Kegg Pathway: Citrate cycle (TCA cycle)

Cell Physiol Biochem. 2009; 24(5-6): 483-92
Peters K, Kamp G, Berz A, Unger RE, Barth S, Salamon A, Rychly J, Kirkpatrick CJ

BACKGROUND: In this study the influence of cultivation and proliferation on energy metabolic characteristics of human umbilical vein endothelial cells (HUVEC) has been examined. The energy metabolic capacities of human endothelial cells freshly isolated from the umbilical vein were compared with those after cultivation for three passages and as subconfluent and confluent cultures. METHODS: Expression of cell type-specific differentiation markers and proliferative activity were studied in dependency on cultivation characteristics. Furthermore, the energy metabolic characteristics of HUVEC were analyzed by measurement of the maximum catalytic activities of marker enzymes of various metabolic pathways. RESULTS: Examination of a typical marker of proliferation, Ki67, confirmed that HUVEC changed in culture from a non-proliferative to a proliferative state. Compared to other cell types, the enzyme pattern of HUVEC showed a high glycolytic and a high NADPH regenerating capacity. These capacities increased by cultivation nearly to the same degree as marker enzymes of other metabolic pathways (e.g. citric acid cycle). CONCLUSION: Our data support the theory that metabolism of EC is primarily by "aerobic glycolysis", i.e. the conversion of glucose to lactate in the presence of oxygen. These characteristics were independent of whether the cells are freshly isolated/non-proliferating or cell culture-adapted/proliferating.

Am J Physiol Endocrinol Metab. 2009 Nov 3;
Ritov VB, Menshikova EV, Azuma K, Wood RJ, Toledo FG, Goodpaster BH, Ruderman NB, Kelley DE

Background Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondria content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Study Design and Methods Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH-oxidase activity of mitochondrial electron transport chain (ETC) and activity of Citrate synthase and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD): key enzymes of TCA cycle and beta-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of beta-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondria content and mitochondrial enzyme profile in lean, obese or T2DM cohort. Results The total activity of NADH oxidase was significantly reduced in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar and, although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of Citrate synthase for lean and T2DM group was similar; however it was significantly increased in obese group. Activity of beta-HAD and mtDNA content was similar for all three groups. Conclusions. The total activity of NADH-oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH-oxidase (per mg cardiolipin) and NADH-oxidase/Citrate synthase and NADH-oxidase/beta-HAD ratios are reduced by 2-3 folds in both T2DM and obesity.

Mol Plant Pathol. 2009 Nov; 10(6): 843-55
Judelson HS, Tani S, Narayan RD

Efficient nutrient acquisition is critical to the fitness of plant pathogens. To address how the late blight agent Phytophthora infestans adapts to nutrients offered by its hosts, genes in glycolytic, gluconeogenic and amino acid pathways were mined from its genome and their expression in different plant tissues and artificial media was measured. Evidence for conventional glycolytic and gluconeogenic processes was obtained, although several steps involved pyrophosphate-linked transformations which are uncommon in eukaryotes. In media manipulation studies, nearly all genes in the pathways were subject to strong transcriptional control. However in rye-sucrose media, tomato leaflets, potato tubers and, at both early and late stages of infection, most glycolytic genes were expressed similarly, which indicated that each plant tissue presented a nutrient-rich environment. Biochemical analyses also demonstrated that sporulation occurred from host material in which sugars were abundant, with fructose and glucose increasing at the expense of sucrose late in the disease cycle. The expression of only a few genes changed late in infection, with the most notable example being lower invertase levels in the sucrose-reduced leaves. Interestingly, most gluconeogenic genes were up-regulated in tubers compared with other tissues. Rather than reflecting a starvation response, this probably reveals the role of such enzymes in converting carbon skeletons from the abundant free amino acids of tubers into citric acid cycle and glycolysis intermediates, as genes involved in amino acid catabolism were also more highly expressed in tubers. The corresponding enzymes also displayed higher activities in defined media when amino acids were abundant, as in tubers.

