Organic Vanadium Chelators Potentiate Vanadium-Evoked Glucose Metabolism In Vitro and In Vivo: Establishing Criteria for Optimal Chelators
- Departments of 1Biological Chemistry (I.G., S.Q., Y.S.) and 2Organic Chemistry (I.G., E.G., M.F.), The Weizmann Institute of Science, Rehovot, Israel
Abstract
Several ligands, when complexed with vanadium, potentiate its insulinomimetic activity both in vivo and in vitro. We have recently found that l-Glu-γ-monohydroxamate (HXM) andl-Asp(β)HXM were especially potent in this regard. In the present study, we used vanadium-enriched adipose cells and cell-free experimental systems to determine the features ofl-Glu(γ)HXM and l-Asp(β)HXM that turn these ligands into optimal-synergizing vanadium chelators. We found thatl-Glu(γ)HXM and l-Asp(β)(HXM) possess the following characteristics: 1) They associate with vanadium(+5) at pH 7.2 within a narrow range of an apparent formation constant of 1.3 to 1.9 × 102 M−1; 2) they have nearly the same binding affinity for the vanadyl(+4) cation and the vanadate(+5) anion at physiological pH values; and 3) they form intense ultraviolet absorbing complexes upon associating with vanadium(+4) at 1 and 3 M stoichiometry, respectively, at pH 3.0. Vanadium ligands lacking any of these three defined criteria synergize less effectively with vanadium to activate glucose metabolism.
Footnotes
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Send reprint requests to: Dr. Yoram Shechter, Departments of Biological Chemistry and Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. Email:cogoldwa{at}wisemail.weizmann.ac.il
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↵1 Essentially the same results were obtained with several other α-amino acid HXMs. For simplicity,l-Ile(α)HXM is referred to throughout the manuscript as a representative of α-amino acid HXMs.
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This study was supported by grants from the Minerva Foundation, Munich, Germany; The Israel Academy of Science Foundation; the Israeli Ministry of Health; and The Lapid Pharmaceutical Company. Y.S. is the incumbent of C.H. Hollenberg Chair in Metabolic and Diabetes Research, established by the friends and associates of Dr. C.H. Hollenberg of Toronto, Canada. M.F. is the Lester Pearson Professor of Protein Chemistry. This work is in partial fulfillment of the requirements for the Ph.D. degree of I.G.
- Abbreviations:
- HXM
- monohydroxamate
- STZ
- streptozocin
- KRBH
- Krebs-Ringer bicarbonate HEPES
- pNPP
- p-nitrophenylphosphate
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- Received March 23, 2000.
- Accepted July 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
