Algorithm-aided engineering of aliphatic halogenase WelO5* for the asymmetric late-stage functionalization of soraphens.

Late-stage functionalization of natural products offers an elegant route to create novel entities in a relevant biological target space. In this context, enzymes capable of halogenating sp carbons with high stereo- and regiocontrol under benign conditions have attracted particular attention. Enabled by a combination of smart library design and machine learning, we engineer the iron/α-ketoglutarate dependent halogenase WelO5* for the late-stage functionalization of the complex and chemically difficult to derivatize macrolides soraphen A and C, potent anti-fungal agents.

Activation, Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii.

The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881-1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli.

Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors.

The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P), peptidic core, (P and P), and end-cap (P) of our scaffold.

Strategy towards the enantioselective synthesis of schiglautone A.

Herein is described a convergent enantioselective route to an advanced intermediate in the synthesis of schiglautone A, a Schisandra triterpenoid with an unusual architecture. The synthetic route to this intermediate displaying 6 of the 7 stereocenters builds upon two fragments, an aldehyde elaborated from the Wieland-Miescher ketone, and a ketone. The preparation of the latter features a lithiation-borylation enzymatic resolution sequence, which led to the formation of the desired product with high enantio- and diastereoselectivities.

Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome.

Selective inhibition of the immunoproteasome is a promising approach towards the development of immunomodulatory drugs. Recently, a class of substituted thiazole compounds that combine a nonpeptidic scaffold with the absence of an electrophile was reported in a patent. Here, we investigated the mode of action of the lead compound by using a sophisticated chimeric yeast model of the human immunoproteasome for structural studies.

Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle.

Sequential Inactivation of Gliotoxin by the S-Methyltransferase TmtA.

The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication of the mold is prevented either by reversible oxidation of reduced gliotoxin or by irreversible conversion to bis(methylthio)gliotoxin. The latter is produced by the S-methyltransferase TmtA and attenuates ETP biosynthesis.

Synthesis and Biological Evaluation of Chlorinated Analogs of Leukotoxin Diol.

This study documents that chlorinated analogs of leukotoxin diol 1, in which the vic-diol has been replaced with vic-chlorides (2), induce caspase 3 activity and apoptosis on HepG2 cells in a dose-dependent manner in analogy to the parent diol. This suggests that chlorides may substitute for hydroxyls in certain lipids as bioisosteres in defined biological settings.

Diagnostic accuracy of community pathologists in the interpretation of colorectal polyps.

Background And Aims: Management of patients with endoscopically removed colorectal polyps is generally dependent on pathological evaluation. The aim of this study was to assess the accuracy and clinical impact of pathologic interpretation of colorectal polyps by community pathologists.

Methods: Two expert gastrointestinal pathologists reviewed the slides of 300 colorectal polyps initially examined by 14 general pathologists.

Hormonal and metabolic changes during exercise in cirrhotic patients.

The metabolic response to exercise was compared in 10 cirrhotic patients (P) in a stable clinical condition and in 6 sedentary, age-matched, normal subjects (C) performing 32 minutes of treadmill exercise with the same constant workload corresponding to three to four times their resting oxygen uptake. Taking indirect calorimetry as reference, respiratory exchanges indicated that cirrhotic patients consumed carbohydrates almost exclusively, unlike the normal controls, who consumed lipids and glucids in about the same proportions (RQ: 0.98 +/- 0.