Jürgen G Okun

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (66)409.1 Total impact

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    ABSTRACT: Inherited deficiencies of the L-lysine catabolic pathway cause glutaric aciduria type I and pyridoxine-dependent epilepsy. Dietary modulation of cerebral L-lysine metabolism is thought to be an important therapeutic intervention for these diseases. To better understand cerebral L-lysine degradation, we studied in mice the two known catabolic routes - pipecolate and saccharopine pathways - using labeled stable L-lysine and brain peroxisomes purified according to a newly established protocol. Experiments with labeled stable L-lysine show that cerebral L-pipecolate is generated along two pathways: i) a minor proportion retrograde after ε-deamination of L-lysine along the saccharopine pathway, and ii) a major proportion anterograde after α-deamination of L-lysine along the pipecolate pathway. In line with these findings, we observed only little production of saccharopine in the murine brain. L-pipecolate oxidation was only detectable in brain peroxisomes, but L-pipecolate oxidase activity was low (7 ± 2μU/mg protein). In conclusion, L-pipecolate is a major degradation product from L-lysine in murine brain generated by α-deamination of this amino acid.
    Journal of Inherited Metabolic Disease 09/2014; · 4.07 Impact Factor
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    ABSTRACT: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
    Nature 06/2014; · 38.60 Impact Factor
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    ABSTRACT: Biochemical detection of inborn errors of creatine metabolism or transport relies on the analysis of three main metabolites in biological fluids: guanidinoacetate (GAA), creatine (CT) and creatinine (CTN). Unspecific clinical presentation of the diseases might be the cause that only few patients have been diagnosed so far. We describe an LC-MS/MS method allowing fast and reliable diagnosis by simultaneous quantification of GAA, CT and CTN in urine, plasma and cerebrospinal fluid (CSF) and established reference values for each material. For quantification deuterated stable isotopes of each analyte were used as internal standards. GAA, CT and CTN were separated by reversed-phase HPLC. The characterization was carried out by scanning the ions of each compound by negative ion tandem mass spectrometry. Butylation is needed to achieve sufficient signal intensity for GAA and CT but is not useful for analyzing CTN. The assay is linear in a broad range of analyte concentrations usually found in urine, plasma and CSF. Comparison of the "traditional" cation-exchange chromatography and LC-MS/MS showed proportional differences but linear relationships between the two methods. The described method is characterized by high speed and linearity over large concentration ranges comparable to other published LCMS methods but with higher sensitivity for GAA and CT. In addition, we present the largest reference group ever published for guanidino compounds in all relevant body fluids. Therefore this method is applicable for high-throughput approaches for diagnosis and follow-up of inborn errors of creatine metabolism and transport.
    Gene 01/2014; · 2.20 Impact Factor
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    ABSTRACT: The ketone body β-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2(-/-) mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6C(Lo) monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain.
    Nature Communications 01/2014; 5:3944. · 10.02 Impact Factor
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    ABSTRACT: Steroid-refractory courses of graft-versus-host disease are life-threatening complications after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease courses associate with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigate if quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant serum nitrates (>26.5 mM) predicted steroid-refractory graft-versus-host disease (p=0.026) and non-relapse mortality (p=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (p=0.0007 and p=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory courses and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of iNOS in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (p=0.031) when pravastatin was taken. In summary, patients at high risk of developing refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort.
    Haematologica 10/2013; · 5.94 Impact Factor
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    ABSTRACT: Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.
    Nature medicine 06/2013; · 27.14 Impact Factor
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    ABSTRACT: This review focuses on the pathophysiology of organic acidurias (OADs), in particular, OADs caused by deficient amino acid metabolism. OADs are termed classical if patients present with acute metabolic decompensation and multiorgan dysfunction or cerebral if patients predominantly present with neurological symptoms but without metabolic crises. In both groups, however, the brain is the major target. The high energy demand of the brain, the gate-keeping function of the blood-brain barrier, a high lipid content, vulnerable neuronal subpopulations, and glutamatergic neurotransmission all make the brain particularly vulnerable against mitochondrial dysfunction, oxidative stress, and excitotoxicity. In fact, toxic metabolites in OADs are thought to cause secondary impairment of energy metabolism; some of these toxic metabolites are trapped in the brain. In contrast to cerebral OADs, patients with classical OADs have an increased risk of multiorgan dysfunction. The lack of the anaplerotic propionate pathway, synergistic inhibition of energy metabolism by toxic metabolites, and multiple oxidative phosphorylation (OXPHOS) deficiency may best explain the involvement of organs with a high energy demand. Intriguingly, late-onset organ dysfunction may manifest even under metabolically stable conditions. This might be explained by chronic mitochondrial DNA depletion, increased production of reactive oxygen species, and altered gene expression due to histone modification. In conclusion, pathomechanisms underlying the acute disease manifestation in OADs, with a particular focus on the brain, are partially understood. More work is required to predict the risk and to elucidate the mechanism of late-onset organ dysfunction, extracerebral disease manifestation, and tumorigenesis.