Ann N Y Acad Sci. 2009 Oct; 1177: 66-73
Weinberg F, Chandel NS

Historically, it has been assumed that glycolytic metabolism, not mitochondrial metabolism, is essential for tumor cell proliferation. However, most tumor cells have functional mitochondria, and recent studies suggest that the citric acid cycle (TCA) cycle intermediates are precursors for synthesis of nucleotides, lipids, and amino acids. Here we review the accumulating evidence that mitochondrial metabolism plays an essential role in tumor cell proliferation.

FEBS J. 2009 Oct 16;
Garavaglia S, Perozzi S, Galeazzi L, Raffaelli N, Rizzi M

The enzyme alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and determines the final fate of the amino acid, i.e. transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions, mainly affecting the central nervous system. As their relative concentrations must be tightly controlled, modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders, including cerebral malaria. Here we report the 2.0 A resolution crystal structure of human ACMSD in complex with the glycolytic intermediate 1,3-dihydroxyacetonephosphate (DHAP), refined to an R-factor of 0.19. DHAP, which we discovered to be a potent enzyme inhibitor, resides in the ligand binding pocket with its phosphate moiety contacting the catalytically essential zinc ion through mediation of a solvent molecule. Arg47, Asp291 and Trp191 appear to be the key residues for DHAP recognition in human ACMSD. Ligand binding induces a significant conformational change affecting a strictly conserved Trp-Met couple, and we propose that these residues are involved in controlling ligand admission into ACMSD. Our data may be used for the design of inhibitors with potential medical interest, and suggest a regulatory link between de novo NAD biosynthesis and glycolysis.

Appl Microbiol Biotechnol. 2009 Oct 14;
Chen Y, Li S, Xiong J, Li Z, Bai J, Zhang L, Ye Q, Ouyang P, Ying H

A whole cell biocatalytic process for uridine 5'-monophosphate (UMP) production from orotic acid by Saccharomyces cerevisiae was developed. The concentration of UMP was increased by 23% when 1 g l(-1) sodium Citrate was fed into the broth. Effects of Citrate addition on UMP production were investigated. Glucose-6-phosphate pool was elevated by onefold, while FBP and pyruvate were decreased by 42% and 40%, respectively. Organic acid pools such as acetate and succinate were averagely decreased by 30% and 49%. The results demonstrated that manipulation of Citrate levels could be used as a novel tool to regulate the metabolic fluxes distribution among glycolysis, pentose phosphate pathway, and TCA cycle.

Pediatr Res. 2009 Oct 9;
Mortensen OH, Olsen HL, Frandsen L, Nielsen PE, Nielsen FC, Grunnet N, Quistorff B

We examined gene expression changes in liver and skeletal muscle of newborn mice subjected to a maternal low (LP) or normal (NP) protein diet during pregnancy, with or without taurine supplementation in the drinking water. LP offspring had a 40% lower birthweight than NP offspring, whereas it was reduced by only 20% with taurine supplementation. Microarray gene expression analysis revealed significant changes in 2012 genes in liver and 967 genes in skeletal muscle of LP offspring. By unknown mechanisms, taurine partially or fully prevented 30% and 46% of these expression changes, respectively. Mitochondrial genes, in particular genes associated with oxidative phosphorylation, were more abundantly changed in LP offspring, with primarily upregulation in liver but downregulation in skeletal muscle. In both tissues, Citrate synthase activity remained unchanged. Taurine preferentially rescued changes in genes concerned with fatty acid metabolism in liver and with oxidative phoshorylation and TCA cycle in skeletal muscle. Conclusion: Gestational protein restriction resulted in lower birthweight associated with significant gene expression changes, which was different in liver and muscle of offspring. However, a major part of the birthweight decrease and the expression changes were prevented by maternal taurine supplementation, implying taurine is a key component in metabolic fetal programming.

