TRICARBOXYLIC ACIDS CYCLE
(synonym: a tricarbonic acid cycle, a cycle of citric acid, a citrate cycle) — the major recycling at aerobic organisms (animals, plants and microorganisms); represents reaction sequence of oxidizing transformation dicarbonic and the tricarboxylic acids providing full oxidation of products of metabolism of proteins, fats and carbohydrates to C02 carbon dioxide and water. In a metabolism and energy (see) Since c. takes the central place since its primary substrate — activated acetic to - that, or the active acetyl rest — atsetil-KOA (see Coenzymes) — is one of the most important general intermediate products which are formed during exchange of all feedstuffs — proteins, lipids and carbohydrates (see. Nitrogen metabolism, Lipometabolism, Carbohydrate metabolism). Essence Since c. consists in oxidizing decomposition of the acetyl rest to C02 and water therefore energy is released, edges stocks up in the form of ATP (see. And denozinfosforny acids). At the person and the highest animals apprx. 2/3vsey the energy received from nutrients it is released in Since by c. (see Bio-energetics). Except formation of energy, Since c. provides formation of C02 necessary for reactions of a carboxylation (see), napr, prp synthesis of fatty acids (see), purine bases (see), the pirimidinovy bases (see), a gluconeogenesis (see Glucose), etc.
Representations about Since c. formed gradually. By 1920 thanks to Tunberg's researches (T. Thunberg) was known that many organic to - you are oxidized in an organism with high speed. In 1935 A. Saint-Djyordyi established that nek-ry di - and tricarboxylic to - you, about to-rykh it is known now that they enter in Since, accelerate oxidation of glucose and other substances in fabrics. G. Krebs and it sotr. carefully investigated aspects of oxidation of pyruvate (see Iiirovinogradnaya acid) in the crushed muscle of a pigeon. They, in particular, showed that anion lemon to - you citrate catalystically accelerate this process. Having generalized a swap and literary data, G. 'Krebs and W. A. Johnson in 1937 formulated idea of the cyclic nature of process and called it «a cycle of citric acid». In 1940 Krebs offered the scheme Since to c., later almost not changing. In 1953 Krebs for the opening was conferred the Nobel Prize.
Since c. consists of 8 consecutive reactions, in to-rykh participate di - and tricarboxylic to - you are (fig.). It should be noted that organic to - you in fabrics are in the dissociated state (see Dissociation in chemistry) therefore for their designation use names of their anions, napr, citrate more often (see. Citric acid), oxaloacetate (see Oxaloacetic acid), succinate (see. Succinic acid), ct-ketoglutarate (see. To an etogl spherical acid), fumarates (see. Fumaric acid), malate (see. Malic acid), etc.
First reaction Since c. — it is condensation atsetil-KOA with mother substance of a cycle — oxalacetic to - that (oxaloacetate):
Are as a result formed tnesti-carbon lemon to - that (citrate), given the name to all cycle, and free recovered To A (HS КоА). Reaction citrate-synthase (KF 188.8.131.52) catalyzes enzyme. Intermediate compound of this process is, apparently, connected with enzyme of a tsitril-Co, to-ry it is spontaneously hydrolyzed. Formation of citrate carries -
sya to endergonic reactions (see) also is implemented thanks to existence of a high-energy energy-rich bond (~ — makroergnchesky communication) between the acetyl rest and KOA in a molecule atsetil-KOA
Substrate of oxidation in Since c. — the active acetyl rest atse-til-KOA — is formed in an organism in the different ways: from lipids at R-okislenpi fatty acids (see), from carbohydrates at oxidizing decarboxylation of pyruvate, from proteins at a catabolism of many amino acids. One of amino acids (a lysine, phenylalanine, tyrosine, a leucine and pzoleytsin) are capable to turn directly in atsetil-KOA, others (alanine, cysteine, serine and glycine) form previously pyruvate.
