Site-directed Mutagenesis Switching a Dimethylallyl Tryptophan Synthase to a Specific Tyrosine C3-Prenylating Enzyme

Fan, Aili; Zocher, Georg; Stec, E; Stehle, Thilo; Li, Shu-Ming

doi:10.1074/jbc.m114.623413

Cited by 20 publications

(31 citation statements)

References 48 publications

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“…With the exception of 2a with 5-DMATS and 6-DMATS Sv , HPLC analysis of the reaction mixtures (Fig. 2A-L)revealed the formation of one product each, confirming the results published previously 17,18,22. Product yields of these reactions are summarized in…”

supporting

confidence: 86%

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Tryptophan prenyltransferases showing higher catalytic activities for Friedel–Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases

Fan

Xie

2015

Org. Biomol. Chem.

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Tryptophan prenyltransferases FgaPT2, 5-DMATS, 6-DMATSSv and 7-DMATS catalyse regiospecific C-prenylations on the indole ring, while tyrosine prenyltransferases SirD and TyrPT catalyse the O-prenylation of the phenolic hydroxyl group. In this study, we report the Friedel-Crafts alkylation of L-o-tyrosine by these enzymes. Surprisingly, no conversion was detected with SirD and three tryptophan prenyltransferases showed significantly higher activity than another tyrosine prenyltransferase TyrPT. C5-prenylated L-o-tyrosine was identified as a unique product of these enzymes. Using L-m-tyrosine as the prenylation substrate, product formation was only observed with the tryptophan prenyltransferases FgaPT2 and 7-DMATS. C4- and C6-prenylated derivatives were identified in the reaction mixture of FgaPT2. These results provided additional evidence for the similarities and differences between these two subgroups within the DMATS superfamily in their catalytic behaviours.

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supporting

confidence: 86%

“…1). 18 These results demonstrated the close relationship between tryptophan C-prenyltransferases and tyrosine O-prenyltransferases. The different regioselectivities of the mentioned enzymes with 2a encouraged us to test the acceptance of the 2a isomers, L-o-tyrosine (3a) and L-m-tyrosine (4a), by tryptophan and tyrosine prenyltransferases.…”

Section: Introductionmentioning

confidence: 72%

Tryptophan prenyltransferases showing higher catalytic activities for Friedel–Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases

Fan

Xie

2015

Org. Biomol. Chem.

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“…Molecular modeling-guided site-directed mutagenesis of FgaPT2 resulted in a mutant, FgaPT2_K174F, which showed much higher specificity toward L-tyrosine than L-tryptophan. The catalytic efficiency of this mutant toward L-tyrosine was found to be 4.9-fold of that of wild type, while its activity toward L-tryptophan was less than 0.4 % of that of FgaPT2 (Fan et al 2015b). Therefore, we created the first specific tyrosine C3-prenylating enzyme and altered the substrate preference of a PT by molecular modeling-guided sitedirected mutagenesis.…”

Section: Acceptance Of Unnatural Dmapp Analogs By the Dmats Enzymesmentioning

confidence: 94%

“…Two tryptophan PTs FgaPT2 and 7-DMATS take L-tyrosine and 4-amino-L-phenylalanine as substrates as well and produce the unique C3-and O/N-prenylated tyrosine or 4-amino-L-phenylalanine, respectively (Table 4) (Fan et al 2015b;. Together with the results of C7-prenylation of L-tryptophan by SirD and TyrPT, these four PTs demonstrated complementary substrate and catalytic promiscuity.…”

Section: Chemoenzymatic Synthesis Of Prenylated Phenylalanine/tyrosinmentioning

confidence: 94%

“…To understand these prenyl transfer reactions, crystal structures of four DMATS enzymes have been solved in the last years, which provide not only detailed insights into the reaction mechanism, but also basic information for protein engineering to create new biocatalysts with desirable features (Fan et al 2015b;Jost et al 2010). Coexpression of PT with nonribosomal peptide synthetase (NRPS) genes for production of prenylated cyclic dipeptides in vivo and development of whole cell biocatalyst with PTs are new potential applications of these intriguing enzymes (Kranen et al 2011;Wunsch et al 2015a).…”

Section: Introductionmentioning

confidence: 99%

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Impacts and perspectives of prenyltransferases of the DMATS superfamily for use in biotechnology

Fan

Winkelblech

2015

Appl Microbiol Biotechnol

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Prenylated compounds are ubiquitously found in nature and demonstrate interesting biological and pharmacological activities. Prenyltransferases catalyze the attachment of prenyl moieties from different prenyl donors to various acceptors and contribute significantly to the structural and biological diversity of natural products. In the last decade, significant progress has been achieved for the prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily. More than 40 members of these soluble enzymes are identified in microorganisms and characterized biochemically. These enzymes were also successfully used for production of a large number of prenylated derivatives. N1-, C4-, C5-, C6-, and C7-prenylated tryptophan and N1-, C2-, C3-, C4-, and C7-prenylated tryptophan-containing peptides were obtained by using DMATS enzymes as biocatalysts. Tyrosine and xanthone prenyltransferases were used for production of prenylated derivatives of their analogs. More interestingly, the members of the DMATS superfamily demonstrated intriguing substrate and catalytic promiscuity and also used structurally quite different compounds as prenyl acceptors. Prenylated hydroxynaphthalenes, flavonoids, indolocarbazoles, and acylphloroglucinols, which are typical bacterial or plant metabolites, were produced by using several fungal DMATS enzymes. Furthermore, the potential usage of these enzymes was further expanded by using natural or unnatural DMAPP analogs as well as by coexpression with other genes like NRPS and by development of whole cell biocatalyst.

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Biocatalytic Friedel‐Crafts Reactions

Leveson-Gower

Roelfes

2022

ChemCatChem

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Friedel-Crafts alkylation and acylation reactions are important methodologies in synthetic and industrial chemistry for the construction of aryl-alkyl and aryl-acyl linkages that are ubiquitous in bioactive molecules. Nature also exploits these reactions in many biosynthetic processes. Much work has been done to expand the synthetic application of these enzymes to unnatural substrates through directed evolution. The promise of such biocatalysts is their potential to supersede inefficient and toxic chemical approaches to these reactions, with mild operating conditions -the hallmark of enzymes. Complementary work has created many bio-hybrid Friedel-Crafts catalysts consisting of chemical catalysts anchored into biomolecular scaffolds, which display many of the same desirable characteristics. In this Review, we summarise these efforts, focussing on both mechanistic aspects and synthetic considerations, concluding with an overview of the frontiers of this field and routes towards more efficient and benign Friedel-Crafts reactions for the future of humankind.

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Site-directed Mutagenesis Switching a Dimethylallyl Tryptophan Synthase to a Specific Tyrosine C3-Prenylating Enzyme

Cited by 20 publications

References 48 publications

Tryptophan prenyltransferases showing higher catalytic activities for Friedel–Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases

Tryptophan prenyltransferases showing higher catalytic activities for Friedel–Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases

Impacts and perspectives of prenyltransferases of the DMATS superfamily for use in biotechnology

Biocatalytic Friedel‐Crafts Reactions

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