Plant Signal Behav. 2009 Jul; 4(7): 660-2
Nakamichi N, Fukushima A, Kusano M, Sakakibara H, Mizuno T, Saito K

The transcriptional/translational feedback loop is thought to play a central role in the circadian clock in Arabidopsis. The loop includes close paralogs of MYB transcription factors CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1, PSEUDO RESPONSE REGULATOR 1[PRR1]), PRR9, PRR7 and PRR5. The prr9 prr7 prr5 triple mutants (d975) and overexpression line of CCA1 (CCA1-ox) are arrhythmic under continuous light conditions followed by light and dark cycles. We recently demonstrated a tight link between the circadian clock and the tricarboxylic acid (TCA) cycle, from the metabolome analysis of d975. The levels of metabolites belonging to TCA cycle, such as 2-oxoglutarate, succinate, fumarate, Citrate and malate increased in d975, whereas those of arginine and ornithine decreased. In this addendum, we further demonstrate that metabolism belonging to TCA cycle in CCA1-ox was partly similar to that of d975. This profiling also supported the linkage between circadian clock and metabolism associated to TCA cycle.

J Bacteriol. 2009 Oct 9;
Koziol U, Hannibal L, Rodríguez MC, Fabiano E, Kahn ML, Noya F

The symbiotic nitrogen-fixing bacterium Sinorhizobium meliloti 1021 (Sm1021) encodes only one predicted aconitase (AcnA) in its genome. AcnA has a significant degree of similarity with other bacterial aconitases that behave as dual proteins: enzymes and post-transcriptional regulators of gene expression. Similar to these bacterial aconitases, AcnA activity was reversibly labile and was regained upon reconstitution with reduced iron. The aconitase promoter was active in root nodules. Mutants in acnA grew very poorly, had secondary mutations and were quickly outgrown by pseudorevertants. The acnA gene was stably interrupted in a Citrate synthase (gltA) null background, indicating that the intracellular accumulation of Citrate may be deleterious for Sm1021 survival. No aconitase activity was detected in this mutant suggesting that the acnA gene encodes the only functional aconitase of Sm1021. To uncover a function of AcnA beyond its catalytic role in the TCA cycle pathway, the gltA acnA double mutant was compared with the gltA single mutant for differences on motility, resistance to oxidative stress, nodulation, and growth on different substrates. However, no differences were found in any of these characteristics.

J Biotechnol. 2009 Oct 4;
Ding MZ, Tian HC, Cheng JS, Yuan YJ

To investigate the metabolic regulation against inoculum density and stress response to high cell density, comparative metabolomic analysis was employed on Saccharomyces cerevisiae under fermentations with five different inoculum sizes by gas chromatography time-of-flight mass spectrometry. Samples from these fermentations were clearly distinguished by principal components analysis, indicating that inoculum size had a profound effect on the metabolism of S. cerevisiae. Potential biomarkers responsible for the discrimination were identified as glycerol, phosphoric acid, succinate, glycine, isoleucine, proline, palmitoleic acid, myo-inositol and ethanolamine. It indicated that enhanced stress protectants in glycerol biosynthesis and amino acid metabolism, depressed citric acid cycle intermediates, as well as decreased metabolites relating to membrane structure and function were involved as the inoculum size of yeast increased. Furthermore, significantly higher levels of glycerol and proline in yeast cells of higher inoculum size fermentation (40gl(-1)) revealed that they played important roles in protecting yeast from stresses in high cell density fermentation. These findings provided new insights into characterizing the metabolic regulation and stress response depending on inoculum density during ethanol fermentation.

BMC Genomics. 2009; 10: 461
Rintala E, Toivari M, Pitkänen JP, Wiebe MG, Ruohonen L, Penttilä M

