Projects
Ochratoxin A
Simulation the binding of Ochratoxin A to phenylalanine hydroxylase.Ochratoxin A (OA) is a toxic isocoumarin derivative released by various species of mold which grow on grain, coffee and nuts, representing a serious worldwide health problem. Among other mechanisms of toxicity, it has been suggested that OA inhibits phenylalanyl-tRNA synthetase (PheRS), thereby reducing protein synthesis. Using the crystal structure of PheRS, we have modelled its interactions with OA. Our results indicate that while OA may be capable of weakly inhibiting PheRS, the OA-PheRS complex cannot adopt the same conformation as the natural substrate Phe-AMP. It seems more likely that the toxicity of OA arises from its strong binding to serum albumin, retarding the wash-out from the body. The ultimate "toxoreceptors" are yet unidentified but there is evidence that OcA may bind to carboxipeptidase (CPA) and phenylalanine hydroxylase (PHY). While CPA could be ruled out as representing an attractive target for OcA (our studies suggested a binding affinity only in the low micromolar range), we are presently investigating the interactions of OcA and PHY (PDB code = 1J8U) at the molecular level using molecular mechanics and molecular dynamics protocols.
Stereo representation of the binding of Ochratoxin A to phenylalanine hydroxylase
(protein = green; solvent = blue OcA: colored by atom)