Disturbance of a normal current Since c. involves serious disorders of metabolism. Most often it is connected with a lack of the first intermediate product of a cycle — oxaloacetate. In this case in a liver collect atsetil
ny groups, to-rye a nesposoona to be oxidized and begin to turn strenuously into ketone bodies (see). Their excess education leads to development patol. states, napr, a metabolic acidosis (see). The ketosis which is usually accompanying an imbalance between oxidation of fats (see) and a catabolism of carbohydrates (see) arises in all cases of relative shortage of oxaloacetate in comparison with KOA when the atsetpl-Koa cannot enter completely condensation with oxaloacetate (i.e. the first reaction Since c.). The lack of oxaloacetate can develop in conditions when in a liver a large amount of alcohol is metabolized, and also at starvation (see) and at a diabetes mellitus (see a diabetes mellitus).
Second reaction Since c. — reversible transformation lemon to - you in izolpmonny. It proceeds through a mode of formation ^ис-акони-товой to - you also are catalyzed by enzyme akonitat-hydratase (aconitase; KF 184.108.40.206). During reaction lemon to - that loses a water molecule and turns in nenasygtsen-
Fig. The scheme of a cycle of tricarboxylic acids and its metabolic bonds in an organism (GTF — guaiozintrifosfat, GDF — guanozindifosfat, Fneorg. — phosphate inorganic) *
ny ^ wc-aconitic to - that, edges attaches water, but in other way, and forms isolemon to - that:
Balance of this reversible test in fiziol. conditions it is strongly shifted to the left. To the share lemon to - you fall 90%, and on a share an isolemon - ache — only 6%. The course of process in the necessary direction is provided with permanent care isols-monnoy to - you from a circle of reaction as a result of the subsequent transformations.
Third reaction Since c. — oxidation and simultaneous decarboxylation (see) isolemon to - you therefore it is formed and - ketoglu-tarovaya to - that:
Value of this reaction catalyzed by an isocitratedehydrogenase is very big since it, apparently, limits the speed of all cycle of tricarboxylic acids.
In tissues of animals two various isocitratedehydrogenases are found.,
the Main role in Since c. plays NAD-za-visimy allosteric
enzyme (KF 220.127.116.11): it is localized only in mitochondrions, has a pier. the weight (weight) of 330 Ltd companies, consists of 8 subunits and for manifestation of activity needs bivalent cations of Mp2 + or Mg2+. Activators of this enzyme are ADF and citrate, inhibitor — NAD-N. Found
participates in mitochondrions and NADF-zavisimaya cytosol of an izotsitratdsgidrogenaz (KF 18.104.22.168) in Since c. in insignificant degree. As an intermediate product in the reaction catalyzed by this enzyme it is formed shchavelevo-amber to - that,
Izotsitratdegidrogenaznaya reaction is the first in Since oxidation-reduction process. At the same time two hydrogen atoms which are chipped off from substrate by means of various carriers, in this case — OVER (a fir-tree of II and-kotinamidadenindinukleotid), are involved in a respiratory chain (see biological oxidation) and, being oxidized oxygen of air, turn into a water molecule.
Fourth reaction Since c. — oxidizing decarboxylation and - keto-glutaric to - you with education suktsinil-KOA:
This process is difficult. It is catalyzed by the multifermental complex including three fermental proteins and proceeds in several stages. Operates on the first stage and-ketoglutaratdegidrogenaza (an oksoglu-taratdegidrogenaza; KF 22.214.171.124). As a coenzyme thiamine pyrophosphate — TPF is used here (see Thiamin). a-Ketoglutarat it is decarboxylized, and the activated four-carbon rest joins TPF:
where Ei — and - ketoglutaratdegidroge-naza.
Further under the influence of the transsuktsi-nilaza using as a coenzyme amide of lipoic acid (see) there is an oxidation of the four-carbon rest to succinyl and its transfer on lipoic to - that
to its simultaneous recovery:
where L — lipoic to - that, E2 — a trance-suktsinilaza. At the third stage of the fourth reaction Since c. under the influence of the same transsuktsinilaza a bough-tsinilny the rest is moved on To And with education suktsinil-KOA, to-ry is exposed to further turning into Since c.:
Then got into condition amide lipoic to - you are oxidized under the influence of flavin enzyme — a lipoamid-dehydrogenase (lipoil-dehydrogenases; KF 126.96.36.199). All process proceeds to similarly oxidizing decarboxylation the feast about wine of is glad ache> acids (see), to-ry leads to formation of substrate Since c. — atsetil-KOA. It is necessary to emphasize that the end product of the reaction catalyzed transsuktsinilazy — suktsinil-KOA is powerful inhibitor of all reaction.
