A Detailed View on Geosmin Biosynthesis

The bacterial geosmin synthase is a fascinating bifunctional enzyme that has been discovered almost two decades ago. Several aspects of the cyclisation mechanism from FPP to geosmin are known, but a detailed picture of the stereochemical course of this reaction is unknown. This article reports on a deep investigation of the mechanism of geosmin synthase through isotopic labelling experiments. Furthermore, the effects of divalent cations on geosmin synthase catalysis were investigated. The addition of cyclodextrin to enzymatic reactions, a molecule that can capture terpenes, suggests that the biosynthetic intermediate (1(10)E,5E)-germacradien-11-ol produced by the N-terminal domain is passed to the C-terminal domain not through a tunnel, but rather through release into the medium and uptake by the C-terminal domain.     

Interactions between intradialytic central venous oxygen saturation,relative blood volume,and all-cause mortality in maintenance hemodialysis patients

Introduction

In maintenance hemodialysis (HD) patients, low central venous oxygen saturation (ScvO₂) and small decline in relative blood volume (RBV) have been associated with adverse outcomes. Here we explore the joint association between ScvO₂ and RBV change in relation to all-cause mortality.

Methods

We conducted a retrospective study in maintenance HD patients with central venous catheters as vascular access. During a 6-month baseline period, Crit-Line (Fresenius Medical Care, Waltham, MA) was used to measure continuously intradialytic ScvO₂ and hematocrit-based RBV. We defined four groups per median change of RBV and median ScvO₂. Patients with ScvO₂ above median and RBV change below median were defined as reference. Follow-up period was 3 years. We constructed Cox proportional hazards model with adjustment for age, diabetes, and dialysis vintage to assess the association between ScvO₂ and RBV and all-cause mortality during follow-up.

Findings

Baseline comprised 5231 dialysis sessions in 216 patients. The median RBV change was −5.5% and median ScvO₂ was 58.8%. During follow-up, 44 patients (20.4%) died. In the adjusted model, all-cause mortality was highest in patients with ScvO₂ below median and RBV change above median (HR 6.32; 95% confidence interval [CI] 1.37–29.06), followed by patients with ScvO₂ below median and RBV change below median (HR 5.04; 95% CI 1.14–22.35), and ScvO₂ above median and RBV change above median (HR 4.52; 95% CI 0.95–21.36).

Discussion

Concurrent combined monitoring of intradialytic ScvO₂ and RBV change may provide additional insights into a patient's circulatory status. Patients with low ScvO₂ and small changes in RBV may represent a specifically vulnerable group of patients at particularly high risk for adverse outcomes, possibly related to poor cardiac reserve and fluid overload.     

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.