Complex molecules, clever solutions – Enzymatic approaches towards natural product and active agent syntheses

Claßen, Thomas; Pietruszka, Jörg

doi:10.1016/j.bmc.2017.06.045

Cited by 26 publications

(28 citation statements)

References 144 publications

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“…These compounds could contribute to an improved microbe resistance management or having stronger bioactivities. Recently, nature inspired prodiginines were produced by combining organic syntheses with a mutasynthesis approach using the HV1-certified bacterium Pseudomonas putida KT2440 as host strain ( Weist and Süssmuth, 2005 ; Kennedy, 2008 ; Kirschning and Hahn, 2012 ; Klein et al, 2017 , 2018 ; Classen and Pietruszka, 2018 ). The previously constructed mutasynthesis strain harbors the prodigiosin ( 1 ) gene cluster from S. marcescens , but the bifurcated biosynthetic pathway is blocked upon gene deletion, thus, only one out of two prodiginine building blocks, namely 4-methoxy-2,2’-bipyrrole-5-carbaldehyde (MBC), is produced biosynthetically ( Domröse et al, 2015 ; Klein et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Prodiginine Derivatives Demonstrate Bioactivities on Plants, Nematodes, and Fungi

et al. 2020

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Bacterial metabolites represent an invaluable source of bioactive molecules which can be used as such or serve as chemical frameworks for developing new antimicrobial compounds for various applications including crop protection against pathogens. Prodiginines are tripyrrolic, red-colored compounds produced by many bacterial species. Recently, due to the use of chemical-, bio-, or mutasynthesis, a novel group of prodiginines was generated. In our study, we perform different assays to evaluate the effects of prodigiosin and five derivatives on nematodes and plant pathogenic fungi as well as on plant development. Our results showed that prodigiosin and the derivatives were active against the bacterial feeding nematode Caenorhabditis elegans in a concentration- and derivative-dependent manner while a direct effect on infective juveniles of the plant parasitic nematode Heterodera schachtii was observed for prodigiosin only. All compounds were found to be active against the plant pathogenic fungi Phoma lingam and Sclerotinia sclerotiorum. Efficacy varied depending on compound concentration and chemical structure. We observed that prodigiosin ( 1 ), the 12 ring- 9 , and hexenol 10 derivatives are neutral or even positive for growth of Arabidopsis thaliana depending on the applied compound concentration, whereas other derivatives appear to be suppressive. Our infection assays revealed that the total number of developed H. schachtii individuals on A. thaliana was decreased to 50% in the presence of compounds 1 or 9 . Furthermore, female nematodes and their associated syncytia were smaller in size. Prodiginines seem to indirectly inhibit H. schachtii parasitism of the plant. Further research is needed to elucidate their mode of action. Our results indicate that prodiginines are promising metabolites that have the potential to be developed into novel antinematodal and antifungal agents.

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Section: Introductionmentioning

confidence: 99%

Novel Prodiginine Derivatives Demonstrate Bioactivities on Plants, Nematodes, and Fungi

et al. 2020

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“…Biocatalytic transformations nowadays comprise an ever expanding toolbox of chemo-, stereo-and regioselective reactions. [1][2][3][4][5][6][7] The use of enzymes to catalyze reactions has several benefits, such as mild reaction conditions, aqueous media as solvents, compatibility of different reaction steps in multi-step syntheses, as well as a reduced need for protecting groups. 3,4,8 Most enzymes are promiscuous to at least some extent, or can be engineered to accept a new substrate, so that the possible range of biocatalyzed transformations is large enough to be of interest to synthetic chemists, as testified by the large number of novel enzymatic cascades for the synthesis of diverse targets that were published in the last decade.…”

Section: Introductionmentioning

confidence: 99%

EHreact: Extended Hasse Diagrams for the Extraction and Scoring of Enzymatic Reaction Templates

Heid

Goldman²,

Sankaranarayanan³

et al. 2021

Preprint

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Data-driven computer-aided synthesis planning utilizing organic or biocatalyzed reactions from large databases has gained increasing interest in the last decade, sparking the development of numerous tools to extract, apply and score general reaction templates. The generation of reaction rules for enzymatic reactions is especially challenging, since substrate promiscuity varies between enzymes, causing the optimal levels of rule specificity and optimal number of included atoms to differ between enzymes. This complicates an automated extraction from databases and has promoted the creation of manually curated reaction rule sets. Here we present EHreact, a purely data-driven open-source software tool to extract and score reaction rules from sets of reactions known to be catalyzed by an enzyme at appropriate levels of specificity without expert knowledge. EHreact extracts and groups reaction rules into tree-like structures, Hasse diagrams, based on common substructures in the imaginary transition structures. Each diagram can be utilized to output a single or a set of reaction rules, as well as calculate the probability of a new substrate to be processed by the given enzyme by inferring information about the reactive site of the enzyme from the known reactions and their grouping in the template tree. EHreact heuristically predicts the activity of a given enzyme on a new substrate, outperforming current approaches in accuracy and functionality.

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“…Similarly to the approach used for other meningococcal vaccines 20 , the polymer chains were then hydrolyzed, sized to a length of avDP10 and, after appropriate functionalization, conjugated to a carrier protein 15,21 . In the last decade, methods for accelerating the production of biologically relevant carbohydrates have encountered fast development [22][23][24][25] . The availability of in vitro prepared defined glycans is key for the production of glycoconjugates devoid of pathogenic contaminants, with higher standards for characterization and more robust correlation between structure and immune activity .…”

Section: Introductionmentioning

confidence: 99%

Combined Chemical Synthesis and Tailored Enzymatic Elongation Provide Fully Synthetic and Conjugation-Ready Neisseria meningitidis Serogroup X Vaccine Antigens

et al. 2018

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Studies on the polymerization mode of Neisseria meningitidis serogroup X capsular polymerase CsxA recently identified a truncated construct that can be immobilized and used for length controlled on-column production of oligosaccharides. Here, we combined the use of a synthetic acceptor bearing an appendix for carrier protein conjugation and the on-column process to a novel chemo-enzymatic strategy. After protein coupling of the size optimized oligosaccharide produced by the one-pot elongation procedure, we obtained a more homogeneous glycoconjugate compared to the one previously described starting from the natural polysaccharide. Mice immunized with the conjugated fully synthetic oligomer elicited functional antibodies comparable to controls immunized with the current benchmark MenX glycoconjugates prepared from the natural capsule polymer or from fragments of it enzymatically elongated. This pathogen-free technology allows the fast total in vitro construction of predefined bacterial polysaccharide fragments. Compared to conventional synthetic protocols, the procedure is more expeditious and drastically reduces the number of purification steps to achieve the oligomers. Furthermore, the presence of a linker for conjugation in the synthetic acceptor minimizes manipulations on the enzymatically produced glycan prior to protein conjugation. This approach enriches the methods for fast construction of complex bacterial carbohydrates.

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Complex molecules, clever solutions – Enzymatic approaches towards natural product and active agent syntheses

Cited by 26 publications

References 144 publications

Novel Prodiginine Derivatives Demonstrate Bioactivities on Plants, Nematodes, and Fungi

Novel Prodiginine Derivatives Demonstrate Bioactivities on Plants, Nematodes, and Fungi

EHreact: Extended Hasse Diagrams for the Extraction and Scoring of Enzymatic Reaction Templates

Combined Chemical Synthesis and Tailored Enzymatic Elongation Provide Fully Synthetic and Conjugation-Ready Neisseria meningitidis Serogroup X Vaccine Antigens

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