Fifth reaction Since c.-^ transformation suktsinil-KOA in amber to - that, (KF 188.8.131.52) catalyzed suktsinil-KOA-spntetazoy. Reaction is interesting that sodryazhyonno with it so-called phosphorylation (see) at the level of substrate, in the course to-rogo from GDF (guanozindi-phosphate) and Fneorg is made. (inorganic phosphate) GTF is synthesized (guano-zintrifosfachg), and high-energy communication suktsinil-KOA is transformed to energy-rich phosphatic bond of GTF:
This reaction, in turn, proceeds in three consecutive stages, in to-rykh the same fermental protein (E) participates:
E + suktsinil-KOA + Ftseorg.^ E-succinyl ~ F + KOA E-succinyl ~ <Ф±Е ~ F
succinate E ~ F + <ГДФ±Е + GTF. The formed GTF with the participation of a mitochondrial nucleoside-difos-veils-kinase (KF 184.108.40.206) can easily react perefosfo-rilirovaniye with ADF therefore ATP is formed:
GTF - f ADF^±gdf + ATP,
the Sixth reaction Since c. — oxidation amber to - you to fumarovop under actions are mute a bough tsinatdeg and d r about a gene elements
(see). Hydrogen acceptor in this reaction is FAD — prosthetic group of enzyme;
Reaction product thanks to existence of a double bond theoretically can exist in a look cis-and trans-isomers. Fumaric to - that represents trans-isomer. i | wc-ii30Mep — maleic to - that is in these conditions is not formed.
Seventh reaction Since c. — hydration fumaric to - you — is catalyzed fumarating - hydratase (fumarase; KF 220.127.116.11) having almost absolute stereospecificity. It is expressed that ions of H+ and OH" waters join a fumarat on a trance - to type and that as reaction product only L-malic acid is formed:
The eighth reaction completing Since c., consists in regeneration of mother substance of a cycle — oxalacetic to - you (oxaloacetate) as a result of oxidation apple to - you under action malatdegidro-
gynases (see), serves as hydrogen acceptor in this reaction OVER:
Thus the cycle became isolated. Formed oxalacetic to - that (oxaloacetate) enters condensation with a new molecule atsetil-KOA, and the following round of a cycle begins.
So, for one turn Since c. there is a full oxidation of one acetyl rest connected to KOA therefore first of all energy is released. In Since c. 4 reactions of a degidro-genirovaniye enter (reactions 3, 4, 6 and 8 cycles). Serves as hydrogen acceptor in three of them OVER, in a respiratory chain at the same time about 3 molecules ATP (see biological oxidation), i.e. only 9 molecules ATP are formed. In one reaction (sixth) when hydrogen acceptor is FAD, 2 molecules ATP are formed. And, at last, in the fifth reaction as a result of a substrate fosforilirova-nnya 1 molecule GTF is formed that is equivalent to 1 molecule ATP. Total, for one turn Since c. the energy accumulated in 12 molecules ATP collects. Thus energy value Since c. it is very big. But not only to these its value is defined. Yek-ry amino acids can be a source of intermediate products Since to c. e.g., from asparaginic to - you are formed oxalacetic to - that, and from glutaminic to - you, proline, a histidine and arginine — and - keto-glutaric to - that. In the drawing communication Since is presented to c. with exchange of the major substances.
