Fumarate, in the citric acid cycle

Succinate-CoQ Reductase (Complex II) Succinate dehydrogenase, the enzyme that oxidizes a molecule of succinate to fumarate in the citric acid cycle, is an integral component of the succinate-CoQ reductase complex. The two electrons released in conversion of succinate to fumarate are transferred first to FAD, then to an iron-sulfur cluster, and finally to CoQ (see Figure 8-17). The overall reaction catalyzed by this complex is... 

A part of Complex 11 catalyzes the conversion of succinate to fumarate in the citric acid cycle. 

The efficiency of an enzyme can be reduced or can even become negligible in the presence of certain substances, known as inhibitors. Many inhibitors have structural resemblances with the substrates and compete with them for the formation of complexes with the enzyme. This is the case of the inactivation of cytochrome c oxidase by the cyanide ion, which blocks the mitochondrial electron-transport chain to oxygen. Similarly, the inactivation of the succinate dehydrogenase by malonate involves its inhibition of the conversion of succinate to fumarate in the citric acid cycle. In the latter case, the mechanism for competitive inhibition is... 

In complex II, Q also obtains hydrogen ions and electrons from FADH2, generated by the conversion of succinate to fumarate in the citric acid cycle, which yields QH2 and the oxidized coenzyme FAD. 

Vlaleic acid has a dipole moment, but the closely related fumaric acid, a substance involved in the citric acid cycle by which food molecules are metabolized, does not. Explain. 

Acid-catalyzed hydration of isolated double bonds is also uncommon in biological pathways. More frequently, biological hydrations require that the double bond be adjacent to a carbonyl group for reaction to proceed. Fumarate, for instance, is hydrated to give malate as one step in the citric acid cycle of food metabolism. Note that the requirement for an adjacent carbonyl group in the addition of water is the same as that we saw in Section 7.1 for the elimination of water. We ll see the reason for the requirement in Section 19.13, but might note for now that the reaction is not an electrophilic addition but instead occurs... 

Steps 7-8 of Figure 29.12 Hydration and Oxidation The final two steps in the citric acid cycle are the conjugate nucleophilic addition of water to fumarate to yield (S)-malate (L-malate) and the oxidation of (S)-malate by NAD+ to give oxaloacetate. The addition is cataiyzed by fumarase and is mechanistically similar to the addition of water to ris-aconitate in step 2. The reaction occurs through an enolate-ion intermediate, which is protonated on the side opposite the OH, leading to a net anti addition. 

The urea cycle results in a net conversion of oxaloacetate to fumarate, both of which are intermediates in the citric acid cycle. The two cycles are thus interconnected. 

The following is the sum of three steps in the citric acid cycle A + B + FAD + H20 — C + FADH2 + NADH Reactant A Reactant B Reactant C A. Succinyl CoA GDP Succinate B. Succinate NAD+ Oxaloacetate C. Fumarate NAD Oxaloacetate D. Succinate NAD Malate E. Fumarate GTP Malate Correct answer = B. Succinate + NAD" + FAD oxaloacetate + NADH + FADH2... 

One of the first persons to study the oxidation of organic compounds by animal tissues was T. Thunberg, who between 1911 and 1920 discovered about 40 organic compounds that could be oxidized by animal tissues. Salts of succinate, fumarate, malate, and citrate were oxidized the fastest. Well aware of Knoop s (3 oxidation theory, Thunberg proposed a cyclic mechanism for oxidation of acetate. Two molecules of this two-carbon compound were supposed to condense (with reduction) to succinate, which was then oxidized as in the citric acid cycle to oxaloacetate. The latter was decarboxylated to pyruvate, which was oxidatively decarboxylated to acetate to complete the cycle. One of the reactions essential for this cycle could not be verified experimentally. It is left to the reader to recognize which one. 

By application of the CIP rules the order of priority of the atoms directly attached to the chirality centre is O > C(0,0,(0)) > C(C,H,H) > H. The atom or group of lowest priority, hydrogen in this case, is already oriented away from the observer. Therefore the sequence of the remaining three groups can be directly deduced from the formula, and these are easily seen to be arranged in a counter-clockwise sense to the observer. It therefore follows that the formula represents (S)-2-hydroxysuccinic acid (formerly known as L-malic acid). The compound is produced in the citric acid cycle from fumaric acid by fumarate-hydratase (fumarase). 

A second competitive pathway for the disposal of PA requires the initial conversion of PA into tyrosine. This reaction is catalyzed by the enzyme PAH (phenylalanine-4-monooxygenase EC 1.14.16.1). The resulting tyrosine molecule can then be catabolized into fumarate and ace-toacetate. Both products are nontoxic and can be further catabolized in the citric acid cycle. In Mrs. Urick and the majority of individuals suffering from HPA and PKU, there is a defect in the PAH enzyme system (NIH Consensus State-... 

The main reason is probably that the system evolved to keep the fumarate concentration low, because fumarate (and arginine) readily inhibits argininosuccinate lyase. Thus, this enzyme is cytoplasmic it is not inhibited by the high concentration of fumarate from the citric acid cycle since this fumarate is in the mitochondrion. 

Recall that FADH i is formed in the citric acid cycle, in the oxidation of sue cinate to fumarate by succinate dehydrogenase (p. 487). This enzyme is of the swccineite-Q reductase complex (Complex 11), an integral membrane protein of the inner mitochondrial membrane. FADH does not leave the complex. Rather, its electrons are transferred to Fe-S centers and then toQ for entry into the electron-transport chain. The succinate-Qreductase complex, in contrast with NADFI-Q oxidoreductase, does not transport protons. Consequently, less ATP is formed from the oxidation of FADH than from NADH. 

The answer is b. (Murray, pp 182-189. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Reducing equivalents are produced at four sites in the citric acid cycle. NADH is produced by the isocitrate dehydrogenase-catalyzed conversion of a-ketoglutarate to succinyl CoA and by the malate dehydrogenase-catalyzed conversion of malate to oxaloacetate. FADH, is produced by the succinate dehydrogenase-catalyzed conversion of succinate to fumarate. Succinyl CoA synthetase catalyzes the formation of succinate from succinyl CoA, with the concomitant phosphorylation of GDP to GTP... 

Addition of water to a double bond is a reaction that we find in several biochemical pathways. For instance, the citric acid cycle is a key metabolic pathway for the complete oxidation of the sugar glucose and the release of the majority of the energy used by the body. It is also the source of starting materials for the s)m-thesis of the biological molecules needed for life. The next-to-last reaction in the citric acid cycle is the hydration of a molecule of fumarate to produce a molecule called malate. 

In the citric acid cycle (and urea cycle), L-malate is produced by addition of HO water to the molecule fiimarate catalyzed by the enzyme fumarate hydratase. D-Malate cannot be produced by the enzyme. 

There are some classes of compounds present in seawater which have known biological activity but have received little attention. Compounds involved in chemical communication, especially halogenated compounds, will be discussed in other chapters. Other compounds of interest are those involved in the citric acid cycle, the major pathway of metabolism in almost all cells. Citric acid cycle intermediates and reactions are involved in the biosynthesis of most of the major metabolites, from amino acids and carbohydrates to long-chain fatty acids and porphyrins (Mahler and Cordes, 1971). The intermediates, such as succinic, fumaric, malic, oxaloacetic, citric, gly-oxylic, and oxoglutaric acids are present in almost all organisms and are certainly being produced in the sea. 

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