title: Why did the Fleming strain fail in penicillin industry?
abstract: Penicillin, discovered 75 years ago by Sir Alexander Fleming in Penicillium notatum, laid the foundations of modern antibiotic chemotherapy. Early work was carried out on the original Fleming strain, but it was later replaced by overproducing strains of Penicillium chrysogenum, which became the industrial penicillin producers. We show how a C(1357)-->T (A394V) change in the gene encoding PahA in P. chrysogenum may help to explain the drawback of P. notatum. PahA is a cytochrome P450 enzyme involved in the catabolism of phenylacetic acid (PA; a precursor of penicillin G). We expressed the pahA gene from P. notatum in P. chrysogenum obtaining transformants able to metabolize PA (P. chrysogenum does not), and observing penicillin production levels about fivefold lower than that of the parental strain. Our data thus show that a loss of function in P. chrysogenum PahA is directly related to penicillin overproduction, and support the historic choice of P. chrysogenum as the industrial producer of penicillin.
authors.affiliation: R&D Biology, Antibióticos S. A., Avenida de Antibióticos 59-61, E-24009 León, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodríguez-Sáiz
authors.forename: Bruno
authors.initials: B
authors.lastname: Díez
authors.forename: José Luis
authors.initials: JL
authors.lastname: Barredo
mesh_terms: D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism*; D010406:Penicillins / Q000096:biosynthesis*; D010408:Penicillium chrysogenum / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010648:Phenylacetates / Q000378:metabolism; D017354:Point Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D010406:Penicillins; D010648:Phenylacetates; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C436302:phenylacetate 2-hydroxylase; C025136:phenylacetic acid