The Addition Of Precursors And Metabolic Regulators To Media

Some components of a fermentation medium help to regulate the production of the product rather than support the growth of the micro-organism. Such additives include precursors, inhibitors and inducers, all of which may be used to manipulate the progress of the fermentation.

Precursors

Some chemicals, when added to certain fermentations, are directly incorporated into the desired product. Probably the earliest example is that of improving penicillin yields (Moyer and Coghill, 1946, 1947). A range of different side chains can be incorporated into the penicillin molecule. The significance of the different side chains was first appreciated when it was noted that the addition of corn-steep liquor increased the yield of penicillin from 20 units cm*3 to 100 units cm*3. Corn-steep liquor was found to contain phenylethylamine which was preferentially incorporated into the penicillin molecule to yield benzyl penicillin (Penicillin G). Having established that the activity of penicillin lay in the side chain, and that the limiting factor was the synthesis of the side chain, it became standard practice to add side-chain precursors to the medium, in particular phenylacetic acid. Smith and Bide (1948) showed that addition of phenylacetic acid and its derivatives to the medium were capable of both increasing penicillin production threefold and to directing biosynthesis towards increasing the proportion of benzyl penicillin from 0 to 93% at the expense of other penicillins. Phenylacetic acid is still the most widely used precursor in penicillin production. Some important examples of precursors are given in Table 4.12.

Inhibitors

When certain inhibitors are added to fermentations, more of a specific product may be produced, or a metabolic intermediate which is normally metabolized is accumulated. One of the earliest examples is the microbial production of glycerol (Eoff et al., 1919). Glycerol production depends on modifying the ethanol fermentation by removing acetaldehyde. The addition of sodium bisulphite to the broth leads to the formation of the acetaldehyde bisulphite addition compound (sodium hydroxy ethyl sulphite). Since acetaldehyde is

Table 4.12. Precursors used in fermentation processes

Precursor

Product

Micro-organism

Reference

Phenylacetic-acid

Penicillin G

Pénicillium chrysogenum

Moyer and Coghill and

related compounds

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