The origin of free brain malonate

Riley, Kathy M.; Dickson, Andrew C.; Koeppen, Arnulf H.

doi:10.1007/bf00965698

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…We tested also malonic acid but without success, even with a K i = 71 μ M, in the order of magnitude of EBHA. Free malonate is present at a high concentration in the rat brain (192 nmol/g wet weight) [14], but the reason why it did not present any effect on serine racemase remains to be elucidated. Regarding the toxicity of these compounds, we injected 500 μ g/10 μ L i.t.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Effect of Rat D-Serine Racemase Inhibitors, L-Serine-O-Sulfate, and L-Erythro-3-Hydroxyaspartate in an Arthritic Pain Model

Laurido

Hernández

Constandil

2012

The Scientific World Journal

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N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D-serine, synthesized from L-serine by a pyridoxal 5′-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L-serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 μg/10 μL) and LEHA (100 μg/10 μL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 μg/10 μL of D-serine were injected intrathecally. Since no in vivo results have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain.

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Section: Discussionmentioning

confidence: 99%

Antinociceptive Effect of Rat D-Serine Racemase Inhibitors, L-Serine-O-Sulfate, and L-Erythro-3-Hydroxyaspartate in an Arthritic Pain Model

Laurido

Hernández

Constandil

2012

The Scientific World Journal

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“…Clinical and biochemical studies of MCD deficiency, a rare inborn error of metabolism, provide another potential mechanism of action of MCD inhibition based on the pathological accumulation of malonylCoA (FitzPatrick et al, 1999;Sacksteder et al, 1999). Patients harboring an inactivating mutation of MCD exhibit elevated cellular levels of malonyl-CoA (FitzPatrick et al, 1999), resulting in high serum and urine levels of malonate, derived from the hydrolysis of malonyl-CoA to free malonate (Riley et al, 1991). Malonate is a dicarboxylic acid that is a potent inhibitor of succinyl-CoA dehydrogenase, a key component of complex II of the electron transport chain and Kreb's cycle (Koeppen and Riley, 1987).…”

Section: Discussionmentioning

confidence: 99%

Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells

Zhou

Simpson

et al. 2009

Oncogene

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Fatty acid synthase (FAS) inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro, which may involve malonyl-CoA metabolism. These findings have led to the exploration of malonyl-CoA decarboxylase (MCD) as a potential novel target for cancer treatment. MCD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetylCoA. Malonyl-CoA is both a substrate for FAS and an inhibitor of fatty acid oxidation acting as a metabolic switch between anabolic fatty acid synthesis and catabolic fatty acid oxidation. We now report that the treatment of human breast cancer (MCF7) cells with MCD small interference RNA (siRNA) reduces MCD expression and activity, reduces adenosine triphosphate levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we synthesized a small-molecule inhibitor of MCD, 5-{(Morpholine-4-carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-pentanoic acid methyl ester (MPA). Similar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a number of human breast cancer cell lines in vitro. Taken together, these data indicate that MCD-induced cytotoxicity is likely mediated through malonyl-CoA metabolism. These findings support the hypothesis that MCD is a potential therapeutic target for cancer therapy.

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“…In fact, the biosynthesis of this dicarboxylic acid is poorly understood. The study of Riley et al (56) on the origin of free brain malonate suggests that it could be the result of the following sequential reactions: acetyl-CoA 3 malonyl-CoA 3 malonate. The first reaction FIG.…”

Section: Discussionmentioning

confidence: 99%

“…The lipoyl and/or the octanoyl group are attached to the H apoprotein by the lipoate transferase (9). could be catalyzed by the cytosolic acetyl-CoA carboxylase, and the latter step could occur by transfer of the CoA group from malonyl-CoA to succinate and/or acetoacetate (56). Malonate could enter into mitochondria via the dicarboxylic acid transporter characterized by Vivekananda et al (57).…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid and Lipoic Acid Biosynthesis in Higher Plant Mitochondria

Gueguen¹,

Macherel²,

Jaquinod³

et al. 2000

Journal of Biological Chemistry

174

139

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Fatty acid and lipoic acid biosynthesis were investigated in plant mitochondria. Although the mitochondria lack acetyl-CoA carboxylase, our experiments reveal that they contain the enzymatic equipment necessary to transform malonate into the two main building units for fatty acid synthesis: malonyl-and acetyl-acyl carrier protein (ACP). We demonstrated, by a new method based on a complementary use of high performance liquid chromatography and mass spectrometry, that the soluble mitochondrial fatty-acid synthase produces mainly three predominant acyl-ACPs as follows: octanoyl(C8)-, hexadecanoyl(C16)-, and octadecanoyl (C18)-ACP. Octanoate production is of primary interest since it has been postulated long ago to be a precursor of lipoic acid. By using a recombinant H apoprotein mutant as a potential acceptor for newly synthesized lipoic acid, we were able to detect limited amounts of lipoylated H protein in the presence of malonate, several sulfur donors, and cofactors. Finally, we present a scheme outlining the new biochemical pathway of fatty acid and lipoic acid synthesis in plant mitochondria.Lipoic acid (6,8-thioctic acid or 1,2-dithiolane-3-pentanoic acid) is a sulfur-containing cofactor involved in several multienzyme complexes such as pyruvate dehydrogenase, ␣-ketoglutarate dehydrogenase, branched-chain keto acid dehydrogenase, and glycine decarboxylase complex. The carboxyl group of lipoic acid is attached to the dihydrolipoamide acyltransferase subunits (E 2 ) of the keto acid dehydrogenase complexes and to the H protein of the glycine decarboxylase complex, by an amide linkage to the ⑀-amino group of a specific lysine (1-4).Recent studies have highlighted the potential of free lipoic acid and dihydrolipoic acid as powerful metabolic antioxidants that are able to scavenge the reactive oxygen species, to recycle other antioxidants (vitamin C, glutathione, and vitamin E), and even to intervene in redox regulation of gene transcription (5, 6). Consequently, lipoic acid is now increasingly used as a therapeutic agent in pathologies associated with oxidative stress (for a review see Packer et al. (5)).In prokaryotic cells, Parry (7) and White (8) showed by labeling experiments that octanoic acid was a direct precursor of lipoic acid, 6-thiooctanoate and 8-thiooctanoate being possible intermediates in lipoic acid biosynthesis (9 -11). Mutant strains of Escherichia coli defective in lipoic acid biosynthesis have allowed the isolation of several genes involved in lipoic acid biosynthesis (12)(13)(14). The characterization of the lip locus revealed that it contained the lipA gene encoding for a 36-kDa protein (14 -16). Despite the fact that LipA activity has never been measured in vitro, the protein is expected to be related to a lipoate synthase. Sequence similarity to biotin synthase strongly suggests that lipA encodes a sulfur insertion enzyme analogous to biotin synthase and, consequently, that the sulfur insertion mechanisms of the two systems could be related (15,16). Moreover, biotin synthase is known to ...

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The origin of free brain malonate

Cited by 11 publications

References 31 publications

Antinociceptive Effect of Rat D-Serine Racemase Inhibitors, L-Serine-O-Sulfate, and L-Erythro-3-Hydroxyaspartate in an Arthritic Pain Model

Antinociceptive Effect of Rat D-Serine Racemase Inhibitors, L-Serine-O-Sulfate, and L-Erythro-3-Hydroxyaspartate in an Arthritic Pain Model

Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells

Fatty Acid and Lipoic Acid Biosynthesis in Higher Plant Mitochondria

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