CHAPTER 1
Biosynthesis of Polyketides
BY T. MONEY
1 Introduction
The polyketides are a structurally diverse group of naturally occurring compounds produced by the acyl–polymalonate biosynthetic route. A description of the essential features of this route (Scheme 1) was given in a previous Report which covered the literature to the end of 1972. The various compounds considered in this Report have been classified into groups (tetraketide, pentaketide, etc.) according to the number of C2-units (acetate and malonate) involved in their biosynthesis, and the literature has been covered for 1973 and 1974.
There has been a dramatic increase in the number of studies in which 13C-labelled acetate has been used as a precursor, including elegant and complementary variations based on the observation of 13C-13C couplings in products labelled alternatively from [1, 2-13C] acetate or from a 1:1 mixture of [1-13C]- and [2-13C]-acetate; examples are noted in this Chapter and are fully described in Chapter 7.
A new text dealing with the biosynthesis of acetate-derived compounds contains an excellent chapter on polyketide biosynthesis.
2 Aromatic Polyketides and Derivatives (Acetate a Chain-initiating Unit)
Tetraketides. — A full account of recent investigations on the biosynthesis of patulin (8) and co-metabolites describes further experimental evidence in support of the metabolic grid shown below. Using replacement cultures of Penicillium patulum and appropriate precursors labelled with 2H, 3H, and 14C it was established that the co-metabolites m-cresol, m-hydroxybenzyl alcohoL m-hydroxybenzaldehyde, and gentis-aldehyde (6) [but not gentisic acid (7)] are intermediates in the biosynthetic sequence leading from 6-methylsalicylic acid (1) to patulin (8). Toluquinol (3) is not an intermediate in the sequence but can be converted into desoxyepoxydon (4) by the fungus The mechanism of cleavage of the aromatic ring in late stages of patulin biosynthesis remains to be elucidated. (For 13C studies on the ring cleavage in penicillic acid biosynthesis, see p. 214).
Further studies on the purification of 6-methylsalicylic acid (6-MSA) synthase and its susceptibility to inhibitors have been reported. The results support the view that inhibition of enzymic activity by acetylenic thiol esters (e.g.3-pentynoyl-NAC* and 2-hexynoyl-NAC) is similar to that previously demonstrated for unsaturated fatty acid synthase in E. coli, namely specific inhibition of the dehydration step in the biosynthetic route (Scheme 2).
Additional studies have shown that concentrations of acetylenic inhibitor which completely inhibit 6-MSA synthesis still allow NADPH oxidation to continue at a significant rate. This result supports the proposal that acetylenic inhibitors act after the reduction step and that the latter process occurs on a 6-carbon rather than an 8-carbon intermediate.
In view of the important anti-cancer properties of mycophenolic acid (10; X = Me) considerable effort has been expended on the synthesis of analogues which could display enhanced or modified biological activity. A recent report has shown that the enzymic system of P. brevicompactum can convert the halogenated phthalides (9a) and (9b) into the corresponding analogues of mycophenolic acid.
Incorporation studies using intact Eupatorium rugosum plants have shown that the aromatic ring in dehydrotremetone (12) is derived from acetate and the furan ring from mevalonate. Further investigations using a cell-free homogenate of E. rugosum leaves demonstrated that isopentenyl pyrophosphate and tremetone (11) are efficient precursors. In contrast, dimethylallyl pyrophosphate and the acetophenones (13) and (14) were poorly utilized by the cell-free system and it has been suggested that isoprenylation of the enzyme-bound β-triketo-thiol ester intermediate occurs prior to aromatization.
Conflicting proposals concerning the biosynthesis of ring B in nidulin (15) and trisdechloronornidulin (16) (syn. yasmin, unguinol) have been resolved by studies which demonstrate that the incorporation of acetate and methionine is consistent with biosynthetic Scheme 3.
Pentaketides. — One of the first examples of the use of 13C – 13C coupling in polyketide biosynthesis is described in a recent report. [1,2-13C]Acetate was used as precursor and the new technique was used to elucidate the biosynthetic route to mollisin (17). Two possible pathways [paths a and b in Scheme 4] to this compound have previously been considerable, but the use of [1,2-13C]acetate has shown that neither is correct and that the biosynthesis of mollisin follows a third route [path c in Scheme 4].
Administration of [1-13C]acetate to Phialophora lagerbergii and the subsequent enhancement of signals due to C(1) C(3), C(4a) C(6) and C(8) in the 13C n.m.r. spectrum of skytalone (18) has demonstrated that this compound is derived by the linear condensation of five acetate units; 14 cf. p. 228.
Hexaketides. — Incorporation studies using[1-13C]-, [2-13C]-, and [1,2-13C]-acetate have shown that the biosynthesis of multicolic acid (21) and multicolosic acid (22) in P. multicolor involves the intermediate formation of 6-pentylresorcylic acid (19) followed by cleavage of the C(4) — C(5) bond. The 13C–13C couplings in the 13C n.m.r. spectrum of multicolic acid derived from doubly labelled acetate showed that intact C2 units were arranged as shown in formula (21), thus excluding the possibility of cleavage at C(1)–C(2) in (19) and the intermediacy of a symmetrical intermediate such as 5-pentylresorcinol (20); a fuller account of the n.m.r. aspects is given on p. 216.
Heptaketides. — The pattern of radioactivity in aloenin (23) after administration of [1-13C]acetate, [2-14C]malonate, and [methyl-14C]methionine to Aloe arborescens has been determined and the results are consistent with the expected biosynthetic route.
Octaketides. — The labelling pattern in asperentin 8-methyl ether (24) after administration of [2–14C]malonate to Aspergillus jlavus has shown that the C(6') — C(7') 'acetate-derived' portion of the molecule is significantly less radioactive than the malonate-derived two-carbon units. Observations of this type have been recorded previously and are to be expected if reconversion of malonate into acetate only occurs to a limited extent The 13C n.m.r. spectra of tajixanthone (29) (Aspergillus variecolor) derived from [1-13C]-...