BACKGROUND: The industrially important yeast Saccharomyces cerevisiae is able to grow both in the presence and absence of oxygen. However, the regulation of its metabolism in conditions of intermediate oxygen availability is not well characterised. We assessed the effect of oxygen provision on the transcriptome and proteome of S. cerevisiae in glucose-limited chemostat cultivations in anaerobic and aerobic conditions, and with three intermediate (0.5, 1.0 and 2.8% oxygen) levels of oxygen in the feed gas. RESULTS: The main differences in the transcriptome were observed in the comparison of fully aerobic, intermediate oxygen and anaerobic conditions, while the transcriptome was generally unchanged in conditions receiving different intermediate levels (0.5, 1.0 or 2.8% O2) of oxygen in the feed gas. Comparison of the transcriptome and proteome data suggested post-transcriptional regulation was important, especially in 0.5% oxygen. In the conditions of intermediate oxygen, the genes encoding enzymes of the respiratory pathway were more highly expressed than in either aerobic or anaerobic conditions. A similar trend was also seen in the proteome and in enzyme activities of the TCA cycle. Further, genes encoding proteins of the mitochondrial translation machinery were present at higher levels in all oxygen-limited and anaerobic conditions, compared to fully aerobic conditions. CONCLUSION: Global upregulation of genes encoding components of the respiratory pathway under conditions of intermediate oxygen suggested a regulatory mechanism to control these genes as a response to the need of more efficient energy production. Further, cells grown in three different intermediate oxygen levels were highly similar at the level of transcription, while they differed at the proteome level, suggesting post-transcriptional mechanisms leading to distinct physiological modes of respiro-fermentative metabolism.

J Bioenerg Biomembr. 2009 Oct 2;
Ferrer I

beta-amyloid (Abeta) deposition, in the form of plaques and amyloid angiopathy, and hyper-phosphorylated tau deposition forming neurofibrillary tangles, dystrophic neurites around beta-amyloid plaques and neuropil threads, are neuropathological hallmarks of Alzheimer's disease (AD) that accumulate in the brain with disease progression. These changes are accompanied by progressive loss of synapses and nerve cell death. Progressive cognitive impairment and dementia are the main neurological deficits. In addition, there is cumulative evidence demonstrating other metabolic disturbances that impair cell function and hamper neuron viability. The main components of the mitochondria are altered: complex IV of the respiratory chain is reduced; complex V which metabolizes ADP to form ATP is oxidatively damaged and functionally altered; and voltage-dependent anion channel VDAC, a major component of the outer mitochondrial membrane that regulates ion fluxes, is damaged as a result of oxidative stress. Mitochondria are a major source of reactive oxygen species that promote oxidative damage to DNA, RNA, proteins and lipids. Protein targets of oxidative damage are, among others, several enzymatic components of the glycolysis, lipid metabolism and cycle of the citric acid that fuel oxidative phosphorylation, mitochondrial respiration and energy production. The lipid composition of lipid rafts, key membrane specializations that facilitate the transfer of substrates, and protein-protein and lipid-protein interactions, is altered as a result of the abnormally low levels of n-3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid) that increase viscosity and augment energy consumption. Abnormal lipid raft composition may also modify the activity of key enzymes that modulate the cleavage of the amyloid precursor protein to form toxic Abeta. This is further complicated by the disruption of the complex VDAC with estrogen receptor alpha at the caveolae which participates, under physiological conditions, in the protection against beta-amyloid. Together, all these alterations converge in reduced energy production and increased energy demands in altered cells. Cell exhaustion is suggested as being a determining element to interpret impaired neuron function, reduced molecular turnover, and enhanced cell death.

J Enzyme Inhib Med Chem. 2009 Dec; 24(6): 1319-31
Chepelev NL, Bennitz JD, Wright JS, Smith JC, Willmore WG

In mammals, aging is linked to a decline in the activity of Citrate synthase (CS; E.C. 2.3.3.1), the first enzyme of the citric acid cycle. We used 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), a water-soluble generator of peroxyl and alkoxyl radicals, to investigate the susceptibility of CS to oxidative damage. Treatment of isolated mitochondria with AAPH for 8-24 h led to CS inactivation; however, the activity of aconitase, a mitochondrial enzyme routinely used as an oxidative stress marker, was unaffected. In addition to enzyme inactivation, AAPH treatment of purified CS resulted in dityrosine formation, increased protein surface hydrophobicity, and loss of tryptophan fluorescence. Propyl gallate, 1,8-naphthalenediol, 2,3-naphthalenediol, ascorbic acid, glutathione, and oxaloacetate protected CS from AAPH-mediated inactivation, with IC(50) values of 9, 14, 34, 37, 150, and 160 muM, respectively. Surprisingly, the antioxidant epigallocatechin gallate offered no protection against AAPH, but instead caused CS inactivation. Our results suggest that the current practice of using the enzymatic activity of CS as an index of mitochondrial abundance and the use of aconitase activity as an oxidative stress marker may be inappropriate, especially in oxidative stress-related studies, during which alkyl peroxyl and alkoxyl radicals can be generated.

