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The Central Role of the Citric Acid Cycle. 3 processes play central roles in ________ metabolism The citric acid cycle (TCA cycle) Electron transport (Chapter 20) Oxidative phosphorylation (Chapter 20) Metabolism consists of Catabolism: the oxidative breakdown of nutrients
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The Central Role of the Citric Acid Cycle 3 processes play central roles in ________ metabolism • The citric acid cycle (TCA cycle) • Electron transport (Chapter 20) • Oxidative phosphorylation (Chapter 20) • Metabolism consists of • Catabolism: the oxidative breakdown of nutrients • Anabolism: the reductive synthesis of biomolecules • The citric acid cycle is ______________________; that is, it plays a role in both catabolism and anabolism. It is the central metabolic pathway
Where does the Citric Acid Cycle Take Place? • In eukaryotes, cycle takes place in the mitochondrial matrix
Pyruvate is Converted to Acetyl-CoA • Pyruvate dehydrogenase complex is responsible for the conversion of pyruvate to CO2 and the acetyl portion of acetyl-CoA • Five enzymes in complex:pyruvate dehydrogenase, dihydrolipoyl transacetylase, dihydrolipoyl dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase phosphatase
Pyruvate is Converted to Acetyl-CoA • First, pyruvate loses CO2 and hydroxyethylTPP (HETPP) is formed • In the second step, the active form of ____________ acid is bound to the enzyme, dihydrolipoyl transacetylase, by an amide bond to the -amino group of a lysine • The hydroxyethyl group (HE) is oxidized and transferred to a sulfur atom of the reduced form of lipoamide • Lipoamide is reduced to dihydrolipoamide • In step 3, the acetyl group is transferred to the ___________ group of coenzyme A • Next, dihydrolipoamide is oxidized to lipoamide
Summary • The two-carbon unit needed at the start of the citric acid cycle is obtained by converting pyruvate to acetyl-CoA • This conversion requires the three primary enzymes of the pyruvate dehydogenase complex, as well as, the cofactors TPP, FAD, NAD+, and lipoic acid • The overall reaction of the pyruvate dehydogenase complex is the conversion of pyruvate, NAD+, and CoA-SH to acetyl-CoA, NADH + H+, and CO2
Individual Reactions of the Citric Acid Cycle • In step 1, there is a condensation of acetyl-CoA with oxaloacetate to form _______________ • G°’ = -32.8 kJ•mol-1, therefore, the reaction is ___________ • Reaction is catalyzed by citrate _____________, an allosteric enzyme that is inhibited by NADH, ATP, and succinyl-CoA
Individual Reactions of the Citric Acid Cycle • In step 2, citrate is isomerized to isocitrate. The reaction is catalyzed by _____________ • Citrate is achiral; it has no stereocenter • Isocitrate is chiral; it has 2 stereocenters, so 4 possible stereoisomers • _____________ of the 4 stereoisomers of isocitrate is formed in the cycle
Individual Reactions of the Citric Acid Cycle • In step 3, there is an oxidation of isocitrate followed by decarboxylation to form ________________ and CO2 • The reaction is catalyzed by isocitrate ______________, an allosteric enzyme, which is inhibited by ATP and NADH, and activated by ADP and NAD+
Individual Reactions of the Citric Acid Cycle • In step 4, there is an oxidative decarboxylation of -ketoglutarate to _____________________ • This reaction is catalyzed by the -ketoglutarate dehydrogenase complex, which is, like pyruvate dehydrogenase, a multienzyme complex and requires _________________________________________________
Individual Reactions of the Citric Acid Cycle • Next, the thioester bond of succinyl-CoA if hydrolyzed in the formation of succinate • The two CH2-COO- groups of succinate are equivalent • This is the first __________________________ step of the cycle • The overall reaction is slightly exergonic
Individual Reactions of the Citric Acid Cycle • Next, there is an oxidation of succinate to _____________ • Then, the hydration of fumarate to _____________________