Since c. it is connected not only with a catabolism, but also with anabolic processes. Formed in the course Since c. C02 carbon dioxide is partially used for reactions of a karboksiliroyeaniye (see). Intermediate products of a cycle of tricarboxylic acids can be removed from a cycle and also participate in synthesis of various connections. Oxaloacetate serves as the predecessor of carbohydrates in the course of a gluconeogenesis, turning in fosfoyenolpiruvat under the influence of a fosfoyenolpiruvat-carboxykinase (KF 18.104.22.168). As a result of transamination (see) oxaloacetate turns into aspartate — the predecessor of pirimidinovy nucleotides, nek-ry amino acids and urea (through arginine). a-Ketoglutarat at transaminiro-vanip turns into a glutamate —
the predecessor of purine nucleotides, piperidic acid (see) — DIN To — and other amino acids. Suktsinil-KOA, being condensed with glycine (see), participates in synthesis of porphyrines (see). Primary substrate Since c. — atsetil-KOA — it is used in synthesis fat to - t, steroids (see), and also in reactions of acetylation, napr, at synthesis of acetylcholine (see).
Thus, Since c. is one of most important «junction stations» of a metabolism and energy, on a cut ways of transformation of various connections are crossed that provides unity and continuous communication of a metabolism in an organism. Nek-ry features of course Since are noted by c. in different fabrics. In a cardiac muscle practically all atsetil-KOA is oxidized in the course Since c., and in a liver and fatty tissue a considerable part atsetil-KOA is spent for biosynthesis fat to - t and steroids.
In tissue of a brain plays an essential metabolic role at-aminobu-tiratny a way. At the same time and - ketoglu-tarat as a result of direct amination or transamination turns into a L-glutamate, from to-rogo as a result of decarboxylation with the participation of a glutamatdekarboksila-za (KF 22.214.171.124) GAMK is formed. The glutamate and GAMK perform specific functions of neurotransmitters in a brain.
Since c., apparently, is absent in mature erythrocytes though its nek-ry enzymes in them are found. Special value in cells, in to-rykh occurs synthesis of hemoglobin (see), has a specific collateral way Since c., so-called succinate-glitspno-vy cycle (Shemin's cycle). This way begins with condensation suktsinil-KOA with glycine, as a result the cut is formed 6-aminolevu-linovaya to - that. From it after deamination it turns out and - ketogluta-rovy semi-aldehyde, and then and - the keto-glutarate turning into suktsi-Nile-KOA. For one turn of this cycle there is an oxidation to C02 and ammonia of one molecule of glycine. An intermediate product of this cycle — 6-aminolevulinic to - that is is the most important biosynthetic predecessor of porphyrines.
Since c. holds central position in system of the basic processes delivering and reserving energy in cells therefore regulation of this cycle plays a cardinal role in adaptation of an organism to change of conditions of the environment. Regulatory mechanisms support a certain ratio between activity Since in c. and other metabolic ways (a gluconeogenesis, ureo-genesis etc.), control and
carry out constant intake of ATP depending on the energy demands existing at present, provide transformation of excess of carbohydrates in fat to - you, control an economical expenditure fat to - t and limit use of pyruvate in case of deficit of carbohydrates. Speed Since c. sensitively reacts to metabolic requirements of fabric and to the nature of the substrates delivered to body. For functioning Since c. receipt in a matrix of mitochondrions (see) pyruvate or other potential source atsetil-KOA is necessary. Through an inner membrane of mitochondrions there can pass only a small amount of substrates according to the mechanism of passive transfer (see Membranes biological). The majority of substrates is transported on the special acyltransferring protein by so-called active transport. The acyltransferring proteins in an inner mitochondrial membrane effectively regulate concentration of substrates Since c. in a matrix of mitochondrions. Speed of receipt of acetyl groups and availability of oxaloacetate are one of the main factors determining the general speed Since by c.