    Journal of Inherited Metabolic Disease 03/2013; · 4.07 Impact Factor
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    ABSTRACT: Abnormalities in metabolite profiles are valuable indicators of underlying pathologic conditions at the molecular level. However, their interpretation relies on detailed knowledge of the pathways, enzymes, and genes involved. Identification and characterization of their physiological function are therefore crucial for our understanding of human disease: they can provide guidance for therapeutic intervention and help us to identify suitable biomarkers for monitoring associated disorders. We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level. This disorder has been associated with varying neurological symptoms. Exome sequencing of a single affected individual revealed compound heterozygosity for an initiating methionine mutation (c.1A>G) and a missense mutation (c.2185G>A [p.Gly729Arg]) in DHTKD1. This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein. Sequence analysis of a second individual identified the same missense mutation together with a nonsense mutation (c.1228C>T [p.Arg410(∗)]) in DHTKD1. Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA. Moreover, investigation of L-lysine metabolism showed an accumulation of deuterium-labeled 2-oxoadipate only in noncomplemented cells, demonstrating that DHTKD1 codes for the enzyme mediating the last unresolved step in the L-lysine-degradation pathway. All together, our results establish mutations in DHTKD1 as a cause of human 2-aminoadipic and 2-oxoadipic aciduria via impaired turnover of decarboxylation 2-oxoadipate to glutaryl-CoA.
    The American Journal of Human Genetics 11/2012; · 11.20 Impact Factor
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    ABSTRACT: Levels of (D)-2-hydroxyglutarate [D2HG, (R)-2-hydroxyglutarate] are increased in some metabolic diseases and in neoplasms with mutations in the isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) genes. Determination of D2HG is of relevance to diagnosis and monitoring of disease. Standard detection methods of D2HG levels are liquid-chromatography-mass spectrometry or gas-chromatography-mass spectrometry. Here we present a rapid, inexpensive and sensitive enzymatic assay for the detection of D2HG levels. The assay is based on the conversion of D2HG to α-ketoglutarate (αKG) in the presence of the enzyme (D)-2-hydroxyglutarate dehydrogenase (HGDH) and nicotinamide adenine dinucleotide (NAD(+)). Determination of D2HG concentration is based on the detection of stoichiometrically generated NADH. The quantification limit of the enzymatic assay for D2HG in tumor tissue is 0.44 μM and in serum 2.77 μM. These limits enable detection of basal D2HG levels in human tumor tissues and serum without IDH mutations. Levels of D2HG in frozen and paraffin-embedded tumor tissues containing IDH mutations or in serum from acute myeloid leukemia patients with IDH mutations are significantly higher and can be easily identified with this assay. In conclusion, the assay presented is useful for differentiating basal from elevated D2HG levels in tumor tissue, serum, urine, cultured cells and culture supernatants.
    Acta Neuropathologica 11/2012; · 9.73 Impact Factor
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    ABSTRACT: To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls. Authors describe semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. Authors determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism. Abnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause. Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.
    World Journal of Gastroenterology 03/2012; 18(10):1067-76. · 2.55 Impact Factor
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    ABSTRACT: IDH1/2 mutations occur at high frequency in diffusely infiltrating gliomas of the WHO grades II and III and were identified as a strong prognostic marker in all WHO grades of gliomas. Mutated IDH1 or IDH2 protein leads to the generation of excessive amounts of the metabolite 2-hydroxyglutarate (2HG) in tumor cells. Here, we evaluated whether 2HG levels in preoperative serum samples from patients with gliomas correlate with the IDH1/2 mutation status and whether there is an association between 2HG levels and glioma size. In contrast to the strong accumulation of 2HG in the serum of patients with IDH1/2 mutated acute myeloid leukaemia, no accumulation was observed in this series of IDH1/2 mutated gliomas. Furthermore, we found no association between glioma size measured by magnetic resonance imaging and 2HG levels. We conclude that 2HG levels in preoperative sera from patients with diffusely infiltrating gliomas of the WHO grades II and III cannot be used as a marker to differentiate between tumors with versus without IDH1/2 mutation. Furthermore, the observation that there is no correlation between 2HG levels and tumor volume may indicate that 2HG cannot be utilized as marker to monitor tumor growth in gliomas.
