Author:

Keywords:

Amino Acid Sequence, hypericin, tyrosine kinase, Ca(2+)-Calmodulin Dependent Protein Kinase, Casein Kinases, map kinase, casein kinase 2, Cytosol, Growth Substances, inhibition, Kinetics, signal transduction, Light, human-immunodeficiency-virus, Molecular Sequence Data, antiretroviral activity, virucidal activity, Perylene, casein kinase-2, Photosensitizing Agents, Protein Kinase Inhibitors, agents, Receptor, Epidermal Growth Factor, pseudohypericin, peptides, Receptor, Insulin, phosphorylation, Research Support, Non-U.S. Gov't, anthraquinones, inactivation, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, HYPERICIN, TYROSINE KINASE, MAP KINASE, CASEIN KINASE 2, INHIBITION, SIGNAL TRANSDUCTION, HUMAN-IMMUNODEFICIENCY-VIRUS, ANTIRETROVIRAL ACTIVITY, VIRUCIDAL ACTIVITY, CASEIN KINASE-2, AGENTS, PSEUDOHYPERICIN, PEPTIDES, PHOSPHORYLATION, ANTHRAQUINONES, INACTIVATION, Anthracenes, Calcium-Calmodulin-Dependent Protein Kinases, ErbB Receptors, 0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences, 3101 Biochemistry and cell biology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

The naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.