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136 CHAPTER 7

this pathway include the mycotoxins of Fusariumspp.
that grow on moist grain, such as T-2 toxinand the
trichothecenes.
The shikimic acid pathway, used normally for
the production of aromatic amino acids, provides the
precursors for the hallucinogenic secondary metabolites,
lysergic acidand psilocybinin toadstools of Psilocybe,
and the toxin muscarinein toadstools of Amanita
muscaria. Other pathways lead from aliphatic amino
acids to the penicillins(see below), amatoxinsand
phallotoxins (in toadstools of the “death cap,”
Amanita phalloides), from fatty acids to the volatile
polyacetylenesproduced by mycelia and fruitbodies
of several Basidiomycota, and from intermediates of the
TCA cycle to the rubratoxinsof Penicillium rubrum.
Against this background, we now consider a few
examples of secondary metabolites of special interest.

Penicillins

Penicillin was discovered by Alexander Fleming in

1929 as a metabolite of Penicillium chrysogenum (ori-

ginally misidentified as P. notatum) that inhibited the

growth of Staphylococcus. However, Fleming could not

purify the compound in stable form, and this was

only achieved in the early 1940s by two British scient-

ists, Florey and Chain, working in the USA during the

Second World War. For this work, they shared with

Fleming the Nobel Prize for Medicine.

Penicillin is most active against Gram-positive bac-

teria. Its mode of action is to prevent the cross-linking

of peptides during the synthesis of peptidoglycan in

bacterial cell walls, so that the walls are weakened and

the cells are susceptible to osmotic lysis. Remarkably,

penicillin is still one of the front-line antibiotics

after more than 60 years of usage. Also of interest is

Fig. 7.16Structure of penicillins.

the fact that the early fermentation systems that made

penicillin production possible were initially developed

for citric acid production, described in Chapter 1.

However, the modern-day penicillins, like the related

cephalosporins (peptide antibiotics), are semisynthetic

products (Schmidt 2002).

Fig. 7.16 shows the basic structure of penicillin. It is

a ring system derived from two amino acids, l-cysteine

and d-valine, but is synthesized from a tripeptide

precursor (α-aminoadipic acid–cysteine–valine) by the

replacement of α-aminoadipic acid with an acyl group

(shown as “R” in Fig. 7.16). This step is catalyzed

by the enzyme acyl transferase. In the early years

of commercial production, it was discovered that

modification of the culture medium would produce

penicillins with different acyl groups, conferring dif-

ferent properties on the penicillin molecule. So a

range of penicillins were produced commercially by

carefully controlling the supply of acyl precursors in

the culture vessels. However, it was then found that

several bacteria produce the enzyme penicillin acylase,

which can be used to remove the acyl side chain and

leave the basic molecule, 6-aminopenicillanic acid

(6-APA). Chemists could then attach any desired side

chain to this molecule, with a high degree of precision.

So the modern production method for semisynthetic

penicillins involves three stages:

1 Culture of the fungus to produce maximum

amounts of any type of penicillin, usually penicillin

G which was the type first discovered. This is done

by fed-batchculture (Chapter 4) in which glucose

is added in stages to prevent suppression of the sec-

ondary metabolic genes, while the precursor amino

acids are supplied in excess. Also, the pH and aera-

tion are carefully controlled, because the penicillin

molecule dissociates above pH 7.5 – a problem that