Tricarboxylic acid cycle intermediates

Senior, A.E. Shenatt, H.S.A. (1968). Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycemic fatty acids. Oxidative phosphorylation and mitochondrial oxidation of pyruvate, 3-hydroxybutyrate and tricarboxylic acid-cycle intermediates. Biochem. J. 110,499-509. 

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]. 

All plants contain a PEPCase enzyme which, among other likely roles (Vidal et al., 1986), serves to replenish tricarboxylic acid cycle intermediates that are consumed during ammonium assimilation (Latzko Kelly, 1983). The role of this enzyme, other than its presumed housekeeping function, has not been studied in any detail and its activity is probably not controlled by environmental factors. Isoforms of PEPCase have been observed in many plants (C3, C4 and CAM) for example, in rice five isoforms have been detected immunologically and in most plants two to four bands that react with anti-PEPCase antibodies are found (Matsuoka Hata, 1987). It is not clear how these isoforms arise, e.g. by post-translational modification of one form, or whether all of these forms are products of different genes. The housekeeping-type PEPCase enzyme, concerned with anaplerotic functions, is distinct from other PEPCase enzymes that function in plants with C4 and CAM metabolism (see below). 

This method can be used to compensate for inhibition of a biochemical pathway which results in a deficiency of an essential metabolic product. Detailed variations of the method are provided by Dayan et al.7 and Amagasa et al.1 The inhibitor concentration should be no higher than that required for strong herbicidal effect. Metabolite concentrations should be below that which is phytotoxic. For example, certain amino acids such at methionine, are growth inhibitors at relatively low concentrations. So, in preliminary work, dose-response studies should be done with amino acids to find the maximum concentrations that do not inhibit growth. Then, seeds of test plants should be imbibed in solutions of the phytotoxin with and without metabolite solutions. Amino acids, tricarboxylic acid cycle intermediates, vitamins, nucleotides, and reducing agents have all been used in complementation studies to elucidate modes of action of a variety of phytotoxins. Examples of each of these is provided by Dayan et al.7... 

Table 5.12. Steady-state content of the tricarboxylic acid cycle intermediates in several cestodes... 

Beis, I. Barrett, J. (1979). The contents of adenine nucleotides and glycolytic and tricarboxylic acid cycle intermediates in activated and non-activated plerocercoids of Schistocephalus solidus (Cestoda Pseudophyllidea). International Journal for Parasitology, 9 465-8. 

Kennedy EP, Lehninger AL (1949) Oxidation of fatty acids and tricarboxylic acid cycle intermediates by isolated rat liver mitochondria. J Biol Chem 179 957-972 Klein R, Conquist A (1967) A consideration of the evolutionary and taxonomic significance of some biochemical, micromorphological and physiological characteristicsm in the Thallophytes. Q Rev Biol 42 105-296... 

Pyruvate Carboxylase Pyruvate carboxylase catalyzes the car-boxylation of pyruvate to oxaloacetate - both the first committed step of gluconeogenesis from pyruvate and also an important anaplerotic reaction, permitting repletion of tricarboxylic acid cycle intermediates and hence fatty acid synthesis. The mammalian enzyme is activated aUosterically by acetyl CoA, which accumulates when there is a need for increased activity of pyruvate carboxylase to synthesize oxaloacetate to permit increased citric acid cycle activity or for gluconeogenesis (Attwood, 1995 Jitrapakdee and Wallace, 1999). 

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). 

The major end-product of glucose metabolism is CO2 (55% of glucose carbon), together with small amounts of acetate (3%) and succinate (4%). For T. brucei procyclics 17% of the glucose carbon was recovered as succinate and 8% as alanine (9). The production of CO 2 was not measured. Proline and the tricarboxylic acid cycle intermediates a-ketoglutarate and succinate also support respiration in T. rhodesiense. 

Further support for this hypothesis was obtained from the results of feeding various labeled tricarboxylic acid cycle intermediates to tobacco plants and root cultures (135, 136). 

Cheng S.-C (1972) Compartmentation of Tricarboxylic Acid Cycle Intermediates and Related Metabolites, in Metabolic Compartmentation m the Brain (Balazs R and Cremer J E, eds ), pp 107-118 MacMillan, London... 

