Insights into the Bioactivity of Mensacarcin and Epoxide Formation by MsnO8

Maier, Sarah; Pflüger, Tobias; Loesgen, Sandra; Asmus, Katharina; Brötz, Elke; Paululat, Thomas; Zeeck, Axel; Andrade, Susana L. A.; Bechthold, Andreas

doi:10.1002/cbic.201300704

Cited by 16 publications

(12 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further attachment of N -acetylcysteine to the oxidized product synthesized by ArpO would generate argimycins PI/PII. Most probably, this would be a non-enzymatic event as it has been reported for the biosynthesis of other N -acetylcysteine-containing compounds ( Suzuki et al, 2006 ; Gómez-Escribano et al, 2012 ; Maier et al, 2014 ).…”

Section: Resultsmentioning

confidence: 72%

New Insights into the Biosynthesis Pathway of Polyketide Alkaloid Argimycins P in Streptomyces argillaceus

Braña

González‐Sabín

et al. 2018

Front. Microbiol.

View full text Add to dashboard Cite

Argimycins P are a recently identified family of polyketide alkaloids encoded by the cryptic gene cluster arp of Streptomyces argillaceus. These compounds contain either a piperideine ring, or a piperidine ring which may be fused to a five membered ring, and a polyene side chain, which is bound in some cases to an N-acetylcysteine moiety. The arp cluster consists of 11 genes coding for structural proteins, two for regulatory proteins and one for a hypothetical protein. Herein, we have characterized the post-piperideine ring biosynthesis steps of argimycins P through the generation of mutants in arp genes, the identification and characterization of compounds accumulated by those mutants, and cross-feeding experiments between mutants. Based in these results, a biosynthesis pathway is proposed assigning roles to every arp gene product. The regulation of the arp cluster is also addressed by inactivating/overexpressing the positive SARP-like arpRI and the negative TetR-like arpRII transcriptional regulators and determining the effect on argimycins P production, and through gene expression analyses (reverse transcription PCR and quantitative real-time PCR) of arp genes in regulatory mutants in comparison to the wild type strain. These findings will contribute to deepen the knowledge on the biosynthesis of piperidine-containing polyketides and provide tools that can be used to generate new analogs by genetic engineering and/or biocatalysis.

show abstract

Section: Resultsmentioning

confidence: 72%

New Insights into the Biosynthesis Pathway of Polyketide Alkaloid Argimycins P in Streptomyces argillaceus

Braña

González‐Sabín

et al. 2018

Front. Microbiol.

View full text Add to dashboard Cite

show abstract

“…No total synthesis of mensacarcin has been published thus far; however, related synthetic programs toward the highly functionalized hexahydroanthracene backbone indicate the importance of the epoxide moieties within mensacarcin for antitumor activity (6 -8). Indeed, semi-synthetic modifications targeting the side chain epoxide revealed a correlation of cytotoxicity with the degree of oxidation in the side chain (9). Detailed studies on mensacarcin's biosynthesis by Bechthold and co-workers (10) enabled the heterologous expression of mensacarcin's biosynthetic gene cluster to yield 1 and analogues.…”

mentioning

confidence: 99%

“…Detailed studies on mensacarcin's biosynthesis by Bechthold and co-workers (10) enabled the heterologous expression of mensacarcin's biosynthetic gene cluster to yield 1 and analogues. Its biogenesis entails several unusual enzyme activities, among them a new mechanism of epoxide formation in polyketides (9,11). Mensacarcin was submitted to the NCI-60 human tumor cell line screen and showed strong anti-proliferative effects in all tested cell lines and low COMPARE correlations to known anticancer agents (12).…”

mentioning

confidence: 99%

The natural product mensacarcin induces mitochondrial toxicity and apoptosis in melanoma cells

