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J. Biol. Chem., Vol. 280, Issue 14, 13229-13240, April 8, 2005

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Antiproliferative Plant and Synthetic Polyphenolics Are Specific Inhibitors of Vertebrate Inositol-1,4,5-trisphosphate 3-Kinases and Inositol Polyphosphate Multikinase^*

Georg W. Mayr, Sabine Windhorst, and Kirsten Hillemeier

From the Institut für Biochemie und Molekularbiologie I: Zelluläre Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany

Inositol-1,4,5-trisphosphate 3-kinases (IP3K) A, B, and C as well as inositol polyphosphate multikinase (IPMK) catalyze the first step in the formation of the higher phosphorylated inositols InsP₅ and InsP₆ by metabolizing Ins(1,4,5)P₃ to Ins(1,3,4,5)P₄. In order to clarify the special role of these InsP₃ phosphorylating enzymes and of subsequent anabolic inositol phosphate reactions, a search was conducted for potent enzyme inhibitors starting with a fully active IP3K-A catalytic domain. Seven polyphenolic compounds could be identified as potent inhibitors with IC₅₀ < 200 nM (IC₅₀ given): ellagic acid (36 nM), gossypol (58 nM), (–)-epicatechin-3-gallate (94 nM), (–)-epigallocatechin-3-gallate (EGCG, 120 nM), aurintricarboxylic acid (ATA, 150 nM), hypericin (170 nM), and quercetin (180 nM). All inhibitors displayed a mixed-type inhibition with respect to ATP and a non-competitive inhibition with respect to Ins(1,4,5)P₃. Examination of these inhibitors toward IP3K-A, -B, and -C and IPMK from mammals revealed that ATA potently inhibits all kinases while the other inhibitors do not markedly affect IPMK but differentially inhibit IP3K isoforms. We identified chlorogenic acid as a specific IPMK inhibitor whereas the flavonoids myricetin, 3',4',7,8-tetrahydroxyflavone and EGCG inhibit preferentially IP3K-A and IP3K-C. Mutagenesis studies revealed that both the calmodulin binding and the InsP₃ binding domain in IP3K are involved in inhibitor binding. Their absence in IPMK and the presence of a unique insertion in IPMK were found to be important for selectivity differences from IP3K. The fact that all identified IP3K and IPMK inhibitors have been reported as antiproliferative agents and that IP3Ks or IPMK often are the best binding targets deserves further investigation concerning their antitumor potential.

Received for publication, January 18, 2005

^* This work was supported by Grants Ma989 and GRK 336 (to G. W. M.) from the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-40-42803-4639; Fax: 49-40-42803-6818; E-mail: mayr{at}uke.uni-hamburg.de.

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