. Chemo‐Enzymatic Cascades

Author

Slabu, Iustina, primary, Bisagni, Serena, additional, Hedley, Simon J., additional, Cherney, Alan H., additional, Pushpanath, Ahir, additional, Bornadel, Amin, additional, LePaih, Jacques, additional, Mennen, Steven M., additional, and Dominguez, Beatriz, additional

Published
2020
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8. Characterisation of a putrescine transaminase from Pseudomonas putida and its application to the synthesis of benzylamine derivatives

Author

Galman, James, Gahloth, Deepanker, Parmeggiani, Fabio, Slabu, Iustina, and Leys, David

Subjects
transaminase, Benzylamines, green chemistry, Manchester Institute of Biotechnology, Biocatalysis, protein structure, ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology
Abstract

The reductive amination of prochiral ketones using biocatalysts has been of great interest to the pharmaceutical industry in the last decade for integrating novel strategies in the production of chiral building blocks with the intent of minimising impact on the environment. Amongst the enzymes able to catalyse the direct amination of prochiral ketones, pyridoxal 5’-phosphate (PLP)dependent ω‐transaminases have shown great promise as versatile industrial biocatalysts with high selectivity, regioselectivity and broad substrate scope. Herein the biochemical characterisation of a putrescine transaminase from Pseudomonas putida (Pp-SpuC) was performed, which showed an optimum pH and temperature of 8.0 and 60°C, respectively. To gain further structuralinsight of this enzyme, we crystallised the enzyme in the apo-form and the structure determined to 2.1 Å resolution which revealed a dimer that adopts a class I transaminase fold comparable to other class III transaminases. Furthermore we exploited its dual substrate recognition for biogenic diamines (i.e., cadaverine) and readily available monoamines (i.e., isopropylamine) forthe synthesis of benzylamine derivatives with excellent product conversions and extremely broad substrate tolerance.

Published
2018
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13. Biocatalytic Routes to Enantiomerically Enriched Dibenz[c ,e ]azepines

Author

France, Scott P., primary, Aleku, Godwin A., additional, Sharma, Mahima, additional, Mangas-Sanchez, Juan, additional, Howard, Roger M., additional, Steflik, Jeremy, additional, Kumar, Rajesh, additional, Adams, Ralph W., additional, Slabu, Iustina, additional, Crook, Robert, additional, Grogan, Gideon, additional, Wallace, Timothy W., additional, and Turner, Nicholas J., additional

Published
2017
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18. Synthesis of 2,5‐Disubstituted Pyrrolidine Alkaloids via A One‐Pot Cascade Using Transaminase and Reductive Aminase Biocatalysts.

Author

Galman, James L., Slabu, Iustina, France, Scott P., Turner, Nicholas J., Costa, Bruna Z., and Marsaioli, Anita J.

Subjects
*PYRROLIDINE synthesis, *ALKALOID synthesis, *BIOCATALYSIS, *AMINOTRANSFERASES, *KETONES, *IMINES, *ENANTIOMERIC purity
Abstract

A multi‐enzymatic cascade process involving transaminases (TAs) and reductive aminases (RedAms) to produce enantiomerically pure 2,5‐disubstituted pyrrolidine alkaloids from their respective 1,4‐diketones is reported. Several TAs were screened and the best results for diketone monoamination were obtained with an R‐selective TA from Mycobacterium chlorophenicum and with an S‐selective TA from Bacillus megaterium. Pyrroline reduction was best performed by a reductive aminase from Ajellomyces dermatitidis (AdRedAm). Finally, a biocatalytic one‐pot cascade was implemented using the aforementioned enzymes and a variety of 2‐methyl‐5‐alkylpyrrolidines were produced with high (>99 %) conversion, diastereomeric and enantiomeric excess values. Cascades get antsy! A one‐pot enzymatic cascade using transaminase and reductive aminase biocatalysts has been successfully implemented for the regio‐ and stereoselective synthesis of a panel of 2‐methyl‐5‐alkylpyrrolidines from the corresponding 1,4‐diketones. [ABSTRACT FROM AUTHOR]

Published
2018
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19. Biocatalytic Routes to Enantiomerically Enriched Dibenz[ c, e]azepines.

Author

France, Scott P., Aleku, Godwin A., Sharma, Mahima, Mangas‐Sanchez, Juan, Howard, Roger M., Steflik, Jeremy, Kumar, Rajesh, Adams, Ralph W., Slabu, Iustina, Crook, Robert, Grogan, Gideon, Wallace, Timothy W., and Turner, Nicholas J.

Subjects
BIOCATALYSIS, ENANTIOMERS, AZEPINES, REDUCTASES, AMINOTRANSFERASES, CRYSTALLOGRAPHY
Abstract

Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of ( R)- and ( S)-5-methyl-6,7-dihydro-5 H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework. [ABSTRACT FROM AUTHOR]

Published
2017
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