Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity

Lukat, Peer; Katsuyama, Yoshihiko; Wenzel, Silke C.; Binz, Tina M.; König, Claudia; Blankenfeldt, Wulf; Brönstrup, Mark; Müller, Rolf

doi:10.1039/c7sc02622f

Cited by 73 publications

(74 citation statements)

References 16 publications

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“…Phylogenetic analysiso ft he Cd omains confirmed the order of the alanine residues to be d, l, d (Figure 2A). [20,21] The architecture of the hep NRPS indicates that the starterC domain incorporates the acetyl group in lieu of long-chain fatty acid tails that are predominantly loaded onto the Ntermini of nonribosomal lipopeptides( Figure 2C). Compared with the large number of known cyclic lipopeptides, N-acetylated cyclopeptides, such as heptarhizin, are surprisingly rare.…”

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confidence: 99%

“…Compared with the large number of known cyclic lipopeptides, N-acetylated cyclopeptides, such as heptarhizin, are surprisingly rare. [21] To gain an insight into the relationships of the starterCdomains andt heir substrate specificities, we performedaphylogenetica nalysiso ft he HepA Cd omains and the Cd omains acquiredf rom the NaPDos database [24] (maximum likelihood [25] ). [20,21] The architecture of the hep NRPS indicates that the starterC domain incorporates the acetyl group in lieu of long-chain fatty acid tails that are predominantly loaded onto the Ntermini of nonribosomal lipopeptides( Figure 2C).…”

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confidence: 99%

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Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

et al. 2018

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The rice seedling blight fungus Rhizopus microsporus harbors endosymbiotic bacteria (Burkholderia rhizoxinica) that produce the virulence factor rhizoxin and control host development. Genome mining indicated a massive inventory of cryptic nonribosomal peptide synthetase (NRPS) genes, which have not yet been linked to any natural products. The discovery and full characterization of a novel cyclopeptide from endofungal bacteria is reported. In silico analysis of an orphan, symbiont-specific NRPS predicted the structure of a nonribosomal peptide, which was targeted by LC-MS/MS profiling of wild-type and engineered null mutants. NMR spectroscopy and chemical derivatization elucidated the structure of the bacterial cyclopeptide. Phylogenetic analyses revealed the relationship of starter C domains for rare N-acetyl-capped peptides. Heptarhizin is produced under symbiotic conditions in geographically constrained strains from the Pacific clade; this indicates a potential ecological role of the peptide.

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Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

et al. 2018

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“…We hypothesize that this functionality is generated by a leucine‐selective enzyme (Fig. 5) involving oxidation, cyclization, and reduction, similar to the respective transformations in the biosynthesis of echinocandin [32], griselimycin [33], and the nostopeptolides [34].…”

Section: Distinct Nonribosomal Peptide Synthetasesmentioning

confidence: 99%

“…10B) [68,69]. They are proposed to share the common precursors notoamide S (5), (+)-6-epi-notoamide T (33), and (+)-6-epi-stephacidin A (9). Additionally, A. taichungensis ZHN-7-07 produces 9, Nhydroxy-6-epi-stephacidin A (43), and 6-epi-avrainvillamide (44), all with anti-relative configuration ( Fig.…”

Section: Taichunamidesmentioning

confidence: 99%

Enzyme evolution in fungal indole alkaloid biosynthesis

Fraley

Sherman

2020

The FEBS Journal

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The class of fungal indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring is comprised of diverse molecules that display a range of biological activities. While much interest has been garnered due to their therapeutic potential, this class of molecules also displays unique chemical functionality, making them intriguing synthetic targets. Many elegant and intricate total syntheses have been developed to generate these alkaloids, but the selectivity required to produce them in high yield presents great barriers. Alternatively, if we can understand the molecular mechanisms behind how fungi make these complex molecules, we can leverage the power of nature to perform these chemical transformations. Here, we describe the various studies regarding the evolutionary development of enzymes involved in fungal indole alkaloid biosynthesis.

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“…Nevertheless, griselimycin remains an exciting prospect, and is undergoing lead optimization by Sanofi and the TB Alliance ( https://www.tballiance.org/portfolio/compound/cyclopeptides ). Of further interest, very elegant recent work elucidating the pathway for griselimycin biosynthesis in the producer organism, Streptomyces DSM 40835, suggests the feasibility of rational modifications to the core pharmacophore (Lukat et al, 2017 ), thereby overcoming a common stumbling block in natural product drug development.…”

Section: The Mycobacterial Dna Replication Machinerymentioning

confidence: 99%

Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

Reiche

Warner

Mizrahi

2017

Front. Mol. Biosci.

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Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR) as well as extensively drug-resistant (XDR) strains of M. tuberculosis, and the complications posed by co-infection with the human immunodeficiency virus (HIV) and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis. Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the development of drug resistance in M. tuberculosis, an organism which is unusual in relying exclusively on de novo mutations and chromosomal rearrangements for evolution, including the acquisition of drug resistance. In that context, we conclude by discussing the feasibility of targeting mutagenic pathways in an ancillary, “anti-evolution” strategy aimed at protecting existing and future TB drugs.

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Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity

Abstract: The biosynthesis of griselimycins in Streptomyces DSM 40835 and the pathway that stereospecifically converts l-leucine to (2S,4R)-4-methyl-proline are reported by means of biochemical and structural analysis.

Cited by 73 publications

References 16 publications

Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

Enzyme evolution in fungal indole alkaloid biosynthesis

Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

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