Iron‐deficient bean plants (Phaseolus vulgaris L. cv. Prélude) exhibited a ferric reducing activity in the roots, with kinetics characteristic for matrix‐bound enzymes: the reaction rate was proportional to substrate (Fe‐EDTA) concentration until 100 μM, and at higher concentrations it leveled off to a maximum; the Lineweaver‐Burk plot yielded a non‐linear relationship between rate −1 and substrate −1. The Arrhenius plot yielded apparent activation energies which were dependent on substrate concentration. No evidence was obtained for the secretion by roots of a low molecular weight metabolite involved in the reduction of iron prior to its uptake. The results are interpreted to indicate that the ferric reducing activity in the roots of iron‐deficient bean plants is located in an enzyme in the plasmalemma of the cortex or epidermis cells.
The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins.
Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharmacophore and its SAR are reviewed herein.
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