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The Citric Acid Cycle: the Catabolism of Acetyl-Coa 16 ch16.qxd 2/13/2003 2:58 PM Page 130 The Citric Acid Cycle: The Catabolism of Acetyl-CoA 16 Peter A. Mayes, PhD, DSc, & David A. Bender, PhD BIOMEDICAL IMPORTANCE cated in the mitochondrial matrix, either free or at- tached to the inner mitochondrial membrane, where The citric acid cycle (Krebs cycle, tricarboxylic acid the enzymes of the respiratory chain are also found. cycle) is a series of reactions in mitochondria that oxi- dize acetyl residues (as acetyl-CoA) and reduce coen- zymes that upon reoxidation are linked to the forma- REACTIONS OF THE CITRIC ACID tion of ATP. CYCLE LIBERATE REDUCING The citric acid cycle is the final common pathway EQUIVALENTS & CO2 for the aerobic oxidation of carbohydrate, lipid, and (Figure 16–3)* protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of The initial reaction between acetyl-CoA and oxaloac- the cycle. It also has a central role in gluconeogenesis, etate to form citrate is catalyzed by citrate synthase lipogenesis, and interconversion of amino acids. Many which forms a carbon-carbon bond between the methyl of these processes occur in most tissues, but the liver is carbon of acetyl-CoA and the carbonyl carbon of ox- the only tissue in which all occur to a significant extent. aloacetate. The thioester bond of the resultant citryl- The repercussions are therefore profound when, for ex- CoA is hydrolyzed, releasing citrate and CoASH—an ample, large numbers of hepatic cells are damaged as in exergonic reaction. acute hepatitis or replaced by connective tissue (as in Citrate is isomerized to isocitrate by the enzyme cirrhosis). Very few, if any, genetic abnormalities of aconitase (aconitate hydratase); the reaction occurs in citric acid cycle enzymes have been reported; such ab- two steps: dehydration to cis-aconitate, some of which normalities would be incompatible with life or normal remains bound to the enzyme; and rehydration to isoci- development. trate. Although citrate is a symmetric molecule, aconi- tase reacts with citrate asymmetrically, so that the two carbon atoms that are lost in subsequent reactions of THE CITRIC ACID CYCLE PROVIDES the cycle are not those that were added from acetyl- SUBSTRATE FOR THE CoA. This asymmetric behavior is due to channeling— RESPIRATORY CHAIN transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solu- The cycle starts with reaction between the acetyl moiety tion. This provides integration of citric acid cycle activ- of acetyl-CoA and the four-carbon dicarboxylic acid ox- ity and the provision of citrate in the cytosol as a source aloacetate, forming a six-carbon tricarboxylic acid, cit- of acetyl-CoA for fatty acid synthesis. The poison fluo- rate. In the subsequent reactions, two molecules of CO2 roacetate is toxic because fluoroacetyl-CoA condenses are released and oxaloacetate is regenerated (Figure with oxaloacetate to form fluorocitrate, which inhibits 16–1). Only a small quantity of oxaloacetate is needed aconitase, causing citrate to accumulate. for the oxidation of a large quantity of acetyl-CoA; ox- Isocitrate undergoes dehydrogenation catalyzed by aloacetate may be considered to play a catalytic role. isocitrate dehydrogenase to form, initially, oxalosucci- The citric acid cycle is an integral part of the process nate, which remains enzyme-bound and undergoes de- by which much of the free energy liberated during the carboxylation to α-ketoglutarate. The decarboxylation oxidation of fuels is made available. During oxidation of acetyl-CoA, coenzymes are reduced and subsequently reoxidized in the respiratory chain, linked to the forma- *From Circular No. 200 of the Committee of Editors of Biochemi- cal Journals Recommendations (1975): “According to standard tion of ATP (oxidative phosphorylation; see Figure biochemical convention, the ending ate in, eg, palmitate, denotes 16–2 and also Chapter 12). This process is aerobic, re- any mixture of free acid and the ionized form(s) (according to pH) quiring oxygen as the final oxidant of the reduced in which the cations are not specified.” The same convention is coenzymes. The enzymes of the citric acid cycle are lo- adopted in this text for all carboxylic acids. 