Abstract
Prenylated natural products have interesting pharmacological properties and prenylation reactions play crucial roles in controlling the activities of biomolecules. They are difficult to synthesize chemically, but enzymatic synthesis production is a desirable pathway. Cyclic dipeptide prenyltransferase catalyzes the regioselective Friedel–Crafts alkylation of tryptophan-containing cyclic dipeptides. This class of enzymes, which belongs to the dimethylallyl tryptophan synthase superfamily, is known to be flexible to aromatic prenyl receptors, while mostly retaining its typical regioselectivity. In this study, seven tryptophan-containing cyclic dipeptides 1a–7a were converted to their C7-regularly prenylated derivatives 1b–7b in the presence of dimethylallyl diphosphate (DMAPP) by using the purified 7-dimethylallyl tryptophan synthase (7-DMATS) as catalyst. The HPLC analysis of the incubation mixture and the NMR analysis of the separated products showed that the stereochemical structure of the substrate had a great influence on their acceptance by 7-DMATS. Determination of the kinetic parameters proved that cyclo-l-Trp–Gly (1a) consisting of a tryptophanyl and glycine was accepted as the best substrate with a KM value of 169.7 μM and a turnover number of 0.1307 s−1. Furthermore, docking studies simulated the prenyl transfer reaction of 7-DMATS and it could be concluded that the highest affinity between 7-DMATS and 1a. Preliminary results have been clearly shown that prenylation at C7 led to a significant increase of the anticancer and antimicrobial activities of the prenylated derivatives 1b–7b in all the activity test experiment, especially the prenylated product 4b.
Highlights
Cyclic dipeptides (CDPs) and derivatives are widely distributed in microorganisms and exhibit diverse biologic and pharmacological activities [1,2]
7-dimethylallyl tryptophan synthase (7-DMATS) is the cyclic dipeptide prenyltransferase with relatively high efficiency [44], which catalyzes a prenylation at the benzene ring in the presence of its natural prenyl donor DMAPP. In view of these findings and in continuation of our study on active indole diketopiperazine, we reported the enzymatic synthesis of C7-prenylation tryptophan-containing cyclic dipeptides, in which isopentenyl was linked to the indole ring of different cyclic dipeptides to enhance their biologic activity
Seven diketopiperazines of L-tryptophan series were used as substrates (1a–7a) and seven prenylated substances (1b–7b) were synthesized by 7-DMATS
Summary
Cyclic dipeptides (CDPs) and derivatives are widely distributed in microorganisms and exhibit diverse biologic and pharmacological activities [1,2]. A further interesting class of CDPs is indole alkaloids often containing prenyl moieties before undergoing additional modifications like cyclization, oxidation or acetylation [3]. Such as the well-known cytotoxic tryprostatin A, B and fumitremorgin. Due to its higher lipophilicity, the introduction of the prenyl moiety can increase biologic activity compared to its nonallylated precursor [7]. Structural analysis shows these natural products are composed of prenyl moieties from prenyl diphosphate and indole or indoline rings from tryptophan [8,9,10,11]. Fungi are the Molecules 2020, 25, 3676; doi:10.3390/molecules25163676 www.mdpi.com/journal/molecules
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