Versicolorin A

Table 5.41. Biosynthetic Pathway, Structures, 13C Chemical Shifts (<5C in ppm) and Carbon-Carbon Coupling Constants (Jcc in Hz) of Averufin and Versicolorin A [1008, 1009].

Figure 23 Putative biosynthetic mechanism from versicolorin A to demethylsterigmatocystin.

The relationship of 13C acetate and averufin (i60)183 and very detailed 13C nuclear magnetic resonance enrichment studies of the abovementioned intermediates have recently led Steyn and co-workers184-187 to conclude187 that a biosynthetic pathway starting with polyketide (161), going through averufin (160), versicolorin A (162), and sterigmatocystin (30), eventually results in aflatoxin Bj (i). 

Figure 5. Sequence of enzymatic conversion steps in the biosynthesis of qflatoxins. A. Steps from norsolorinic acid to versicolorins. B. Steps from versicolorin A to sterigmatomcystin. C Steps from O-methylsterigmatocystin to the qflatoxins. Some of the intermediates shown are hypothetical. A question mark indicates that the enzyme suggested for the conversion step has not been proven.

The conversion fix>m averufin (AVF) to versiconal hemiacetal acetate (VHA) is catalyzed by an averufin oxidase encoded by afll (oyfA) (41). VHA was converted to versiconal (VAL) by an esterase (29, 63, 64, 65). VAL is converted to Versicolorin B (VERB) by a VERB synthase (31). The gene, qflK (ybs), was cloned, characterized and expressed (66,67,68). It was demonstrated that the versicolorin B synthase catalyzes the side chain cyclodehydration of racemic VHA to VERB. This is a key step in the aflatoxin formation since it closed the bisfuran ring of aflatoxin for binding to DNA. VERB is converted to versicolorin A (VERA) by a desaturase encoded by qflL (verB) (31). 

KELLER, N.P., SEGNER, S., BHATNAGAR, D., ADAMS, T.H., stcS, a putative P-450 monooxygenase, is required for the conversion of versicolorin A to sterigmatocystin in Aspergillus nidulans, Appl Environ. Microbiol, 1995, 61, 3628-3632. 

ANDERSON, J.A., CHUNG, C.H., CHO, S.-H., Versicolorin A hemiacetal, hydroxydihydro-sterigmatocystin and aflatoxin G2 a reductase activity in extracts from Aspergrillus parasiticus, Mycopathologia, 1990, 111, 39-45. 

BiosyntheticaUy, the aflatoxins are all formed from the same precursor, versiconal hemiacetal acetate (12) (25). Compound 12 is formed from acetate, the units of which are converted into a polyketide. The polyketide is then metabolized to the xanthone 12 (see Scheme 2.1) (26). Intermediate 12 can then be transformed either into versicolorin A (13) or versicolorin B (14) in several steps. Versicolorin A (13) may be converted to sterigmatocystin (15), while 14 can lead to dihydro-sterigmatocystin (16). Sterigmatocystin (15) can be metabolized to aflatoxins Gi (3) or Bi (1) and the latter may then be transformed to aflatoxin Mi (5). Aflatoxins B2 (2) and G2 (4) are formed from dihydrosterigmatocystin (16) and aflatoxin M2 (6) is formed by conversion from B2 (2). Pathways also exist to convert aflatoxin Bi (1) to B2 (2), Ml (5) to M2 (6), and Gj (3) to G2 (4), and vice versa. Important biosynthesis steps are shown in Scheme 2.1. 

The synthesis of rac-versicolorin A (13) is shown in Scheme 2.18. Resorcinol (107) was MOM-protected and formylated to yield 108. Horner-Wadsworth-Emmons reaction with 109, followed by deprotection and reaction with ethyl bromoacetate gave, after hydrolysis, phenyl acetaldehyde 110. With TIPSOTf and triethylamine, cyclization occurred rapidly, followed by mono deprotection. 

The aflatoxins are derived from anthraquinone derivatives of the averufin type (Fig. 80). Of special interest in the conversion of the Cg-side-chain present in averufin to the C4-chain found, e.g., in versicolorin A. A key intermediate is the xanthone sterigmatocystin. It is probably formed via intermediate I with rotation of the right-hand part of the molecule. 

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