[Orchratoxin A and B: A three-dimensional molecular model for a mechanistic explanation of their toxicity]
Ochratoxins are toxic substances produced and released by Aspergillus alutaceum and other molds. So far, it was generally believed that the inhibition of the enzyme phenylalanin-t-RNA-synthetase was responsible for the toxicity of ochratoxin A. Most recent in vitro results, however, suggest a non-competitive mechanism with respect to phenylalanin and, consequently, the existence of a proper ochratoxin receptor. Based on the structure ochratoxin A and B, mellein and phenylalanine, we have generated a three-dimensional molecular model for the binding site of a putative ochratoxin receptor by means of pseudoreceptor modeling. The model consists of twelve amino-acid residues. In this model, the high affinity (and, hence, the receptor-mediated toxicity) of ochratoxin A and B is explained by a hydrogen-bond network - a network that is not possible with both mellein and phenylalanine as substrates. Consequently, these compounds do not exhibit toxic effects at comparable concentrations. The relevance of the model is supported by the quantitative prediction of the binding affinity of three test compounds.
Vedani
Angelo
A
Biografik-Labor, Schweiz. Institut für Alternativen zu Tierversuchen (SIAT), CH-Basel.
Arend
Bruinink
B