    International Journal of Cancer 09/2011; 131(3):766-8. · 6.20 Impact Factor
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    ABSTRACT: Wilson disease (WD) is caused by mutations of the WD gene ATP7B resulting in copper accumulation in different tissues. WD patients display hepatic and neurological disease with yet poorly understood pathomechanisms. Therefore, we studied age-dependent (3, 6, 47weeks) biochemical and bioenergetical changes in Atp7b(-/-) mice focusing on liver and brain. Mutant mice showed strongly elevated copper and iron levels. Age-dependently decreasing hepatic reduced glutathione levels along with increasing oxidized to reduced glutathione ratios in liver and brain of 47weeks old mice as well as elevated hepatic and cerebral superoxide dismutase activities in 3weeks old mutant mice highlighted oxidative stress in the investigated tissues. We could not find evidence that amino acid metabolism or beta-oxidation is impaired by deficiency of ATP7B. In contrast, sterol metabolism was severely dysregulated. In brains of 3week old mice cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol were all highly increased. These changes reversed age-dependently resulting in reduced levels of all previously increased sterol metabolites in 47weeks old mice. A similar pattern of sterol metabolite changes was found in hepatic tissue, though less pronounced. Moreover, mitochondrial energy production was severely affected. Respiratory chain complex I activity was increased in liver and brain of mutant mice, whereas complex II, III, and IV activities were reduced. In addition, aconitase activity was diminished in brains of Atp7b(-/-) mice. Summarizing, our study reveals oxidative stress along with severe dysfunction of mitochondrial energy production and of sterol metabolism in Atp7b(-/-) mice shedding new light on the pathogenesis of WD.
    Biochimica et Biophysica Acta 09/2011; 1812(12):1607-15. · 4.66 Impact Factor
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    ABSTRACT: Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes occur frequently in diffuse astrocytoma and oligodendroglioma. The consecutive amino acid substitutions in the mutant proteins result in a gain of the function to catalyze the reduction of alpha-ketoglutarate to 2-hydroxyglutarate (2HG). So far, all investigated IDH mutations share this gain of function. We here describe a method to detect 2HG levels in archival formalin-fixed paraffin-embedded tumor specimens by stable isotope dilution using gas chromatography followed by mass spectrometry (GC/MS). While 2HG levels are notably decreased during the routine embedding process, preserved amounts are still sufficient to indicate a mutation. Detection of 2HG in archival specimens could make routinely processed tissue accessible for research on 2HG accumulation and may allow studies on correlation with clinical data.
    Brain Pathology 06/2011; 22(1):26-31. · 4.74 Impact Factor
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    ABSTRACT: Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.
    Journal of Inherited Metabolic Disease 03/2011; 34(3):677-94. · 4.07 Impact Factor
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    ABSTRACT: Studies in vitro and in mice indicate a role for Coenzyme Q(10) (CoQ(10) ) in gene expression. To determine this function in relationship to physiological readouts, a 2-week supplementation study with the reduced form of CoQ(10) (ubiquinol, Q(10) H(2) , 150 mg/d) was performed in 53 healthy males. Mean CoQ(10) plasma levels increased 4.8-fold after supplementation. Transcriptomic and bioinformatic approaches identified a gene-gene interaction network in CD14-positive monocytes, which functions in inflammation, cell differentiation, and peroxisome proliferator-activated receptor-signaling. These Q(10) H(2) -induced gene expression signatures were also described previously in liver tissues of SAMP1 mice. Biochemical and NMR-based analyses showed a reduction of low density lipoprotein (LDL) cholesterol plasma levels after Q(10) H(2) supplementation. This effect was especially pronounced in atherogenic small dense LDL particles (19-21 nm, 1.045 g/L). In agreement with gene expression signatures, Q(10) H(2) reduces the number of erythrocytes but increases the concentration of reticulocytes. In conclusion, Q(10) H(2) induces characteristic gene expression patterns, which are translated into reduced LDL cholesterol levels and altered parameters of erythropoiesis in humans.
