From Cellular Function to Industrial Products
35
2.1.5 Secondary Metabolism
We have now treated the part of cellular metabolism that is associated with the growth process.
This is referred to as the primary metabolism. A large number of industrially important products
are, however, formed in cellular reactions that are not directly associated with the growth process.
Secondary metabolites may be derived from precursor metabolites or building blocks - but
typically only through a large number of reaction steps. This part of cellular metabolism is
referred to as secondary metabolism, and the products formed in these reactions are called
secondary metabolites
just as metabolites formed in the primary metabolism are called primary
metabolites. Secondary metabolites serve many different functions, and in many cases their exact
role in the overall cell function is unknown. It is believed that many secondary metabolites serve as
a defense system for the producing microorganisms against other microorganisms (this is
particularly the case for many secondary metabolites produced by plant cells).
The most important group of secondary metabolites produced by microorganisms is antibiotics,
and today about 12,000 antibiotics have been discovered. Of these about 150 have been approved
for human use, and Table 2.7 lists some of the more common antibiotics. The world market for
antibiotics has increased from 18 bio USS in 1994 to 23 bio US$ in 1996, and it currently
growing with about 10% per year, even though only a few new antibiotics are approved for
human use every year. With the increasing demand for antibiotics it becomes important to
improve the yield and productivity of existing processes as well as developing synthesis routes
for novel compounds. The possibilities offered by the secondary metabolism of microorganisms
are of such magnitude that the topic must fall outside the scope of the present text, but we will
treat biosynthesis of P-lactams shortly.
P-Lactams constitute by far the largest group of antibiotics, with about 120 compounds approved
for human use. The P-lactams can be divided into penicillins and cephalosporins, with penicillins
having a five member thiazolidine ring associated with the four member P-lactam ring and
cephalosporins having a six member dihydrothiazine associated with the four member P-lactam
(Fig. 2.8). Different microorganisms can form both types of compounds naturally, and the
pathways for their synthesis are shown in Fig. 2.8. Cephalosporins can also be derived
chemically from penicillins by ring expansion, and most of the clinically applied P-lactams are
chemically synthesized from penicillin V or G, which are produced by fermentation with the
filamentous fungus
Penicillium chrysogenum.
Much effort has been spent to improve the yield
and productivity of this classical fermentation process. As seen in Fig. 2.8 the two first steps are
identical in the biosynthesis of penicillins and cephalosporins, and the two enzymes catalyzing
these two reactions are therefore present in all P-lactam producing organisms. In the production
of penicillin the side-chain of isopenicillin N is exchanged with a phenoxyacetic acid or
phenylacetic acid, which are added to the medium, leading to the formation of penicillin V or
penicillin G, respectively. In the production of cephalosporins isopenicillin is converted to
penicillin N by an epimerase. The next step is ring expansion of the thiazolidine ring resulting in
deacetoxycephalosporin C, which is a common precursor in the synthesis of cephalosporins,
e.g.
cephalosporin C by
A. chrysogenum
and cephamycin by
S. clavuligerus.
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