History of Secondary Metabolism

Howard W. Florey, Ernst B. Chain, and their colleagues which led to the successful preparation of a stable form of penicillin and the demonstration of its remarkable antibacterial activity and lack of toxicity in mice. Production of penicillin by the strain of Penicillium notatum in use was so slow, however, that it took over a year to accumulate enough material for a clinical test on humans [3]. When the clinical tests were found to be successful, large-scale production became essential. Florey and his colleague Norman Heatley realized that conditions in wartime Britain were not conducive to the development of an industrial process for producing the antibiotic. They came to the US in the summer of 1941 to seek assistance and convinced the US Department of Agriculture in Peoria, Illinois, and several American pharmaceutical companies, to develop the production of penicillin. Heatley remained for a period at the USDA laboratories in Peoria to work with Moyer and Coghill. 

The importance of penicillin was that it was the first successful chemotherapeutic agent produced by a microbe. The tremendous success attained in the battle against disease with this compound not only led to the Nobel Prize being awarded to Fleming, Florey, and Chain, but to a new field of antibiotics research, and a new antibiotics industry. Penicillin opened the way for the development of many other antibiotics, and yet it still remains the most active and one of the least toxic of these compounds. Today, about 100 antibiotics are used to combat infections to humans, animals, and plants. 

Despite the thousands of secondary metabolites made by microorganisms, they are synthesized from only a few key precursors in pathways that comprise a relatively small number of reactions and which branch off from primary metabolism at a limited number of points. Acetyl-CoA and propionyl-CoA are the most important precursors in secondary metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty acids. Other secondary metabolites are derived from intermediates of the shikimic acid pathway, the tricarboxylic acid cycle, and from amino acids. The regulation of the biosynthesis of secondary metabolites is similar to that of the primary processes, involving induction, feedback regulation, and catabolite repression [6]. 

There was a general lack of interest in the penicillins in the 1950s after the exciting progress made during World War II. By that time, it was realized that P. chrysogenum could use additional acyl compounds as side-chain precursors (other than phenylacetic acid for penicillin G) and produce new penicillins, but only one of these, penicillin V (phenoxymethylpenicillin), achieved any 

For many years, basic biologists were uninterested in secondary metabolism. There were so many exciting discoveries to be made in the area of primary 

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