Biosynthesis of hyalodendrin and didethiobis(methylthio)hyalodendrin, sulphur-containing 2,5-dioxopiperazines of the 3S,6S series

Abstract

cyclo-(L-[4′-³H]Phe-L-[3-¹⁴C] Ser)8, a known biosynthetic precursor of the (3R,6R)-epidithiodioxopiperazine gliotoxin 4, was efficiently incorporated (42%), in Hyalodendron sp. (FSC-601) cultures, into the 3S,6S metabolite didethiobis(methylthio)hyalodendrin (DBH)7 without significant change in the ³H: ¹⁴C ratio. None of the three diastereoisomers of cyclo-(L-Phe-L-Ser) was incorporated into DBH to any significant extent. The ¹³C label from cyclo-(L-Phe-L-[3-¹³C]Ser) was located, in the expected site, in DBH by ¹³C NMR spectroscopy. Gliotoxin derived in Gliocladium virens from the doubly labelled precursor 8 was degraded to locate, in similar manner, the ¹⁴C label. The N-methyl derivative 16 of cyclo-(L-Phe-L–Ser) was not incorporated detectably into either gliotoxin or DBH. Radioactivity from the doubly labelled, linear dipeptides 17 and 18, possible precursors for the cyclodipeptide 8, was incorporated with moderate efficiency into gliotoxin. However, the ³H: ¹⁴C ratios for the dipeptides and the derived gliotoxin differed substantially, indicating that the peptides had undergone cleavage in the fungus before incorporation.