Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

Tars, K.; Leitans, Janis; Kazāks, Andris; Zeļencova, Diāna; Liepinsh, Edgars; Kuka, Janis; Makrecka, Marina; Lola, Daina; Andrianovs, Viktors; Gustina, Daina; Grı̄nberga, Solveiga; Лиепиньш, Э. Э.; Kalvinsh, Ivars; Dambrova, Maija; Loza, Einars; Pugovičs, Osvalds

doi:10.1021/jm401603e

Cited by 40 publications

(48 citation statements)

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“…The IC 50 values are presented as the mean ± SD of at least three independent experiments and are taken from Tars et al . () and Liepinsh et al . ().…”

Section: Resultsmentioning

confidence: 88%

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Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

Liepinsh

Makrecka-Kūka

Kuka

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEThe important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury. KEY RESULTSIn this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg ) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%. CONCLUSIONS AND IMPLICATIONSReduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism. AbbreviationsAAR, area at risk; ACOX, acyl-CoA oxidase 1; ACSL, long-chain fatty acid CoA synthetase; AN, area of necrosis; BBOX, γ-butyrobetaine dioxygenase; CD36, fatty acid translocase; CPT I, carnitine palmitoyltransferase I; FABP, fatty acid binding protein; FAO, fatty acid oxidation; HR, heart rate; IHD, ischaemic heart disease; IS, infarct size; KH, Krebs-Henseleit; LAD, left anterior descending coronary artery; LCFA, long-chain fatty acids; LV, left ventricle; LVDP, left ventricle developed pressure; IntroductionIschaemic heart disease (IHD) is a major medical problem causing disability and death for millions of people annually (Lavie et al., 2009). The important pathological consequences of IHD arise from the detrimental effects of the accumulation of long-chain fatty acids (LCFAs) in the case of acute ischaemia-reperfusion (Wang and Lopaschuk, 2007;Liepinsh et al., 2013b). Therefore, pharmacological intervention that targets LCFA accumulation has been suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with IHD (Horowitz et al., 2010;Lopaschuk et al., 2010). The main advantages of reduced LCFA oxidation are the reduction of energy waste through mitochondrial uncoupling induced by LCFA overload as well as the reduction of direct damage by LCFA metabolites on glucose metabolism and insulin signalling (Zhang et al., 2011). In addition, pharmacological manipulation of energy metabolism does not directly influence the haemodynamic parameters of th...

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“…The IC 50 values are presented as the mean ± SD of at least three independent experiments and are taken from Tars et al . () and Liepinsh et al . ().…”

Section: Resultsmentioning

confidence: 88%

“…Methyl‐GBB was synthesized according to the method described previously (Kalvinsh et al ., ; Tars et al ., ). Meldonium was a kind gift from JSC Grindeks, Riga, Latvia.…”

Section: Methodsmentioning

confidence: 97%

Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

Liepinsh

Makrecka-Kūka

Kuka

et al. 2015

British J Pharmacology

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“…Focusing on meldonium as a WADA-prohibited substance since January 2016, there is a lack of a systematic, scientific fundament as well as a lack of studies performed with highly trained athletes and published in peer-reviewed journals that prove that meldonium actually improves exercise performance. However, since several compounds acting as BBOX inhibitors with molecular structures similar to that of meldonium were recently described,73 one can assume that such compounds will enter the pharmaceutical market in the future both for patients and athletes.…”

Section: Resultsmentioning

confidence: 99%

Story behind meldonium–from pharmacology to performance enhancement: a narrative review

et al. 2016

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Recent reports from the World Anti-Doping Agency (WADA) indicate an alarming prevalence in the use of meldonium among elite athletes. Therefore, in January 2016, meldonium was added to WADA's prohibited list after being monitored since 2015. Meldonium has been shown to have beneficial effects in cardiovascular, neurological and metabolic diseases due to its anti-ischaemic and cardioprotective properties, which are ascribed mainly to its inhibition of ß-oxidation and its activation of glycolysis. Despite its widespread use, there are only a few clinical studies or clinical trials available. Meldonium is registered in most Baltic countries and is easily accessible through the internet with no serious adverse effects reported by the manufacturer so far. Among athletes, meldonium is used with the purpose of increasing recovery rate or exercise performance. The benefit of taking meldonium in view of performance enhancement in athletes is quite speculative and is discussed without sound scientific evidence. This narrative review provides a detailed overview of the drug meldonium, focusing on the main topics pharmacology and biochemical actions, clinical applications, pharmacokinetics, methods of detection and potential for performance enhancement in athletes.