    International Union of Biochemistry and Molecular Biology Life 01/2011; 63(1):42-8. · 2.79 Impact Factor
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    ABSTRACT: The objectives of this study were to determine the value of phenylalanine (Phe) loading for diagnosing dopa-responsive dystonia (DRD) in children. We investigated orally administered Phe loading tests (100 mg/kg) in seven patients with confirmed DRD and 17 pediatric patients with clinically suspected but excluded DRD. Results of Phe, tyrosine (Tyr), and biopterin from plasma and dried blood spot (DBS) analyses were correlated, and pediatric cutoff values established. The peak Phe concentration following a Phe load in the pediatric DRD population is lower than reported in adults. By using adult cutoff values and either Phe/Try ratios or biopterin concentrations only, false positive and false negative results are frequent. Only the combined analysis of the Phe/Tyr ratio and biopterin concentration is reliable in children. In children with DRD, dried blood Phe/Tyr ratio exceeded 4.6 (plasma Phe/Tyr ratio >5.4) after 2 h and biopterin concentration in dried blood remained below 16.2 nmol/L (plasma biopterin <14 nmol/L) 1 h after Phe challenge. Phe loading is a useful tool for diagnosing DRD in children. Test duration can be reduced to only 2 h, and specific pediatric cutoff values need to be applied. Simultaneous measurements of the Phe/Tyr ratio and biopterin in plasma or DBS are essential in pediatric patients.
    Journal of Inherited Metabolic Disease 12/2010; 33(6):697-703. · 4.07 Impact Factor
  • European Journal Of Haematology 11/2010; 85(5):457-9. · 2.55 Impact Factor
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    ABSTRACT: Studies in humans and mice indicate a role for coenzyme Q(10) (CoQ(10)) in gene expression. To analyze this function in relation to metabolism, SAMP1 mice were supplemented with the reduced (ubiquinol) or oxidized (ubiquinone) form of CoQ(10) (500 mg/kg BW/d) for 14 months. Microarray analyses in liver tissues of SAMP1 mice identified 946 genes as differentially expressed between ubiquinol-treated and control animals (≥1.5-fold, P < 0.05). Text mining analyses revealed for a part of the ubiquinol-regulated genes, a functional connection in PPARα and LXR/RXR signalling pathways. Because these pathways are involved in cholesterol homeostasis, relevant metabolites were determined by gas chromatography/mass spectrometry (GC/MS). We found a significant increase of desmosterol (2.0-fold, P < 0.001) in the liver of ubiquinol-supplemented SAMP1 mice when related to control animals. In agreement, cholesterol concentrations were also distinctly increased (1.3-fold, P = 0.057). The Q(10)H(2)-induced PPARα and LXR/RXR gene expression signatures and effects on cholesterol metabolism were not apparent for the oxidized form of CoQ(10). In conclusion, the reduced form of CoQ(10) mediates distinct effects on cholesterol metabolism at the transcriptional and metabolite level in SAMP1 mice.
    International Union of Biochemistry and Molecular Biology Life 11/2010; 62(11):812-8. · 2.79 Impact Factor
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    ABSTRACT: Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A dehydrogenase localized in the final common catabolic pathway of L-lysine, L-hydroxylysine and L-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low L-lysine diet and L-carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A dehydrogenase-deficient mice, an animal model with complete loss of glutaryl-coenzyme A dehydrogenase activity, focusing on the tissue-specific changes of neurotoxic metabolites and key enzymes of L-lysine metabolism. Here, we demonstrate that low L-lysine diet, but not L-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. L-carnitine supplementation restored the free L-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low L-lysine diet was amplified by add-on therapy with L-arginine, which we propose to result from competition with L-lysine at system y(+) of the blood-brain barrier and the mitochondrial L-ornithine carriers. L-lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate-limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of L-lysine oxidation, 2-aminoadipate semialdehyde dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of L-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl-coenzyme A dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative L-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic L-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between L-lysine and L-arginine at physiological barriers and enhancement of peroxisomal L-lysine oxidation and glutaric acid breakdown.
    Brain 10/2010; 134(Pt 1):157-70. · 9.92 Impact Factor
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    Journal of Inherited Metabolic Disease 09/2010; · 4.07 Impact Factor

Publication Stats

1k Citations
409.10 Total Impact Points

Institutions

  • 2002–2014
    • Universität Heidelberg
      • • Division of General Pediatrics
      • • Institute of Pathology (Mannheim)
      • • Interdisciplinary Center for Neurosciences
      Heidelburg, Baden-Württemberg, Germany
  • 2001–2014
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2012
    • Technische Universität München
      München, Bavaria, Germany
  • 2011
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 2004
    • Universität Witten/Herdecke
      • Chair of Pediatrics
      Witten, North Rhine-Westphalia, Germany