Rational and combinatorial tailoring of bioactive cyclic dipeptides

Abstract

Modified cyclic dipeptides represent a diverse family of microbial secondary metabolites. They display a broad variety of biological and pharmacological activities and have long been recognized as privileged structures with the ability to bind to a wide range of receptors. This is due to their conformationally constrained 2, 5-diketopiperazine (DKP) scaffold and the diverse set of DKP tailoring enzymes present in nature. After initial DKP assembly through different biosynthetic systems modifying enzymes are responsible for installing functional groups crucial for the biological activities of the resulting modified DKPs. They represent a vast and largely untapped enzyme repository very useful for synthetic biology approaches aiming at introducing structural variations into DKP scaffolds. In this review we focus on these DKP modification enzymes found in various microbial secondary metabolite gene clusters. We will give a brief overview of their distribution and highlight a select number of characterized DKP tailoring enzymes before turning to their application potential in combinatorial biosynthesis with the aim of producing molecules with improved or entirely new biological and medicinally relevant properties.

Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway

“…bond formation represents a novel and small, but growing, activity of the P450 enzyme superfamily (21). The work described here represents an initial experimental effort to unveil the C-C bond coupling mechanisms mediated by the P450 enzymes.…”

“…P450 enzymes are normally known to promote a wide range of catalytic activities of aliphatic and aromatic hydroxylation, dealkylation, desaturation, epoxidation, deamination, dehalogenation, dehydration, and isomerization. The C-C bond formation represents an unusual activity of the P450 enzyme superfamily (20,21).…”

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

“…The pharmacophore model is in the present project for the first time transformed onto the cyclic 2,5‐diketopiperazine (DKP) scaffold to yield a library of amphiphilic tetrasubstituted cyclic dipeptides. The 2,5‐DKP represents a versatile scaffold, and it is found in many bioactive natural products . Their mode of preparation and bioactivities were recently extensively reviewed by Borthwick .…”

“…The 2,5-DKP represents a versatile scaffold, and it is found in many bioactive natural products. 39 Their mode of preparation and bioactivities were recently extensively reviewed by Borthwick. 40 Herein, synthetic developments enabling rapid development of mixed amphiphilic 2,5-DKPs are reported, and a library of compounds with ranging functionalities has been prepared and evaluated for both antibacterial and antifungal properties against 11 different microbes.…”

Acceptor substrate determines donor specificity of an aromatic prenyltransferase: expanding the biocatalytic potential of NphB

“…This reaction scheme, delivers a high level of chemical diversity among the products of PT reactions arising from a combination of factors (Kumano et al 2008;Kuzuyama et al 2005;Shindo et al 2011;Tanner 2015;Tello et al 2008). For example, the accepted prenyl groups can vary in size (5-carbon dimethyallyl, 10-carbon geranyl, 15-carbon farnesyl, 20carbon geranylgeranyl) between PTs, while the attachment can occur from either C1′ or C3′ of the prenyl donors onto various positions of the aromatic acceptors, resulting in normal or reverse prenylation, respectively (Giessen and Marahiel 2015;Winkelblech et al 2015a). Furthermore, PTs have been shown to catalyze the formation of C-C (Araya-Cloutier et al 2017;Bandari et al 2019;Elshahawi et al 2017;Fan et al 2015b;Haagen et al 2007;Winkelblech et al 2015b), C-O (Bandari et al 2017;Haagen et al 2007; Bryce P. Johnson and Erin M. Scull contributed equally to this work.…”