Plitzko¹,

Kaweesa

Loesgen

2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Mensacarcin is a highly oxygenated polyketide that was first isolated from soil-dwelling bacteria. It exhibits potent cytostatic properties (mean of 50% growth inhibition = 0.2 μm) in almost all cell lines of the National Cancer Institute (NCI)-60 cell line screen and relatively selective cytotoxicity against melanoma cells. Moreover, its low COMPARE correlations with known standard antitumor agents indicate a unique mechanism of action. Effective therapies for managing melanoma are limited, so we sought to investigate mensacarcin's unique cytostatic and cytotoxic effects and its mode of action. By assessing morphological and biochemical features, we demonstrated that mensacarcin activates caspase-3/7-dependent apoptotic pathways and induces cell death in melanoma cells. Upon mensacarcin exposure, SK-Mel-28 and SK-Mel-5 melanoma cells, which have the BRAF mutation associated with drug resistance, showed characteristic chromatin condensation as well as distinct poly(ADP-ribose)polymerase-1 cleavage. Flow cytometry identified a large population of apoptotic melanoma cells, and single-cell electrophoresis indicated that mensacarcin causes genetic instability, a hallmark of early apoptosis. To visualize mensacarcin's subcellular localization, we synthesized a fluorescent mensacarcin probe that retained activity. The natural product probe was localized to mitochondria within 20 min of treatment. Live-cell bioenergetic flux analysis confirmed that mensacarcin disturbs energy production and mitochondrial function rapidly. The subcellular localization of the fluorescently labeled mensacarcin together with its unusual metabolic effects in melanoma cells provide evidence that mensacarcin targets mitochondria. Mensacarcin's unique mode of action suggests that it may be a useful probe for examining energy metabolism, particularly in BRAF-mutant melanoma, and represent a promising lead for the development of new anticancer drugs.

show abstract

“…C2C12 cells were plated at a confluency of 30 -40% in a MatTek six-well plate. The cells were incubated with 1 M mensacarcin, a compound known to influence mitochondrial function (28,35), for 30 min in Krebs-Henseleit buffer containing (in mM) 118 NaCl, 24 NaHCO3, 4.8 KCl, 2 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, and 10 glucose. Radioactive 2DG (1.5 Ci/mL) and 2DG (10 M) were placed in the media for an additional 30 min.…”

Section: Methodsmentioning

confidence: 99%

Bioenergetics underlying single-cell migration on aligned nanofiber scaffolds

Padhi

Thomson

Perry

et al. 2020

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

Cell migration is centrally involved in a myriad of physiological processes, including morphogenesis, wound healing, tissue repair, and metastatic growth. The bioenergetics that underlie migratory behavior are not fully understood, in part because of variations in cell culture media and utilization of experimental cell culture systems that do not model physiological connective extracellular fibrous networks. In this study, we evaluated the bioenergetics of C2C12 myoblast migration and force production on fibronectin-coated nanofiber scaffolds of controlled diameter and alignment, fabricated using a nonelectrospinning spinneret-based tunable engineered parameters (STEP) platform. The contribution of various metabolic pathways to cellular migration was determined using inhibitors of cellular respiration, ATP synthesis, glycolysis, or glucose uptake. Despite immediate effects on oxygen consumption, mitochondrial inhibition only modestly reduced cell migration velocity, whereas inhibitors of glycolysis and cellular glucose uptake led to striking decreases in migration. The migratory metabolic sensitivity was modifiable based on the substrates present in cell culture media. Cells cultured in galactose (instead of glucose) showed substantial migratory sensitivity to mitochondrial inhibition. We used nanonet force microscopy to determine the bioenergetic factors responsible for single-cell force production and observed that neither mitochondrial nor glycolytic inhibition altered single-cell force production. These data suggest that myoblast migration is heavily reliant on glycolysis in cells grown in conventional media. These studies have wide-ranging implications for the causes, consequences, and putative therapeutic treatments aimed at cellular migration.

show abstract

Insights into the Bioactivity of Mensacarcin and Epoxide Formation by MsnO8

Cited by 16 publications

References 64 publications

New Insights into the Biosynthesis Pathway of Polyketide Alkaloid Argimycins P in Streptomyces argillaceus

New Insights into the Biosynthesis Pathway of Polyketide Alkaloid Argimycins P in Streptomyces argillaceus

The natural product mensacarcin induces mitochondrial toxicity and apoptosis in melanoma cells

Bioenergetics underlying single-cell migration on aligned nanofiber scaffolds

Contact Info

Product

Resources

About