Individual Reactions of the Citric Acid Cycle • Then, malate is oxidized to __________________________
Summary • In the citric acid cycle and the pyruvate dehydrogenase reaction, one molecule of pyruvate is oxidized to three molecules of CO2 as a result of oxidative decarboxylation • The oxidations are accompanied by reductions involving NAD+ to NADH & FAD to FADH2 • GDP is phosphorylated to GTP
Control of the Citric Acid Cycle • There are 3 points of control within the cycle: • Citrate synthase: inhibited by ATP, NADH, and succinyl CoA; also product inhibition by citrate • Isocitrate dehydrogenase: activated by ADP and NAD+, inhibited by ATP and NADH • -ketoglutarate dehydrogenase complex: inhibited by ATP, NADH, and succinyl CoA; activated by ADP and NAD+ • There is one control point outside the cycle • Pyruvate dehydrogenase: inhibited by ATP and NADH; also product inhibition by acetyl-CoA
The Glyoxylate Cycle • In plants and some bacteria, there may be a modification of the citric acid cycle to produce 4-carbon dicarboxylic acids & eventually glucose • The glyoxylate cycle bypasses the two oxidative decarboxylations of the citric acid cycle • Instead, it routes isocitrate via glyoxylate to malate • Key enzymes in this cycle are _______ _________ and _______________ _______________
The Glyoxylate Cycle • The glyoxylate cycle takes place: • In _______: in glyoxysomes, specialized organelles devoted to this cycle • In _______and _______: in the cytoplasm • Helps plants grow in the dark: • Seeds are rich in lipids, which contain fatty acids • During germination, plants use the acetyl-CoA produced in fatty acid oxidation to produce oxaloacetate and other intermediates for carbohydrate synthesis • Once plants begin photosynthesis and can fix CO2, glyoxysomes disappear
The Citric Acid Cycle in Catabolism • The catabolism of _______, _______, and _______ _______ all feed into the citric acid cycle at one or more points
Summary • All metabolic pathways are related, and all of them operate simultaneously • In catabolic pathways, nutrients, many of which are macromolecules, are broken down to smaller molecules, such as sugars, fatty acids, and amino acids • Small molecules are processed further, and the end products of catabolism frequently enter the citric acid cycle, which plays a key role in metabolism
The Citric Acid Cycle in Anabolism • The citric acid cycle is the source of starting materials for the biosynthesis of other compounds • If a component of the citric acid cycle is taken out for biosynthesis, it must be replaced • Oxaloacetate, for example, is replaced by the ______________ ____________ _____________ • A reaction that replenishes a citric acid cycle intermediate is called an _________________ reaction
Lipid Anabolism • Lipid anabolism begins with acetyl-CoA and takes place in the ______________ • acetyl-CoA is produced mainly in mitochondria from catabolism of fatty acids and carbohydrates • an indirect transfer mechanism exists involving citrate Citrate + CoA-SH + ATP Acetyl-CoA + Oxaloacetate + ADP + Pi • the oxaloacetate thus formed provides a means for the production of the NADPH needed for biosynthesis
Lipid Anabolism Oxaloacetate + NADH + H+ Malate + NAD+ Malate + NADP+ Pyruvate + CO2 + NADPH + H+ • The net effect of these two reactions is replacement of NADH by NADPH • While there is some NADPH produced by this means, its principal source is the pentose phosphate pathway • The anabolic reactions that produce amino acids and many other biomolecules begin with TCA cycle molecules that are transported into the cytosol
Summary • The citric acid cycle plays a central role in anabolic pathways as well as in catabolism • Pathways that give rise to sugars, fatty acids, and amino acids all originate with components of the citric acid cycle
The Link To Oxygen • The citric acid cycle is considered part of the aerobic metabolic process because of its link to the _______________ and _______________ • NADH and FADH2, two important cofactors generated by the citric acid cycle, ultimately pass their electrons to _____________
