A Case of Convergent Evolution: The Bacterial Sesquiterpene Synthase for 1-epi-Cubenol from Nonomuraea coxensis

A terpene synthase from Nonomuraea coxensis was identified as (+)-1-epi-cubenol synthase. The enzyme is phylogenetically unrelated to the known enzyme of the same function that is widespread in streptomycetes. Isotopic labelling experiments were performed to unambiguously assign the NMR data and to investigate hydrogen migrations during terpene cyclisations. Epoxidations of (+)-1-epi-cubenol and of the plant derived compounds (−)-cubenol and (−)-1-epi-cubenol confirmed the structure of a natural product isolated from the brown alga Dictyopteris divaricata and allowed to conclude on its absolute configuration. The crystal structures of the epoxides from (+)- and (−)-1-epi-cubenol and the acid catalysed conversion into an isomeric ketone are reported.     

Cladosporin,A Highly Potent Antimalaria Drug?

Cladosporin, a unique natural product from the fungus Cladosporium cladosporioides, exhibits nanomolar inhibitory activity against Plasmodium falciparum by targeting its cytosolic lysyl-tRNA synthetase (PfKRS) to inhibit protein biosynthesis. Due to its exquisite selectivity towards pathogenic parasites, cladosporin has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria and cryptosporidiosis infections. Here we review the recent research progress of cladosporin covering aspects of the chemical synthesis, biosynthesis, bioactivity, cellular target and structure–activity relationship.     

First principles prediction of NRTL binary interaction parameters for furfural derivatives

Biobased molecules constitute sustainable alternatives for fossil-based chemicals. However, to allow further valorization, the complex product mixtures resulting from biomass processing typically require downstream separation. Although many (semi)empirical thermodynamic models, like NRTL, are available for separation process design, their application for biobased molecules is hampered due to the lack of the necessary data to determine the binary interaction parameters used in these models. Therefore, in this work a case study comprising a set of furfural derivates has been used to showcase a methodology to efficiently determine these parameters. Based on first principles, COSMO-RS is used to generate a dataset of thermodynamic activities, which is subsequently used to regress the NRTL model against. Comparison of NRTL-HOC simulated vapor–liquid equilibria (VLE's) with experimental VLE's showed excellent agreement, confirming that COSMO-RS can be used to extend the use of (semi)-empirical models toward applications involving biobased molecules of which limited experimental data is available.     

4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors

Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.     

Nocturnal tidal barrier management improves glass eel migration in times of drought and salinization risk

Adjusted tidal barrier management (ATBM, setting tidal doors ajar during tidal rise) is currently applied in Belgium to improve glass eel passage through tidal gates. However, salt intrusion in the receiving waters due to upwelling and accumulation of saline groundwater as a result of intensive drought put severe pressure on the unrestrained use of this cost-efficient mitigation measure. We evaluated the efficacy of a very restricted ATBM at a tidal barrier on a small canalized waterway, located 3.5 km from the sea: one out of seven gate doors was left 20 cm ajar for ca. 30 min when the water levels on both sides of the tidal barrier were approximately equal. During 20 inflow events differing in tidal flow (i.e., flood or ebb tide) and daytime (i.e., day or night) in March/April 2019, migrating glass eels were caught with a fyke net fixed on the temporally opened gate. In total, 12,853 glass eels were captured, almost all during flood tides at night (96%), with a maximum catch of 3,827 individuals per inflow event. These results show that even small windows of opportunity can help glass eels pass tidal barriers.