Biofizika. 2009 Jul-Aug; 54(4): 748-59
Makarushev SA, Belonogova OV

The physicochemical analysis of parageneses, which is based on the method of thermodynamic potentials, has been applied to study the organic compounds of the system C-H-O, in particular the components of the biomimetically constructed cycles of chemoautotrophic fixation of carbon dioxide, e.g., the reducing cycle of citric acid, 3-hydroxypropionate cycle, and acetyl-CoA pathway. The thermodynamic analysis of the redox mode at different pressures and temperatures has allowed one to isolate a hydrocarbon-organic system capable to independently generate acetate and succinate upon oxidation of deep hydrothermal hydrocarbon fluids emerging on the sea surface. The area of thermodynamic stability (facies) of the hydrothermal system has been determined, which corresponds to the conditions of generation and self-organization of the components of archaic fixation of CO2. A unified system of archaic fixation of CO2 as a combination of the reducing cycle of citric acid, 3-hydroxypropionate cycle, and acetyl-CoA pathway has been proposed, which contains a succinate-fumarate core capable of switching the electron stream in the forward or reverse direction, depending on the redox potential of the surrounding geochemical environment. The geochemical redox mode, which depends on temperature, the structure of a hydrothermal fluid, and the mineral environment, determines the stability of the components of the archaic fixation of CO2 in paragenesis with hydrocarbons and the probability of the self-organization of the cycle.

Aging Cell. 2009 Dec 1; 8(6): 765-768
Williams DS, Cash A, Hamadani L, Diemer T

Reduced dietary intake increases lifespan in a wide variety of organisms. It also retards disease progression. We tested whether dietary supplementation of citric acid cycle metabolites could mimic this lifespan effect. We report that oxaloacetate supplementation increased lifespan in Caenorhabditis elegans. The increase was dependent on the transcription factor, FOXO/DAF-16, and the energy sensor, AMP-activated protein kinase, indicating involvement of a pathway that is also required for lifespan extension through dietary restriction. These results demonstrate that supplementation of the citric acid cycle metabolite, oxaloacetate, influences a longevity pathway, and suggest a tractable means of introducing the health-related benefits of dietary restriction.

BMC Microbiol. 2009; 9: 209
Fürch T, Preusse M, Tomasch J, Zech H, Wagner-Döbler I, Rabus R, Wittmann C

BACKGROUND: In the present work the central carbon metabolism of Dinoroseobacter shibae and Phaeobacter gallaeciensis was studied at the level of metabolic fluxes. These two strains belong to the marine Roseobacter clade, a dominant bacterial group in various marine habitats, and represent surface-associated, biofilm-forming growth (P. gallaeciensis) and symbiotic growth with eukaryotic algae (D. shibae). Based on information from recently sequenced genomes, a rich repertoire of pathways has been identified in the carbon core metabolism of these organisms, but little is known about the actual contribution of the various reactions in vivo. RESULTS: Using 13C labelling techniques in specifically designed experiments, it could be shown that glucose-grown cells of D. shibae catabolise the carbon source exclusively via the Entner-Doudoroff pathway, whereas alternative routes of glycolysis and the pentose phosphate pathway are obviously utilised for anabolic purposes only. Enzyme assays confirmed this flux pattern and link the lack of glycolytic flux to the absence of phosphofructokinase activity. The previously suggested formation of phosphoenolpyruvate from pyruvate during mixotrophic CO2 assimilation was found to be inactive under the conditions studied. Moreover, it could be shown that pyruvate carboxylase is involved in CO2 assimilation and that the cyclic respiratory mode of the TCA cycle is utilised. Interestingly, the use of intracellular pathways was highly similar for P. gallaeciensis. CONCLUSION: The present study reveals the first insight into pathway utilisation within the Roseobacter group. Fluxes through major intracellular pathways of the central carbon metabolism, which are closely linked to the various important traits found for the Roseobacter clade, could be determined. The close similarity of fluxes between the two physiologically rather different species might provide the first indication of more general key properties among members of the Roseobacter clade which may explain their enormous success in the marine realm.

