Nonactin biosynthesis: the initial committed step is the condensation of acetate (malonate) and succinate.
Nonactin is a macrotetrolide antibiotic produced by Streptomyces griseus subsp. griseus ETH A7796 that has shown activity against the P170-glycoprotein efflux pump associated with multiple drug resistant cancer cells. Nonactin is a polyketide, albeit a highly atypical one. The structure is composed of two units of each of the enantiomers of nonactic acid, arranged in a macrocycle, so that the molecule has S4 symmetry and is achiral. The monomer units, (+)- and (-)-nonactic acid, are derived from acetate, succinate, and propionate, although the exact details of the assembly process are quite unclear. We have used feeding experiments with a series of multiple stable isotope labeled precursors to elucidate the details of the first committed step of nonactic acid biosynthesis. We have found that the (13)C label from 3-ketoadipate is incorporated specifically into both nonactic acid and its homologue, homononactic acid. The data conclusively show that the first committed step of nonactin biosynthesis is the coupling of a succinate derivative with either acetate or malonate. The differentiation into either nonactate or homononactate occurs after the initial condensation; the homologues are not derived from use of a different "starter unit" by the nonactate polyketide synthase. The first step of nonactin biosynthesis involves achiral intermediates; differentiation between the known enantiocomplementary biosynthesis pathways to form each enantiomer of the precursor monomer units likely occurs after the initial condensation reaction.
Nelson
Michael E
ME
Department of Chemistry, The University of Montana, Missoula, MT 59812-1656, USA.
Priestley
Nigel D
ND
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D018942:Macrolides / Q000378:metabolism*; D008314:Malonates / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D013305:Streptomyces griseus / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D018942:Macrolides; D008314:Malonates; C030290:malonic acid; D019802:Succinic Acid; C050476:nonactin