|Signaling effects of demethylasterriquinone B1, a selective insulin receptor modulator. |
Nicholas J G Webster,Kaapjoo Park,Michael C Pirrung
Chembiochem : a European journal of chemical biology
A possible breakthrough in the treatment of diabetes was made with the discovery that a fungal natural product, demethylasterriquinone B1 (DAQ B1), is an orally active, small-molecule mimic of insulin. Subsequent work has shown that the glucose-lowering effects of DAQ B1 are not accompanied by enhanced vascular proliferation, which is a side effect of chronic insulin administration that can lead to arteriosclerosis. Our recent short and modular total synthesis of DAQ B1 could be readily modified to create congeners and afforded ample supplies of the natural product, which permitted intracellular signal transduction of DAQ B1 to be examined. The activities of DAQ B1 and over a dozen related structures were studied for insulin receptor (IR) and insulin receptor substrate-1 phosphorylation. Examination of the effect of DAQ B1 on kinases downstream of the IR in insulin signal transduction showed selective activation of Akt kinase (a metabolic effect) but not of extracellular-regulated kinase (a proliferative effect). The influence of DAQ B1 on gene expression (determined by a microarray study) was also divergent from that of insulin, which activates both proliferative and metabolic pathways. The action of DAQ B1 as a selective insulin receptor modulator can be accounted for by its ability to selectively activate one kinase among the many emanating from insulin receptor autophosphorylation and its reduced effects on gene expression.
|Two additional common subunits, ABC10 alpha and ABC10 beta, are shared by yeast RNA polymerases. |
C Carles,I Treich,F Bouet,M Riva,A Sentenac
The Journal of biological chemistry
Yeast nuclear RNA polymerases are multisubunit enzymes that contain in common some small subunits. We show that the smallest, a 10-kDa component of three enzymes (A10, B10, and C10), is heterogeneous. In each case, it can be resolved into two distinct polypeptides (alpha and beta) by reverse-phase chromatography. A10 alpha, B10 alpha, and C10 alpha were indistinguishable on the basis of their electrophoretic and chromatographic behaviors, characteristic silver staining, and tryptic peptide analysis. All three polypeptides are blocked at their amino termini. By the same criteria, A10 beta, B10 beta, and C10 beta were also indistinguishable. The amino-terminal sequence of A10 beta and C10 beta corresponded to that of subunit B10 recently cloned by Woychik and Young (Woychik, N. A., and Young, R. A. (1990) J. Biol. Chem. 265, 17816-17819). Thus, the three forms of RNA polymerase share two additional and distinct polypeptides, ABC10 alpha and ABC10 beta, that therefore can be considered bona fide subunits of these enzymes. Interestingly, these two subunits bind zinc.