Venturicidin A

The synthesis of chiral synthons by means of microbial and enzymatic function and its application to the synthesis of complex, bioactive substances, the aglycone of venturicidins A and B are reviewed. 1) The syntheses of chiral synthons having two chiral centers are described based on the microbial asymmetric reduction of alpha-methyl beta-keto esters or enzymatic asymmetric hydrolysis of alpha-methyl beta-acetoxy esters. 2) The new chiral synthons synthesized in 1) have been successfully applied for the total syntheses of oudemansins A and B. 3) Purification and properties of the asymmetric reduction enzyme of alpha-methyl beta-keto esters in Saccharomyces cerevisiae or Saccharomyces fermentati were investigated. 4) Formal total synthesis of (-)-indolmycin is described based on the asymmetric hydrolysis of alpha-acetoxy ester with lipases. 5) Enzymatic hydrolysis in organic solvents for kinetic resolution of water-insoluble alpha-acyloxy esters with immobilized lipases is described. 6) The first total synthesis of the aglycone of venturicidins A and B has been successfully achieved from the new chiral synthon based on the developed method in 1).

The question of the possible identity of catalytic and regulatory proton pathways in the chloroplast FoF1 ATPase has been studied using different energy-transfer inhibitors. Venturicidin, a reversible inhibitor of Fo, affects neither the delta mu H(+)-dependent thiol reduction of the membrane-bound chloroplast ATPase nor its ability to be activated by the proton gradient. It seems therefore to block only the proton flow required by the catalytic function of the enzymes. Venturicidin, however, also slows down the deactivation of the thiol-reduced ATPases during uncoupled ATP hydrolysis, following a delta mu H+ activation, but phloridzin, a reversible F1 inhibitor, has the same effect. Tentoxin, an irreversible F1 inhibitor, decreases the rate of ATP hydrolysis but does not affect the rate of deactivation. These findings suggest that catalytic and regulatory H(+)-binding sites are different. No distinction can be made, if any, between protons involved in unmasking the thiol-sensitive groups of F1 and in activating the enzyme. The effect of venturicidin and phloridzin on the deactivation is consistent with an inhibitory effect of newly formed--by ATP hydrolysis--ADP molecules, which might affect the enzyme without passing through the medium. Phosphate at millimolar concentration has an effect similar to low concentrations of phloridzin and venturicidin, probably by a simple back-reaction effect.

After correlation of the majority of signals by COSY and one-bond heteronuclear correlation, the complete assignment of the1H and13C NMR spectra of the macrolide antibiotic venturicidin A required the application of long-range CH coupling information. This was accessible by the COLOC-S and selective INEPT experiments, and the sensitivity of these experiments is discussed. Steric information was obtained from a NOESY spectrum, and the solution structure compared with that in the crystal.