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Cardioprotective activity of a novel and potent competitive inhibitor of lactate dehydrogenase |
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| Authors: | Alexander B Kotlyar Antonio Randazzo Zhu-Qui Jin Gary Cecchini |
| Institution: | a Molecular Biology Division, Veterans Affairs Medical Center, San Francisco, CA 94121, United States b Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, United States c Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel d Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli “Federico II”, via D. Montesano 49, I-80131 Napoli, Italy e Cardiology Section, Department of Medicine, University of California at San Francisco and VA Medical Center (111C), San Francisco, CA 94121, United States |
| Abstract: | Alkaline incubation of NADH results in the formation of a very potent inhibitor of lactate dehydrogenase. High resolution mass spectroscopy along with NMR characterization clearly showed that the inhibitor is derived from attachment of a glycolic acid moiety to the 4-position of the dihydronicotinamide ring of NADH. The very potent inhibitor is competitive with respect to NADH. The inhibitor added in submicromolar concentrations to cardiomyocytes protects them from damage caused by hypoxia/reoxygenation stress. In isolated mouse hearts, addition of the inhibitor results in a substantial reduction of myocardial infarct size caused by global ischemia/reperfusion injury. |
| Keywords: | LDH lactate dehydrogenase MDH malate dehydrogenase Q1 2 3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1 4-benzoquinone APAD 3-acetylpyridine nicotinamide adenine dinucleotide NAD-Pyr nicotinamide adenine dinucleotide-pyruvate ANAD-Pyr 3-acetylpyridine nicotinamide adenine dinucleotide-pyruvate GA glycolic acid HRMS high resolution mass spectroscopy HRESIMS high resolution electron spray ionization mass spectra COSY correlated spectroscopy TOCSY total correlated spectroscopy HSQC heteronuclear single quantum coherence HMBC heteronuclear multiple bond correlation I/R ischemia/reperfusion K-Pi potassium phosphate |
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