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“…In the case of carnitine, crystal structures have been solved in complex that include carnitine in complex with the periplasmic binding protein OpuCC (Du et al, 2011), the carnitine:c-butryobetaine antiporter CaiT (Schulze et al, 2010;Tang et al, 2010) and similar aromatic cage architecture of the quaternary amine-binding site with c-butyrobetaine has been determined for c-butyrobetaine hydroxylase (Tars et al, 2014). Therefore, as in the situation for glycine betaine (Schiefner et al, 2004), high-affinity binding of carnitine and its metabolites seems to occur via an aromatic cage enabling the cation-p interaction with the trimethylamine moiety coupled with properly spaced hydrogenbonding residues to coordinate the carboxylic acid.…”

Section: Sensing and Binding Carnitinementioning

confidence: 99%

Carnitine in bacterial physiology and metabolism

2015

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Carnitine is a quaternary amine compound found at high concentration in animal tissues, particularly muscle, and is most well studied for its contribution to fatty acid transport into mitochondria. In bacteria, carnitine is an important osmoprotectant, and can also enhance thermotolerance, cryotolerance and barotolerance. Carnitine can be transported into the cell or acquired from metabolic precursors, where it can serve directly as a compatible solute for stress protection or be metabolized through one of a few distinct pathways as a nutrient source. In this review, we summarize what is known about carnitine physiology and metabolism in bacteria. In particular, recent advances in the aerobic and anaerobic metabolic pathways as well as the use of carnitine as an electron acceptor have addressed some long-standing questions in the field. Received 5 January 2015 Accepted 17 March 2015Introduction Carnitine (c-trimethylamino-b-hydroxybutyric acid) ( Fig. 1) is a quaternary amine compound that can be produced by all domains of life, and was discovered in muscle extract in 1905 by Gulewitsch & Krimberg (1905) and Kutscher (1905). It was shown to be essential for larval development of the mealworm Tenebrio molitor and was originally designated vitamin B T based on this requirement. Later, it was discovered that carnitine can be synthesized in mammals and is now considered to be a quasi-nutrient or conditionally essential nutrient (Flanagan et al., 2010), as neonates have reduced biosynthesis and rely on placental transfer of carnitine in utero and exogenous sources after birth (Combs, 2012). Fifty years after the discovery of carnitine, it was demonstrated that assorted Gram-positive and Gram-negative bacteria could use carnitine in either aerobic or anaerobic environments for a variety of cellular functions, including as an electron acceptor, as a compatible solute to survive environmental insults or as a sole carbon, nitrogen and energy source. Bacterial carnitine metabolism was most recently reviewed in 1998 (Bieber, 1988;Bremer, 1983;Kleber, 1997;Rebouche & Seim, 1998) and the field has seen important advances. This review summarizes what we knew at the time of the previous reviews and emphasizes what we have learned since, including: (i) how anaerobic bacteria synthesize and utilize crotonobetaine and carnitine as final electron acceptors, (ii) the impact of carnitine degradation by the intestinal microbiota and the genes responsible for this anaerobic conversion, (iii) the genes involved in aerobic degradation of carnitine, and (iv) how carnitine as a compatible solute impacts survival within and outside of the host. Carnitine in the environmentRecent work makes it clear that while animals represent the most readily accessible source of carnitine, carnitine is often present and sometimes abundant in soil and natural waters. Quaternary ammonium compounds are abundant in a number of soil ecosystems, including comprising a quarter of the most abundant organic nitrogen compounds in the soil water of a subalpine gras...

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Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

Cited by 40 publications

References 48 publications

Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

Story behind meldonium–from pharmacology to performance enhancement: a narrative review

Carnitine in bacterial physiology and metabolism

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