Curr Microbiol. 2009 Sep 19;
Söderberg MA, Cianciotto NP

Legionella pneumophila is an aquatic bacterium that is also the agent of Legionnaires' disease pneumonia. Since L. pneumophila is transmitted directly from the environment to the lung, it is important to understand how legionellae survive at low temperatures. To identify genes that are needed for L. pneumophila growth at low temperature, we screened a population of mutagenized legionellae for strains that are specifically impaired for growth at 17 degrees C. From the 7,400 mutants tested, 11 displayed defects ranging from ca. 10-fold to a complete inability to grow at the low temperature. PCR and sequence analysis were then utilized to identify the genes whose loss had compromised growth. The proteins thereby implicated in low-temperature growth included components of the type II secretion system (LspE, LspG, LspH), a lipid A biosynthetic enzyme (LpxP), a ribonuclease (RNAse R), an RNA helicase (CsdA/DeaD), TCA cycle enzymes (Citrate synthase), enzymes linked to fatty acid (FadB) or amino acid (aspartate aminotransferase) catabolism, and two putative membrane proteins that were, based upon their sequences, unlike previously characterized proteins. Given the magnitude of their mutant's defect, the aspartate aminotransferase, RNA helicase, and one of the putative membrane proteins were the factors most critical for L. pneumophila low-temperature growth. Thus, L. pneumophila not only employs some of the same processes and factors as other bacteria do in order to survive at low temperatures (e.g., LpxP, CsdA), but it also appears to possess novel modes of cold adaptation.

Brain Res. 2009 Nov 17; 1298: 186-93
Zanatta A, Schuck PF, Viegas CM, Knebel LA, Busanello EN, Moura AP, Wajner M

The present work investigated the in vitro effects of D-serine (D-Ser) on important parameters of energy metabolism in cerebral cortex of young rats. The parameters analyzed were CO(2) generation from glucose and acetate, glucose uptake and the activities of the respiratory chain complexes I-IV, of the citric acid cycle enzymes Citrate synthase, aconitase, isoCitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase and malate dehydrogenase and of creatine kinase and Na(+),K(+)-ATPase. Our results show that D-Ser significantly reduced CO(2) production from acetate, but not from glucose, reflecting an impairment of the citric acid cycle function. Furthermore, D-Ser did not affect glucose uptake. We also observed that the activity of the mitochondrial enzyme Citrate synthase from mitochondrial preparations and purified Citrate synthase was significantly inhibited by D-Ser, whereas the other activities of the citric acid cycle as well as the activities of complexes I-III, II-III, II and IV of the respiratory chain, creatine kinase and Na(+),K(+)-ATPase were not affected by this D-amino acid. We also found that L-serine did not affect Citrate synthase activity from mitochondrial preparations and purified enzyme. The data indicate that D-Ser impairs the citric acid cycle activity via Citrate synthase inhibition, therefore compromising energy metabolism production in cerebral cortex of young rats. Therefore, it is presumed that this mechanism may be involved at least in part in the neurological damage found in patients affected by disorders in which D-Ser metabolism is impaired, with altered cerebral concentrations of this D-amino acid.

Cancer Cell. 2009 Sep 8; 16(3): 180-2
Kaelin WG

Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma.

Curr Neuropharmacol. 2009 Mar; 7(1): 60-4
Moharregh-Khiabani D, Linker RA, Gold R, Stangel M

Fumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase. At present, fumaric acid esters (FAE) are licensed for the treatment of psoriasis. Several lines of evidence have demonstrated immunomodulatory effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4(+)- and CD8(+)-T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethyl fumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-kappaB)-dependent transcription of tumor necrosis factor-alpha (TNF-alpha) induced genes in human endothelial cells. Animal studies using a model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE), revealed a reduction of microglia and macrophages in inflamed lesions. A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as "proof of principle" a significant reduction in the number of gadolinium enhancing lesions after 24 weeks of treatment as compared to placebo. Further phase III studies have now started to explore the long-term efficacy of FAE.