Succinate and fumarate

JMJD2 demethylases are inhibited by analogues of the cofactor 2-OG that include N-oxalylamino acids, pyridine dicarboxylates, and related bipyridyl derivatives. Other chemotypes that are also presumed to bind to the active-site Fe(II) include catechols, hydroxamic acids (including the clinically used HD AC inhibitor SAHA/Vorinostat), and tricarboxylic acid cycle intermediates, such as succinate and fumarate [59,62]. 

FIGURE 16-7 Reactions of the citric acid cycle. The carbon atoms shaded in pink are those derived from the acetate of acetyl-CoA in the first turn of the cycle these are not the carbons released as CO2 in the first turn. Note that in succinate and fumarate, the two-carbon group derived from acetate can no longer be specifically denoted because succinate and fumarate are symmetric molecules, C-l and C-2 are indistinguishable from C-4 and C-3. The number beside each... 

Most anaerobically functioning mitochondria use endogenously produced fumarate as a terminal electron-acceptor (see before) and thus contain a FRD as the final respiratory chain complex (Behm 1991). The reduction of fumarate is the reversal of succinate oxidation, a Krebs cycle reaction catalysed by succinate dehydrogenase (SDH), also known as complex II of the electron-transport chain (Fig. 5.3). The interconversion of succinate and fumarate is readily reversible by FRD and SDH complexes in vitro. However, under standard conditions in the cell, oxidation and reduction reactions preferentially occur when electrons are transferred to an acceptor with a higher standard redox potential therefore, electrons derived from the oxidation of succinate to fumarate (E° = + 30 mV) are transferred by SDH to ubiquinone,... 

C4 chemistry on succinic and fumaric acids, C5 chemistry on furfural and levu-linic acids, C6+ on lysine and sorbitol. Large amounts of BTX are not available, but some natural complex aromatic molecules can be extracted with high benefit. 

Fig. 6. Two pathways leading from propionate to pyruvate. The methyl citrate pathway gives retention of the carbon positions. The methylmalonyl-CoA pathway proceeds via the symmetrical intermediates succinate and fumarate, and the carbon atoms in pyruvate therefore reflect the scrambling that may take place as a consequence of the symmetry of these intermediates. If metabolic channeling takes place, only one of the two possible labeling patterns of malate is formed...

The next reaction occurs in the cytoplasm. Malate is transported to the cytoplasm by a dicarboxylate carrier which is specific for malate, succinate, and fumarate and which requires the entry of P, or one of these dicarboxylate anions. Cytoplasmic malate is then converted to oxaloacetate by cytoplasmic malate dehydrogenase ... 

Evidence suggests that elevated levels of the tricarboxylic acid cycle intermediates fumarate and succinate (the latter a product of hydroxylase catalysis) in some tumors may lead to activation of the HIF system via hydroxylase inhibition (97,98). Both succinate and fumarate are PHD2 inhibitors competing with 20G for binding to Fe(II) (99, 100). 

Childs, S.L. Chyall, L.J. Dunlap, J.T. Smolenskaya, V.N. Stahly, B.C. Stahly, G.P. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J. Am. Chem. Soc. 2004, 126, 13,335-13,342. 

Figure 4-8. Voltammetry of succinate dehydrogenase adsorbed on a rotating PGE electrode in the presence of equal concentrations of succinate and fumarate.

Oxidation-reduction potentials are expressed in volts relative to the standard hydrogen electrode at 0 volts, and represent the tendency of a compound to lose electrons (oxidation) or gain electrons (reduction). Various enzyme systems in respiration reactions (e.g., the cytochromes) utilizing ascorbic acid, hemoglobin, as well as reactions in the Krebs cycle (succinic and fumaric acids) involve electron transfers. Drugs can affect all these systems, and the consequences must be taken into account. 

A one-month-old baby boy was brought to the hospital showing severely delayed development and cerebral atrophy. Blood tests showed high levels of lactate and pyruvate. By three months of age, very high levels of succinate and fumarate were found in the urine. Fumarase activity was absent in the liver and muscle tissue. The baby died at five months of age. This was the first reported case of fumarase deficiency and the defect was recognized too late for effective therapy to be administered. What reaction is catalyzed by fumarase How would a deficiency of this mitochondrial enzyme account for the baby s symptoms and test results ... 

K6kuI6 investigated the electrolysis of maleic acid and brom-maleic acid. The former gave acetylene, besides a small quantity of succinic and fumaric acid the latter, on the contrary, gave only hydrobromic acid and carbon monoxide. Like malic fumaric acid, at the beginning of the experiment, gave only pure acetylene, but after the operation had continued... 

Succinic and fumaric acids are key metaboiites in the citric acid pathway. Adipic acid is used in the synthesis of nyion. The isomers of phthaiic acid are used in making poiyesters. See Speciai Topic C in WileyPLUS for further information on poiymers. 

When he found that malate and oxaloacetate had the same action as succinate and fumarate, and that their intervention is abolished by malon-ate, Szent-Gybrgyi introduced the oxaloacetate-malate S3rstem into his scheme, which became ... 

Apart from reactions involving constituents of the citrate cycle such as a-oxoglutarate, oxaloacetate, succinate and fumarate, reactions involving the triose phosphates and pyruvate from carbohydrate metabolism and acetyl-CoA and glycerol from fat metabolism also fall into this category. These compounds provide the carbon skeletons for more complex molecules, while in certain cases simple carbon groupings may be introduced into molecules in various ways, e.g. as methyl (CH3) or formyl (-CHO) groups, or as carbon dioxide. 

In the first of these three reactions two hydrogen atoms are removed from succinate and fumarate is formed. In this dehydrogenation the hydrogen acceptor is not NAD but a flavo-protein (FF). The flavoprotein is in fact the enzyme succinate dehydrogenase which contains flavin adenine dinucleotide (FAD) as a covalently bound prosthetic group and also non-haem iron. It differs from other enzymes of the citrate cycle in being an integral constituent of the inner mitochondrial membrane and directly linked to the electron-transport chain. 

Succinate and fumarate are symmetrical molecules, and label that passes through these intermediates can become scrambled. Introduction of label from a-ketoglutarate into succinate (Figure 9)... 

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