A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of ...15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts.
A compilation of the rich diversity of bacterial secondary metabolite glycosides.
The late‐stage functionalization of peptides and proteins holds significant promise for drug discovery and facilitates bioorthogonal chemistry. This selective functionalization leads to innovative ...advances in in vitro and in vivo biological research. However, it is a challenging endeavor to selectively target a certain amino acid or position in the presence of other residues containing reactive groups. Biocatalysis has emerged as a powerful tool for selective, efficient, and economical modifications of molecules. Enzymes that have the ability to modify multiple complex substrates or selectively install nonnative handles have wide applications. Herein, we highlight enzymes with broad substrate tolerance that have been demonstrated to modify a specific amino acid residue in simple or complex peptides and/or proteins at late‐stage. The different substrates accepted by these enzymes are mentioned together with the reported downstream bioorthogonal reactions that have benefited from the enzymatic selective modifications.
Biocatalysis is a powerful tool to achieve selective modifications on peptides with strong potential in the development of pharmaceuticals and in biological research. This review focuses on amino acid residue‐specific enzymes with broad substrate tolerance as well as their nonnative substrates. These enzymes have enabled the modification of a wide range of peptides and proteins at late‐stage.
The late‐stage functionalization of indole‐ and tryptophan‐containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. ...Here, the synthesis of two hydroxy‐bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy‐bearing allyl moiety directly on the indole ring of tryptophan‐containing peptides. This is the first report of late‐stage indole modifications with this reactive group.
The late‐stage functionalization of indole‐ and tryptophan (Trp)‐containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. The synthesis of two hydroxy‐bearing allyl pyrophosphates is described and a chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase (IPT) enzyme to install a dual reactive hydroxy‐bearing allyl group directly on the indole ring of tryptophan‐containing peptides.
Daptomycin (DAP) is a calcium (Ca2+)‐dependent FDA‐approved antibiotic drug for the treatment of Gram‐positive infections. It possesses a complex pharmacophore hampering derivatization and/or ...synthesis of analogues. To mimic the Ca2+‐binding effect, we used a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp‐modified DAP analogues. We demonstrated that the modified DAPs are several times more active than the parent molecule against antibiotic‐susceptible and antibiotic‐resistant Gram‐positive bacteria. Strikingly, and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity.
Ca not required: Daptomycin relies on calcium as an essential element for its strong antibiotic activity. Herein, a chemoenzymatic approach is used to synthesize regiospecific daptomycin derivatives that are independent of calcium and are more active than the parent drug against daptomycin‐susceptible and daptomycin‐resistant Gram‐positive bacteria.
Site-selective modification of complex peptides and the functionalization of their C–H bonds hold great promise for expanding their use in therapeutics and biomedical research. Herein, we leverage ...the power of late-stage chemoenzymatic catalysis using an indole prenyltransferase (IPT) enzyme and alkyl diphosphates to specifically modify the indole ring of tryptophan in clinically relevant peptides. Furthermore, the installed handle enables bioorthogonal click chemistry through an inverse electron-demand Diels–Alder (IEDDA) reaction with a biotin-conjugated tetrazine probe.
This study highlights the biochemical and structural characterization of the L-tryptophan C6 C-prenyltransferase (C-PT) PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to ...a diverse array of prenyl donors and acceptors including daptomycin. Two additional PTs also produced novel prenylated daptomycins with improved antibacterial activities over the parent drug.
The relationship between tunicates and the uncultivated cyanobacterium Prochloron didemni has long provided a model symbiosis. P. didemni is required for survival of animals such as Lissoclinum ...patella and also makes secondary metabolites of pharmaceutical interest. Here, we present the metagenomes, chemistry, and microbiomes of four related L. patella tunicate samples from a wide geographical range of the tropical Pacific. The remarkably similar P. didemni genomes are the most complex so far assembled from uncultivated organisms. Although P. didemni has not been stably cultivated and comprises a single strain in each sample, a complete set of metabolic genes indicates that the bacteria are likely capable of reproducing outside the host. The sequences reveal notable peculiarities of the photosynthetic apparatus and explain the basis of nutrient exchange underlying the symbiosis. P. didemni likely profoundly influences the lipid composition of the animals by synthesizing sterols and an unusual lipid with biofuel potential. In addition, L. patella also harbors a great variety of other bacterial groups that contribute nutritional and secondary metabolic products to the symbiosis. These bacteria possess an enormous genetic potential to synthesize new secondary metabolites. For example, an antitumor candidate molecule, patellazole, is not encoded in the genome of Prochloron and was linked to other bacteria from the microbiome. This study unveils the complex L. patella microbiome and its impact on primary and secondary metabolism, revealing a remarkable versatility in creating and exchanging small molecules.
The isolation and structure elucidation of six new bacterial metabolites spoxazomicin D (2), oxachelins B and C (4, 5), and carboxamides 6–8 and 11 previously reported bacterial metabolites (1, 3, ...9–12a, and 14–18) from Streptomyces sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for 2, 11, and 12a,b. Complete 2D NMR assignments for the known metabolites lenoremycin (9) and lenoremycin sodium salt (10) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035 as phenol-dihydrooxazoles. Bioactivity analysis including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection revealed 2 and 5 as potent neuroprotectives and lenoremycin (9) and its sodium salt (10) as potent UPR modulators, highlighting new functions for phenol-oxazolines/salicylates and polyether pharmacophores.
The isolation and structure elucidation of four new naturally occurring amino-nucleoside puromycins B–E (1–4) metabolites from a Himalayan isolate (Streptomyces sp. PU-14-G, isolated from the Bara ...Gali region of northern Pakistan) is reported. Consistent with prior reports, comparative antimicrobial assays revealed the need for the free 2″-amine for anti-Gram-positive bacteria and antimycobacterial activity. Similarly, comparative cancer cell line cytotoxicity assays highlighted the importance of the puromycin-free 2″-amine and the impact of 3′-nucleoside substitution. These studies extend the repertoire of known naturally occurring puromycins and their corresponding SAR. Notably, 1 represents the first reported naturally occurring bacterial puromycin-related metabolite with a 3′-N-amino acid substitution that differs from the 3′-N-tyrosinyl of classical puromycin-type natural products. This discovery suggests the biosynthesis of 1 in Streptomyces sp. PU-14G may invoke a uniquely permissive amino-nucleoside synthetase and/or multiple synthetases and sets the stage for further studies to elucidate, and potentially exploit, new biocatalysts for puromycin chemoenzymatic diversification.
We report the identification of the ter gene cluster responsible for the formation of the p-terphenyl derivatives terfestatins B and C and echoside B from the Appalachian Streptomyces strain RM-5-8. ...We characterize the function of TerB/C, catalysts that work together as a dual enzyme system in the biosynthesis of natural terphenyls. TerB acts as a reductase and TerC as a dehydratase to enable the conversion of polyporic acid to a terphenyl triol intermediate. X-ray crystallography of the apo and substrate-bound forms for both enzymes provides additional mechanistic insights. Validation of the TerC structural model via mutagenesis highlights a critical role of arginine 143 and aspartate 173 in catalysis. Cumulatively, this work highlights a set of enzymes acting in harmony to control and direct reactive intermediates and advances fundamental understanding of the previously unresolved early steps in terphenyl biosynthesis.
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