Intensity of oxidizing stages Since c. substantially is defined by the speed of reoxidation of NAD-N. In nek-ry cases it a limitit rutsya by the speed of receipt of 02, however at aerobic organisms it usually is defined by concentration of ADF and (or) Fneorg. necessary for transformation of ADF into ATP at oxidizing phosphorylation. At excess of ATP intensity of phosphorylation decreases due to reduction of concentration of ADF. It conducts to a shortcoming oxidized by NAD and FAD that, in turn, activity of dehydrogenases oppresses (see). In a different way regulation Since c. influence on a stage phosphorus silt of an irovaniye Since c is connected with a fos-forplirovaniye of adenylic system., the demanding GDF. In this case the defining role is played by the size of a ratio of GTF/GDF. When sizes of the relations OVER • N/NAD +, ATF/ADF, ATF/AMF, atsetil-KOA/KOA, suk-tsinil-KOA/KOA are high, the cell is rather provided with energy, and a flow of the turned connections through Since to c. it is slowed down; if these ratios are low, the cell feels the need for energy, and a flow through Since c. accelerates. Apparently, the ratio of quantities of free mitochondrial NAD-N and NAD + is the major regulatory factor defining a flow of substances through Since in c. OVER - dependent
dehydrogenases have different sensitivity to this factor. Change of activity of a pzotsitratdegidrogenaza — one of key enzymes Since c is especially important. Speed Since c. it is regulated also poplars you iteit l ny and fe r to cops and (pi ru-vatdegidrogenazy, piruvatkarbok-with and l and z about y, of l at t and m and t d eg and d r about ge N and z oh,
karbamoilfosfatsintetazy, etc.), influencing formation of nek-ry intermediate products Since c. A special role is played by regulation of a complex of oxidizing decarboxylation of a ppruvat — the irreversible reaction delivering substrate Since to c. — atsetil-KOA. This reaction is activated by intermediate products of glycolysis (see) and very quickly inhibited by own products — NAD-N and atsetil-KOA. There is also another, slower, but is long the operating mechanism of modulation of activity of a pyruvatedehydrogenase (KF 126.96.36.199) by fosforilirova-npya — dephosphorylations of components multifermental pyruvate-degpdrogenaznogo of a complex. Phosphorylation of the rest of serine (see) and-tsepp a gshruvatdegidrogenazny component, catalyzed by an ATP-dependent kinase (see Kinases), causes an inactivation of this complex, to-ry it is reactivated by specific phosphatase. At accumulation of ATP activity of a pyruvatedehydrogenase decreases due to its phosphorylation, and at decrease in concentration of ATP the ATP-dependent kinase is inactivated, and phosphatase continues to function, activating a pyruvatedehydrogenase.
Activity of many enzymes Since c. depends on ion concentration of Sa2+. These ions influence interconversions active (diphosphorus of ilirovanny) and inactive (fosforilirovanny) pyruvatedehydrogenases of forms, activate OVER - a dependent isocitratedehydrogenase, and also and - the ketoglutaratdegidrogena-storage. Assume that the maintenance of ions of Sa2 + always is in limits of the sating concentration for a pzotsitratdegidrogenaza and and - ke-toglutaratdegidrogenazy and that binding of ions of Sa2 + leads to decrease in the inhibiting effect of high sizes of the relations of NAD*N/NAD+ and ATF/ADF. Ions of Sa2 + influence also activity of the enzymes which are indirectly connected with Since in c., they, e.g., oppress activity piruvatkarbo-ks and l elements (KF 188.8.131.52) and karbamo-ilfosfatsintetaza (KF 184.108.40.206). Bibliography: At l y y M. F. Main
recyclings, Kiev, 1968; Mac-Murray U. A metabolism at the person, the lane with English, M., 1980; M e c of l of e r D. Biokhimiya, the lane with English, t. 2, page 423, M., 1980; Whyte A. and d river. Fundamentals of biochemistry, the lane with English, t. 1 — 3, M., 1981; Halestrap A. P., Scott R. D. a * Thomas A.
P. Mitochondrial pyru vate transport and its hormonal regulation, Int. J. Biochem., v. 11, p. 97, 198U;
Krebs H. A. a. Jo h n s o n W. A. The role of citric acid in intermediate metabolism in animal tissues, Enzymologia, v. 4, p. 148, 1937; La None K. F. a. Schoolwerth A. C. Metabolite transport in mitochondria, Ann. Rev. Biochem., v. 48, p. 871, 1979; Williamson J. R. Mitochondrial function in the heart, Ann. Rev. Physiol., v. 41, p. 485, 1979; Williamson J. R. a. Cooper R. H. Regulation of the citric acid cycle in mammalian systems, FEBS Letters, v. 117, Suppi., p. K73, 1980.
V. I. Rozengart, H. V. Gulyaeva.