Odd one out: Marine polyether ladders are probably the most well‐known of all marine natural products, not only for their fascinating structures, but also for their characteristic toxicity. A very straightforward model for the biosynthesis of all known polyether ladders, including maitotoxin (the largest and most toxic of this structural family; see formula) is described, but is the structure of this giant molecule really known?

Ionophoric polyethers are produced by the exquisitely stereoselective oxidative cyclization of a linear polyketide, probably via a triepoxide intermediate. We report here that deletion of either or both of the monBI and monBII genes from the monensin biosynthetic gene cluster gave strains that produced, in place of monensins A and B, a mixture of C-3-demethylmonensins and a number of minor components, including C-9-epi-monensin A. All the minor components were efficiently converted into monensins by subsequent acid treatment. These data strongly suggest that epoxide ring opening and concomitant polyether ring formation are catalyzed by the MonB enzymes, rather than by the enzyme MonCII as previously thought. Consistent with this, homology modeling shows that the structure of MonB-type enzymes closely resembles the recently determined structure of limonene-1,2-epoxide hydrolase from Rhodococcus erythropolis.

Long-term depression (LTD) and long-term potentiation (LTP) in the cerebellum are important for motor learning. However, the signaling mechanisms controlling whether LTD or LTP is induced in response to synaptic stimulation remain obscure. Using a unified model of LTD and LTP at the cerebellar parallel fiber-Purkinje cell (PF-PC) synapse, we delineate the coordinated pre- and postsynaptic signaling that determines the direction of plasticity. We show that LTP is the default response to PF stimulation above a well-defined frequency threshold. However, if the calcium signal surpasses the threshold for CaMKII activation, then an ultrasensitive "on switch" activates an extracellular signal-regulated kinase (ERK)-based positive feedback loop that triggers LTD instead. This postsynaptic feedback loop is sustained by another, trans-synaptic, feedback loop that maintains nitric oxide production throughout LTD induction. When full depression is achieved, an automatic "off switch" inactivates the feedback loops, returning the network to its basal state and demarcating the end of the early phase of LTD.

Evidence for the intermediate in the polyether biosynthesis of the ionophore antibiotic monensin A has been obtained. A tridecaketide E,E,E‐triene (see formula) has been isolated by using mutant strains of Streptomyces cinnamonensis. Characterization of this intermediate allows the likely biosynthetic route to monensin to be discriminated.

The biosynthetic pathways to polyketide-derived polycyclic ethers, in bacteria, plants and marine organisms, have, until now, tended to be considered separately. The purpose of this article is to provide an integrated review of the common mechanistic aspects of polyether biosynthesis from these diverse sources. In particular, the focus will be on the proposed mechanisms of oxidative cyclisation, as well as on the known differences in polyketide chain construction between the terrestrial and marine polyethers.1 Introduction, 2 Fatty acid and polyketide biosynthesis, 3 Polyether ionophores, 4 The annonaceous acetogenins, 5 Marine polyethers, 6 Chain construction in polyether biosynthesis, 7 Acknowledgements, 8 References.