Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.

Patched acts catalytically to suppress the activity of Smoothened

http://science.sciencemag.org/content/sci/197/4303/527.full.pdf

Bioactivation as a model for drug design bioreductive alkylation

The phytochemistry of the annonaceae

Plant disease resistance can be conferred by constitutive features such as structural barriers or preformed antimicrobial secondary metabolites. Additional defence mechanisms are activated in response to pathogen attack and include localized cell death (the hypersensitive response)1,2. Pathogens use different strategies to counter constitutive and induced plant defences, including degradation of preformed antimicrobial compounds3 and the production of molecules that suppress induced plant defences4,5,6. Here we present evidence for a two-component process in which a fungal pathogen subverts the preformed antimicrobial compounds of its host and uses them to interfere with induced defence responses. Antimicrobial saponins are first hydrolysed by a fungal saponin-detoxifying enzyme. The degradation product of this hydrolysis then suppresses induced defence responses by interfering with fundamental signal transduction processes leading to disease resistance.

M.M. Dhar

Papers

Aporphine alkaloids of annona squamosa

Naphthaquinones of Arnebia nobilis

A flavonol glycoside with anticancer activity from Tephrosia candida

The aporphine alkaloids of Litsea glutenosa

Aporphine alkaloids of Litsea sebifera, L. wightiana and Actinodaphne obovata