3-(2,2,2-Trimethylhydrazinium)propionate(thp)-a novel γ-butyrobetaine hydroxylase inhibitor with cardioprotective properties

Simkhovich, Boris Z.; Shutenko, Zh. V.; Meirena, Dainuvite; Khagi, Kh. B.; Mezapuķe, R J; Molodchina, T N; Kalviņš, Ivars; Lukevics, É.

doi:10.1016/0006-2952(88)90717-4

Cited by 110 publications

(114 citation statements)

References 24 publications

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“…24,25 Mildronate was designed as a carnitine analog inhibiting its biosynthesis by interaction with the ␥-butyrobetaine hydroxylase, which in turn leads to reduced ␤-oxidation. 26,27 Our results indicate OCTN2 as another molecular target of mildronate.…”

Section: Discussionmentioning

confidence: 63%

Uptake of Cardiovascular Drugs Into the Human Heart

et al. 2006

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Background-To date, the uptake of drugs into the human heart by transport proteins is poorly understood. A candidate protein is the organic cation transporter novel type 2 (OCTN2) (SLC22A5), physiologically acting as a sodiumdependent transport protein for carnitine. We investigated expression and localization of OCTN2 in the human heart, uptake of drugs by OCTN2, and functional coupling of OCTN2 with the eliminating ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein). Methods and Results-Messenger RNA levels of OCTN2 and ABCB1 were analyzed in heart samples by quantitative polymerase chain reaction. OCTN2 was expressed in all auricular samples that showed a pronounced interindividual variability (35 to 1352 copies per 20 ng of RNA). Although a single-nucleotide polymorphism in OCTN2 (G/C at position Ϫ207 of the promoter) had no influence on expression, administration of ␤-blockers resulted in significantly increased expression. Localization of OCTN2 by in situ hybridization, laser microdissection, and immunofluorescence microscopy revealed expression of OCTN2 mainly in endothelial cells. For functional studies, OCTN2 was expressed in Madin-Darby canine kidney (MDCKII) cells. Using this system, verapamil, spironolactone, and mildronate were characterized both as inhibitors (EC 50 ϭ25, 26, and 21 mol/L, respectively) and as substrates. Like OCTN2, ABCB1 was expressed preferentially in endothelial cells. A significant correlation of OCTN2 and ABCB1 expression in the human heart was observed, which suggests functional coupling. Therefore, the interaction of OCTN2 with ABCB1 was tested with double transfectants. This approach resulted in a significantly higher transcellular transport of verapamil, a substrate for both OCTN2 and ABCB1. Conclusions-OCTN2 is expressed in the human heart and can be modulated by drug administration. Moreover, OCTN2can contribute to the cardiac uptake of cardiovascular drugs.

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Section: Discussionmentioning

confidence: 63%

Uptake of Cardiovascular Drugs Into the Human Heart

et al. 2006

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“…[3] 2OG oxygenases show promise as therapeutic targets. An inhibitor of γ-butyrobetaine hydroxylase (BBOX) is used for the treatment of cardiovascular disease [4,5] and inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases are in clinical trials for the treatment of anaemia. [6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Demethylases by 4‐Carboxy‐2,2′‐Bipyridyl Compounds

et al. 2011

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# These authors contributed equally to this work. Keywordsepigenetics; histone demethylase; bipyridyl; enzyme inhibitors; 2-oxoglutarate In eukaryotes, nuclear DNA is packaged into chromatin by binding to histones and associated factors. Covalent modifications to histone tails are associated with specific transcriptional states of the associated DNA. Acetylation of lysine side-chains normally correlates with transcriptional activation, while deacetylation leads to transcriptional silencing. The regulatory roles of methylation of lysine and arginine residues appear to be more complex. Methylation of certain lysine residues is associated with active transcription, while methylation of others is associated with silencing and heterochromatin formation. Each methylation 'mark' is placed, removed and 'interpreted' in a site-specific manner by histone methyltransferases, demethylases and methyl-binding domains, respectively. The biological functions of the individual enzymes are largely undefined, and are the focus of current investigations (for review see [1,2] The JmjC histone demethylases are 2-oxoglutarate (2OG) dependent oxygenases that catalyse N ε -lysyl demethylation via hydroxylation of the methyl group in a 2-oxoglutarate and Fe(II)-dependent manner (Scheme 1). Human 2OG oxygenases catalyse a range of reactions, including hydroxylation of amino acids, DNA and small molecules, and demethylation of proteins and DNA. [3] 2OG oxygenases show promise as therapeutic targets. An inhibitor of γ-butyrobetaine hydroxylase (BBOX) is used for the treatment of cardiovascular disease [4,5] and inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases are in clinical trials for the treatment of anaemia. [6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis. [7,8] The discovery of the JmjC domain histone demethylases, and the suggestions that some of them are potential therapeutic targets for cancer treatment, [9] Figure 1). [10][11][12][13] Compounds which catalyse the ejection of a structural Zn(II) ion from the JMJD2 demethylases have also been reported ( Figure 1). [14] In a study describing various template inhibitors of the JmjC demethylases, we found that 2,2′-bipyridyl compounds with at least one 4-carboxylate group inhibit the histone demethylase JMJD2E. [11] A related series of compounds, 5,5′-dicarboxylate-2,2′-bipyridyls, is reported to inhibit the collagen prolyl-4-hydroxylases. [15] 2,2′-Bipyridine and bipyridyl compounds have also been used as inhibitors of the HIF hydroxylases. [16] Although it is likely that in some cases the enzyme inhibition effects of bipyridyl compounds result from metal chelation in solution, they also have the potential to inhibit via active site binding, as is the case for some 2OG oxygenases; however, to date there is no structural information on their mechanism of action. Here we report structure-activity relationship studies and analyses on bipyridyl inhibitors of JMJD2E.The bipyridyl com...

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“…To date, no biochemical and structural studies have investigated the interactions of CrAT with pharmacological agents that modulate energy metabolism reactions. Mildronate (3-(2,2,2-trimethylhydrazinium)propionate) (Figure 1b) is a cardioprotective drug that acts as an L-carnitine concentration lowering agent and inhibitor of free fatty acid -oxidation 8,9 . Structurally, mildronate is related to L-carnitine and its bioprecursor, -butyrobetaine (GBB) (Figure 1c).…”

Section: Introductionmentioning

confidence: 99%

“…Mildronate is known to interact with proteins that are involved in the pathways of the carnitine biosynthesis and transport systems. It is known that mildronate inhibits the biosynthesis of carnitine through GBB hydroxylase 9 , carnitine reabsorption in the kidneys 10,11 , and organic cation/carnitine transporter OCTN2 in the heart 12 . However, it has also been shown that mildronate inhibits CrAT activity to some extent 13 .…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, it has been reported by several authors that mildronate does not directly inhibit CPT I 10,14 . Instead, mildronate treatment induces a decrease in carnitine bioavailability for the CPT I catalyzed reaction and, as a result, partially inhibits fatty acid transport into mitochondria and the subsequent production of acetyl-CoA from -oxidation of fatty acids 9,15 . In the presence of low carnitine concentrations and limited availability of acetyl-CoA, the inhibition of CrAT by mildronate might be an important pharmacological mechanism for maintenance of intra-mitochondrial metabolic pathways under ischemic conditions.…”

Section: Introductionmentioning

confidence: 99%

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