130 ch16.qxd 2/13/2003 2:58 PM Page 131 THE CITRIC ACID CYCLE: THE CATABOLISM OF ACETYL-CoA / 131 Acetyl-CoA Carbohydrate Protein Lipids (C2) CoA Acetyl-CoA (C2) H O Citrate Oxaloacetate Citrate Oxaloacetate 2 (C6) (C4) (C6) (C4) H2O Citric acid cycle Cis-aconitate (C6) H O Malate 2 (C4) 2H Isocitrate CO H2O 2 CO2 (C6) 2H CO2 Figure 16–1. Citric acid cycle, illustrating the cat- Fumarate (C4) α-Ketoglutarate alytic role of oxaloacetate. (C5) 2H NAD CO Succinate 2 (C ) Succinyl-CoA 2+ 2+ 4 requires Mg or Mn ions. There are three isoenzymes (C4) + P F of isocitrate dehydrogenase. One, which uses NAD , is 2H p + H O P found only in mitochondria. The other two use NADP 2 and are found in mitochondria and the cytosol. Respi- ratory chain-linked oxidation of isocitrate proceeds al- Q most completely through the NAD+-dependent en- zyme. Cyt b P Oxidative α-Ketoglutarate undergoes oxidative decarboxyla- phosphorylation tion in a reaction catalyzed by a multi-enzyme complex similar to that involved in the oxidative decarboxylation Cyt c of pyruvate (Figure 17–5). The ␣-ketoglutarate dehy- drogenase complex requires the same cofactors as the pyruvate dehydrogenase complex—thiamin diphos- Cyt aa3 P 1/2 O phate, lipoate, NAD+, FAD, and CoA—and results in 2 the formation of succinyl-CoA. The equilibrium of this – Anaerobiosis reaction is so much in favor of succinyl-CoA formation (hypoxia, anoxia) H O that it must be considered physiologically unidirec- Respiratory chain 2 tional. As in the case of pyruvate oxidation (Chapter F 17), arsenite inhibits the reaction, causing the substrate, p Flavoprotein ␣ -ketoglutarate, to accumulate. Cyt Cytochrome Succinyl-CoA is converted to succinate by the en- zyme succinate thiokinase (succinyl-CoA synthe- P High-energy phosphate tase). This is the only example in the citric acid cycle of Figure 16–2. The citric acid cycle: the major catabo- substrate-level phosphorylation. Tissues in which glu- lic pathway for acetyl-CoA in aerobic organisms. Acetyl- coneogenesis occurs (the liver and kidney) contain two CoA, the product of carbohydrate, protein, and lipid ca- isoenzymes of succinate thiokinase, one specific for tabolism, is taken into the cycle, together with H O, and GDP and the other for ADP. The GTP formed is 2 used for the decarboxylation of oxaloacetate to phos- oxidized to CO2 with the release of reducing equivalents phoenolpyruvate in gluconeogenesis and provides a (2H). Subsequent oxidation of 2H in the respiratory chain leads to coupled phosphorylation of ADP to ATP. regulatory link between citric acid cycle activity and ᭺ the withdrawal of oxaloacetate for gluconeogenesis. For one turn of the cycle, 11~ P are generated via ox- Nongluconeogenic tissues have only the isoenzyme that idative phosphorylation and one ~᭺P arises at substrate uses ADP. level from the conversion of succinyl-CoA to succinate. ch16.qxd 2/13/2003 2:58 PM Page 132 CH3 CO* S CoA Acetyl-CoA O MALATE CITRATE SYNTHASE – DEHYDROGENASE C COO CoA SH – CH COO* – CH2 COO 2 NADH + H+ Oxaloacetate H O 2 HO C COO– HOCH COO* – NAD+ – CH2 COO – CH2 COO* Citrate L-Malate ACONITASE FUMARASE Fe2+ H2O – Fluoroacetate CH2 COO* H2O C COO– H C COO* – CH COO– –OOC* C H Cis-aconitate Fumarate FADH 2 H2O + SUCCINATE ACONITASE Fe2 DEHYDROGENASE FAD Malonate – CH2 COO* CH COO* – 2 CH COO– CH COO* – 2 HO CH COO– Succinate Isocitrate ATP NAD+ Mg2+ CoA SH NADH + H+ ADP + P i ISOCITRATE SUCCINATE – DEHYDROGENASE THIOKINASE CH2 COO* – CH2 COO* CH2 Arsenite NADH + H+ CH COO– O C S CoA + CO2 NAD – Succinyl-CoA – O C COO CH2 COO* α-KETOGLUTARATE Oxalosuccinate DEHYDROGENASE COMPLEX CH 2 Mn2+ ISOCITRATE CoA SH DEHYDROGENASE O C COO– CO2 α-Ketoglutarate Figure 16–3. Reactions of the citric acid (Krebs) cycle. Oxidation of NADH and FADH2 in the respiratory chain leads to the generation of ATP via oxidative phosphorylation. In order to follow the passage of acetyl-CoA through the cycle, the two carbon atoms of the acetyl radical are shown labeled on the carboxyl carbon (designated by as- • terisk) and on the methyl carbon (using the designation ). Although two carbon atoms are lost as CO2 in one revo- lution of the cycle, these atoms are not derived from the acetyl-CoA that has immediately entered the cycle but from that portion of the citrate molecule that was derived from oxaloacetate. However, on completion of a single turn of the cycle, the oxaloacetate that is regenerated is now labeled, which leads to labeled CO2 being evolved during the second turn of the cycle. Because succinate is a symmetric compound and because succinate dehydro- genase does not differentiate between its two carboxyl groups, “randomization” of label occurs at this step such that all four carbon atoms of oxaloacetate appear to be labeled after one turn of the cycle. During gluconeogene- sis, some of the label in oxaloacetate is incorporated into glucose and glycogen (Figure 19–1). For a discussion of the stereochemical aspects of the citric acid cycle, see Greville (1968). The sites of inhibition ( − ) by fluoroacetate, malonate, and arsenite are indicated. 132 ch16.qxd 2/13/2003 2:58 PM Page 133 THE CITRIC ACID CYCLE: THE CATABOLISM OF ACETYL-CoA / 133 When ketone bodies are being metabolized in extra- the coenzyme for three dehydrogenases in the cycle— hepatic tissues there is an alternative reaction catalyzed isocitrate dehydrogenase, α-ketoglutarate dehydrogen- by succinyl-CoA–acetoacetate-CoA transferase (thio- ase, and malate dehydrogenase; (3) thiamin (vitamin phorase)—involving transfer of CoA from succinyl- B1), as thiamin diphosphate, the coenzyme for decar- CoA to acetoacetate, forming acetoacetyl-CoA (Chap- boxylation in the α-ketoglutarate dehydrogenase reac- ter 22).
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