Substrate and reaction intermediate mimics as inhibitors of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase

Abstract

3-Deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase catalyses the aldol-like addition of phosphoenolpyruvate (PEP) to D-erythrose 4-phosphate in the first step of the shikimate pathway to aromatic amino acids. A series of compounds, designed to mimic intermediates in the enzyme-catalysed reaction, have been synthesised and tested as inhibitors for the DAH7P synthase from Escherichia coli. The most potent inhibitor was the vinyl phosphonate, (E)-2-methyl-3-phosphonoacrylic acid, with a K i of 4.7 lM.

Structural analysis of substrate-mimicking inhibitors in complex with Neisseria meningitidis 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase – The importance of accommodating the active site water

“…Active site inhibitors have been previously reported for the phenylalanine-sensitive type Ia DAH7PS from Escherichia coli (Eco-DAH7PS) and the type II enzyme from M. tuberculosis (MtuDAH7PS) [3,12,[22][23][24]. PEP-like analogues were found to inhibit EcoDAH7PS, with the most potent inhibitor being the vinyl phosphonate, (E)-2-methyl-3-phosphonoacrylate 6, followed by the (R)-phospholactate 7 [23].…”

“…PEP-like analogues were found to inhibit EcoDAH7PS, with the most potent inhibitor being the vinyl phosphonate, (E)-2-methyl-3-phosphonoacrylate 6, followed by the (R)-phospholactate 7 [23]. (S)-Phospholactate 8 was the poorest inhibitor.…”

“…The vinyl phosphonate 6 was found to have a K i of 4.7 ± 0.7 lM, which approaches the K m for PEP of 2 lM for this enzyme [23].…”

Chemical Biology: What is Its Role in Drug Discovery?

“…Compounds with antibacterial activity included sulfone-based nucleotide isosteres which were shown to be inhibitors of CMP-sialic acid synthetase, an important enzyme in bacterial polysaccharide biosynthesis (Wong et al, 2009). By using mimics of the substrates and reaction intermediates of 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase, inhibition of this important bacterial enzyme was achieved (Walker et al, 2009). A synthesis of a library of 2,5-dihydrochorismate analogues has been described by Payne and Abell (Payne et al, 2009).…”

P-C bond formation in reactions of Morita-Baylis-Hillman adducts with phosphorus nucleophiles

“…The compounds presented in Scheme 25 were tested as mechanism-based inhibitors of 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase (an enzyme that catalyzes the first step of the shikimate pathway for aromatic compound biosynthesis) 43,44 and UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA, catalyzes the first step of the peptidoglycan biosynthesis). 24 The products of these substitutions, trifunctional electron-withdrawing group-functionalized allylphosphonates (phosphinates, phosphine oxides, etc.…”