Porphobilinogen synthase: A challenge for the chemist?

The initial steps in the biosynthesis of the tetrapyrrolic dyes, called the 'pigments of life', are highly convergent. The formation of porphobilinoge n, the pyrrolic precursor of the tetrapyrrolic skeleton, uses delta -aminol evulinate as the starting material. This amino acid is dedicated to the bio synthesis of tetrapyrroles, However, the chemical condensation of delta -am inolevulinate leads to a symmetric pyrazine, Attempts to imitate the biosyn thesis using one of the proposed pathways for the biosynthesis of porphobil inogen as a guideline has allowed us to synthesize a protected precursor of porphobilinogen in an efficient way. Based on the two major proposals for the biosynthesis, a series of specifically synthesized inhibitors was also tested. The inhibition behavior and the potency of the inhibitors expressed as their K-i value has unraveled an interesting relationship between the s tructure of the inhibitor and the strength of its interaction with the acti ve site. The concerted use of mechanistic analysis, synthesis and kinetic s tudies of inhibitors has increased our knowledge about the enzyme porphobil inogen synthase, Structural studies of enzyme-inhibitor complexes will hope fully complement the kinetic results accumulated so far.