Regulation of ACV synthetase in penicillin- and cephalosporin-producing microorganisms

ACV synthetase is the first enzyme in the biosynthetic pathway for all natural penicillins and cephalosporins. Its activity catalyzes the possible rate-limiting step and is subject to various regulatory controls. In both the fungus Cephalosporium acremonium and the actinomycete Streptomyces clavuligerus, formation of the enzyme is repressed by ammonium and phosphate ions, but not by easily-utilized carbon sources; it is induced by methionine in C. acremonium. The action of the crude enzyme is indirectly inhibited in vitro by sugars such as glucose and by the carbon source metabolite glyceraldehyde-3-phosphate (G3P). Sugars are not inhibitory to the purified enzyme activity but G3P is inhibitory. The sugar inhibition is reversed by ATP and the G3P inhibition by L-cysteine (L-cys). Addition of L-cys to fermentation media increases beta-lactam production by both microorganisms. Phosphate and ferrous ions inhibit enzyme activity. Dissolved oxygen levels do not affect enzyme formation. Regulation of ACVS formation most likely occurs at the transcriptional level.