Manipulation of the physiology of clavulanic acid biosynthesis with the aid of metabolic flux analysis

A pH of 6.8 is favorable for obtaining high titers of CA in submerged cultures.

“Previous studies have shown that CA stability increases at slightly acidic pH values [10,11]; several authors found a pH of 6.8 as favorable for obtaining high titers of CA in submerged cultures [5,7,9,12,13,14,15,16].”

The potential repressive effect of phosphate on clavulanic acid production in S. clavuligerus was demonstrated by selected studies.

“The potential repressive effect of phosphate on clavulanic acid production in S. clavuligerus was demonstrated by two selected studies (Lebrihi et al., 1987; Bushell et al., 2006; Saudagar and Singhal, 2007b).”

Several recent studies have reported arginase activity in S. clavuligerus.

“Even though presence of the urea cycle in prokaryotes was once considered unusual, several recent studies have reported arginase activity in S. clavuligerus (Mendz and Hazell, 1996; Bushell et al., 2006).”

Supplementation of L-threonine prevents anaplerotic flux on pyruvate to synthesize amino acids such as isoleucine, which increases availability of C3 precursors and eventually enhances clavulanic acid production.

“Indeed the supplementation of L-threonine was found to prevent the anaplerotic flux on pyruvate to synthesize amino acids such as isoleucine, which in turn increased the availability of C3 precursors and eventually enhanced clavulanic acid production (Ives and Bushell, 1997; Bushell et al., 2006; Saudagar and Singhal, 2007b).”