Tricarboxylic Acid Cycle Intermediates and the Control of Fatty Acid Synthesis and Ketogenesis... 

Deamination removal of the amino group (-NH ) from a chemical compound (usually an amino acid). MetaboUcally, D. may occur by a) oxidative D. of amino acids to ketoacids and ammonia by Flavin enzymes (see) and pyridine nucleotide enzymes (see Amino acids, Table 3) b) Transamination (see) in which an amino group is transferred fiom an amino to a keto compound, and c) removal of ammonia from a compound, leaving a double bond, e.g. the D. of L-aspartate to marate, and the D. of histidine to urocanic acid. IVansamination is important in the synthesis of amino acids from tricarboxylic acid cycle intermediates the reverse reactions feed excess amino acids into the tricarboxylic acid cycle for oxidation. 

This reaction is stimulated by adding the tricarboxylic acid cycle intermediates, and citric acid is particularly effective in that respect. Thus, is interesting that in starved diabetic rats acetyl CoA carboxylase activity is reduced. Furthermore, Frohman and his associate have found that the concentration of the Krebs cycle intermediate is greatly reduced in liver of diabetic rats [141]. 

Catabolism of amino acids, except for leucine and lysine, results in synthesis of tricarboxylic acid cycle intermediates or the production of pyruvate (see p. 210). Conversion of the latter into glucose then takes place as shown in Fig. 9.20. The tricarboxylic acid cycle intermediates enter the cycle and are converted into malate. 

Peuhkurinen KJ (1982)Accumulation and disposal of tricarboxylic acid cycle intermediates during propionate oxidation in the isolated perfused rat heart. Biochem. Biophys. Acta 721 124-134 Randle PJ, Tubbs PK (1979) Carbohydrate and fatty acid metabolism. In Berne, RM, Spherelakis N, Geiger SR (eds) Handbook of Physiology, The Cardiovascular System. Bethesda pp 804-844... 

Gibala, M.J., Tarnopolsky, M.A., and Graham, T.E., Tricarboxylic acid cycle intermediates in human muscle at rest and during prolonged cycling. Am J Physiol, 272, E239, 1997. 

FIGURE 13.2 The role of BCAAs in energy metabolism. Following removal of their amino group by reversible transamination (a) and the irreversible decarboxylation of the resulting branched-chain a-keto acids to form coenzyme A (CoA) compounds (b), BCAAs act as precursors of acetyl CoA and tricarboxylic acid cycle intermediates. CoA-SH, reduced form of CoA IB-CoA, isobutyryl-CoA ILE, isoleucine IV-CoA, isovaleryl-CoA KIC, a-ketoiso-caproate KIV, a-ketoisovalerate KMV, a-keto-P-methylvalerate LEU, leucine MB-CoA, a-methylbutyryl-CoA NADHj, reduced nicotinamide adenine dinucleotide VAL, valine. 

Usol tseva VA, Pobedinskaya AI, Kobenina NM (1970) Thermographic analysis of Krebs tricarboxylic acid cycle intermediates and their systems. Izv Vyss Ucheb Zaved Khimiya... 

Kloos D, Derks RJE, Wijtmans M, Lingeman H, Mayboroda OA, Decider AM, Niessen WMA, Giera M (2012) Derivatization of the tricarboxylic acid cycle intermediates and analysis by online solid-phase extraction-liquid chromatography-mass spectrometry with positive-ion electrospray ionization. J ChromatogrA 1232 19-26... 

The H NMR spectroscopy was successfully applied as reliable diagnostic method of heart failure patients. The metabolite profiles obtained from urine NMR measurement exhibited increased levels of ketone bodies accompanied by reduced levels of tricarboxylic acid cycle intermediates, suggesting altered energy metabolism including changes in the tricarboxylic acid cycle and fatty acid metabolism. Perturbations in metabolic pathways involved in methylmalonate and nucleotide metabolism were observed. 

Stahl, K.W., Schafer, G. and Lamprecht, W. (1972), Design of a high efficiency liquid chromatograph using specific detection and its evaluation for analysis of tricarboxylic acid cycle intermediates and related compounds on a nano-equivalent scale. J. Chromatogr. Sci., 10,94. 

---