Biosynthesis of lycopodine from lysine and acetate. The pelletierine hypothesis

Abstract

The biosynthesis of lycopodine (5) was studied in intact plants and in excised shoots of the clubmoss Lycopodium tristachyum Pursh. Specific incorporation of label from lysine and from acetate was demonstrated by partial degradation. The observed distribution of activity was incompatible with a polyketide origin of lycopodine. The incorporation pattern is consistent with the hypothesis that lycopodine is a modified dimer of pelletierine (4), which, in turn, is derivable from lysine and acetate.

Biosynthesis of Lycopodine. The Question of the Intermediacy of Piperidine-2-acetic Acid

“…If 14C-labelled malonate were incorporated into lycopodine, the labelling pattern to be expected would be identical with that found after administration of correspondingly labelled [14C]acetate (2). Activity from [l-14C]malonate should thus be equally distributed among C-7 and -15 of lycopodine, each of these containing 50% of the total activity of the alkaloid.…”

“…The entry into lycopodine of an intact C, fragment (C-2 to -6 of lysine), derived from lysine by decarboxylation, may be inferred from earlier In an earlier feeding experiment with a doubly labelled sample of lysine, ~L-[4,5-3H2,6-14C]lysine, incorporation into lycopodine was accompanied by 22% loss of tritium, relative to 14C (Experiment 5) (2). A maximum loss of 25% of tritium, relative to 14C, may be accounted for, without breakdown of the carbon skeleton of lysine other than loss of the carboxyl group, by removal of tritium from C-5 of lysine, as shown in Scheme 3 (2).…”

“…The salient features of this scheme are that pelletierine (7), the precursor of the C, chain, C-9 to -16, of lycopodine, is derived from piperidine-2-acetoacetate (6) in an irreversible decarboxylation, that the piperidine-2-acetoacetate (or its coenzyme A derivative (5)) is the precursor of the C, chain, C-1 to -8, of lycopodine, and that a CO, unit is expelled from the system at some stage after combination of piperidine-2-acetoacetate with pelletierine. Provided the steady state concentration of pelletierine is small compared to that of its postulated precursor, piperidine-2-acetoacetate, all experimental observations (1)(2)(3)(4)6) are accounted for by this hypothesis (6).…”

“…In the course of our studies of the biosynthesis of the Lycopodium alkaloids (1-6) it was found that acetate (2), lysine (1) (1, 2), cadaverine (2) (2, 6), A'-piperideine (3) (4,6), and pelletierine (7) (3, 4) serve as specific precursors of lycopodine (8). Activity from radioactively labelled samples of all these substrates is incorporated nonrandomly into the alkaloid.…”

Biosynthesis of lycopodine. Incorporation of Δ1-piperideine and of pelletierine

“…Indications are thus strong that lycopodine is generated by modification of a true dimer, CI6N2 (e.g., 6), formed from a C,N monomer which is in turn derived from lysine and acetate. On the basis of the observed pattern of incorporation of these substrates into lycopodine (2,3) and into N-methylpelletierine (1 1) we advanced the idea (2,3) that pelletierine (5) might serve as the required C,N monomer. Radioactivity from labelled pelletierine is indeed incorporated into lycopodine (Table 1).…”