Chemistry Reference
In-Depth Information
the potent hepatotoxin aflatoxin B
1
(
17
) being derived by extensive ring cleav-
ages and rearrangements of norsolorinic acid (
7
). Other metabolites contain a
polyketide-derived moiety as part of a larger molecule whose biosynthesis is
other than polyketide. A classic example is mycophenolic acid (
18
), in which
the branched carboxylic side chain is derived via a cleaved farnesyl moiety.
Other compounds of mixed terpenoid-polyketide origin include the mycotoxin
viridicatumtoxin (
19
). Again the origins of the polyketide-derived moiety may
be disguised as a result of extensive metabolism as observed in the meroterpenoid
metabolites austin (
20
) and paraherquonin (
21
), which are all derived via 3,5-
dimethylorsellinic acid (2). The xenovulenes (
22
)-(
24
) are an interesting group
where it has been shown that the cyclopentananone, benzenoid, and tropolone
moieties all have a common biosynthetic origin via ring expansion and ring
contaction of 3-methylorcinaldehyde. Other groups contain Krebs' cycle inter-
mediates, for example, the tetronic acid, carlosic acid (
25
), and the squalestatins
(
29
) or amino-acid derived moieties (e.g., fusarin C (
26
)).
6.1 BIOLOGICAL PROPERTIES
Another important feature of fungal polyketides is their vast range of biolog-
ical activities both beneficial and harmful. Thus, griseofulvin (
27
) was one of
the first effective antifungal agents. Penicillic acid (
15
), which was discovered
shortly after the penicillins, is also a powerful antibiotic, but unfortunately it
proved too toxic for clinical use. Mycophenolic acid (
18
) has been “rediscov-
ered” as an immunosuppressive agent. The strobilurins (e.g., (
28
)), although not
themselves used in the field formed the basis for the development of the widely
used methoxyacrylate group of antifungal agents and, of course the statins, as
represented by lovastatin (
10
), are among the most widely prescribed drugs for
control of cholesterol levels and associated heart disease. As a cursory inspec-
tion of their structures would suggest, the squalestatins (e.g., (
29
)), are effective
inhibitors of squalene synthase though their early promise as cholesterol-lowering
clinical candidates declined because of inherent toxicity. They contain two sep-
arate polyketide chains linked to oxaloacetate. Overall, fungal metabolites and
their pharmaceutical and agrochemical derivatives have total sales of many tens
of billions of pounds annually. In addition to these beneficial effects, the large
group of mycotoxins represented first and foremost by aflatoxin B
1
(
17
) and oth-
ers such as the fuminosins (
30
), zearaleneone (
12
), citrinin (
3
), ochratoxins (e.g.,
(
31
)), are the cause of many problems in both animal and human health, and
spoilage of both growing crops and stored foodstuffs through contamination by
mycotoxin producing fungi is a cause of major economic losses worldwide.
6.2 BIOSYNTHESIS
Although diverse in structure, the class is defined by the common biosynthetic
origin of the carbon atoms: These atoms are derived from the CoA thiolesters
