Inhibition studies of Porphobilinogen synthase from escherichia coli using diacids

Caroline Jarret, Janette Bobálová, Frédéric Stauffer, Matthias Henz and Reinhard Neier

Institute of Chemistry , University of Neuchâtel , CH-2000 Neuchâtel, Switzerland


Porphobilinogen Synthase (PBGS, E.C.4.2.1.24) is the second enzyme in the biosynthesis of the "pigments of life" and catalyses the formation of porphobilinogen (PBG) starting from two molecules of 5-aminolevulinic acid (ALA). The enzyme catalyses twice the same substrate and must have therefore two sites of recognition for two identical substrates (A Side and P Side).

Despite the fact of intensive studies of the PBGS , the exact mechanism of formation of PBGS is not yet clear and no high resolution X-ray structure has been published so far. According Shemin's [1] or Jordan's [2] mechanistic proposals and the fact that there is double recognition, a series of diacids were tested as potential analogues of the intermediate.

The variation of the chain length connecting the two acid functions was investigated, in particular analogues of pimelic acid (Shemin's intermediate C7) and sebacic acid (Jordan's intermediate C10).

[1] D.L. Nandi, D. Shemin, J.Biol.Chem. 1968, 243,1296.

[2] P.M. Jordan, J.S. Seehra, J.Chem.Soc.Chem.Comm. 1980, 240.


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