Harper's Biochemistry Chapter 16 - The Citric Acid Cycle

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Questions and Answers

What regulates the activity of citrate synthase?

Long-chain fatty acyl-CoA (correct)

NADH

ADP

NADPH

Which enzyme catalyzes the conversion of pyruvate to oxaloacetate?

Pyruvate carboxylase (correct)

Citrate synthase

Succinate dehydrogenase

Malate dehydrogenase

What is the fate of oxaloacetate released by citrate lyase?

It is reduced to malate. (correct)

It directly reenters the mitochondrion.

It is converted to citrate.

It is phosphorylated.

Which molecule provides half of the NADPH required for fatty acid synthesis?

Malate Signup and view all the answers

Which vitamin coenzyme is utilized by pyruvate carboxylase?

Biotin Signup and view all the answers

What is the primary role of the citric acid cycle in metabolism?

To oxidize acetyl-CoA and produce ATP Signup and view all the answers

Which substance is primarily depleted in hyperammonemia, causing impaired function of the citric acid cycle?

α-ketoglutarate Signup and view all the answers

Which enzyme is primarily responsible for converting pyruvate to acetyl-CoA?

Pyruvate dehydrogenase Signup and view all the answers

What is an anaplerotic reaction in the context of the citric acid cycle?

A reaction that replenishes cycle intermediates Signup and view all the answers

Which of the following vitamins is known to function as a coenzyme in the citric acid cycle?

Vitamin B1 (Thiamine) Signup and view all the answers

What is the main function of the citric acid cycle besides ATP formation?

Provision of carbon skeletons for gluconeogenesis Signup and view all the answers

Which metabolic pathway involves both anabolic and catabolic processes?

Citric acid cycle Signup and view all the answers

What type of phosphorylation occurs during the reactions of the citric acid cycle?

Substrate-level phosphorylation Signup and view all the answers

The citric acid cycle is often described as amphibolic. What does this mean?

It is involved in both catabolic and anabolic pathways Signup and view all the answers

What activates the dehydrogenases in the citric acid cycle?

Calcium ions (Ca2+) Signup and view all the answers

Which of the following ratios reflects the energy status of the cell during the citric acid cycle?

[ATP]/[ADP] and [NADH]/[NAD+] Signup and view all the answers

How does the availability of oxidized cofactors influence the activity of the citric acid cycle?

Increased oxidized cofactors enhance the cycle's activity Signup and view all the answers

Which of the following substances is a key product of the citric acid cycle that can be used for fatty acid synthesis?

Acetyl-CoA Signup and view all the answers

Which metabolic pathways can produce intermediates for the citric acid cycle?

Glycolysis and the pentose phosphate pathway Signup and view all the answers

Which vitamin coenzyme is involved in the decarboxylation processes of the citric acid cycle?

Vitamin B1 (Thiamine) Signup and view all the answers

What term refers to the balance of precursor and product molecules in the citric acid cycle?

Anaplerosis and cataplerosis Signup and view all the answers

Which enzyme of the citric acid cycle is most directly linked to the generation of NADH?

Isocitrate dehydrogenase Signup and view all the answers

During high energy demand in muscle contraction, what process occurs to finally produce ATP?

Oxidative phosphorylation Signup and view all the answers

What is the role of Acetyl-CoA in the citric acid cycle?

It combines with oxaloacetate to form citrate. Signup and view all the answers

Which process is responsible for the generation of one ATP directly in the citric acid cycle?

Cataplerosis during the conversion of succinyl-CoA to succinate. Signup and view all the answers

What is anaplerosis in the context of the citric acid cycle?

The addition of carbon to replenish cycle intermediates. Signup and view all the answers

Which coenzyme is involved in the conversion of pyruvate to Acetyl-CoA?

Coenzyme A Signup and view all the answers

Which of the following statements best describes the amphibolic nature of the citric acid cycle?

It can both catabolize and anabolize carbon compounds. Signup and view all the answers

Which enzyme is responsible for the isomerization of citrate to isocitrate?

Aconitase Signup and view all the answers

The reduction of coenzymes in the respiratory chain leads to what process in the citric acid cycle?

Phosphorylation of ADP to ATP. Signup and view all the answers

Which metabolic pathway exemplifies cataplerosis from the citric acid cycle?

Conversion of oxaloacetate to phosphoenolpyruvate. Signup and view all the answers

What key feature characterizes the enzymes involved in the citric acid cycle?

They are located in the mitochondrial matrix and attached to membranes. Signup and view all the answers

Which vitamin coenzyme is primarily involved in the oxidative reactions of the citric acid cycle?

Vitamin B3 (Niacin) Signup and view all the answers

What role does succinyl-CoA–acetoacetate-CoA transferase play in metabolism?

It catalyzes the transfer of CoA to acetoacetate. Signup and view all the answers

Which vitamin is primarily linked with the coenzyme for the decarboxylation reaction in α-ketoglutarate dehydrogenase?

Vitamin B1 Signup and view all the answers

What is a characteristic feature of the citric acid cycle regarding metabolic processes?

It is amphibolic, serving both anabolic and catabolic functions. Signup and view all the answers

What does the term 'cataplerosis' refer to in the context of metabolism?

The withdrawal of intermediates from the citric acid cycle. Signup and view all the answers

In the context of the citric acid cycle, what is succinate oxidized to during its metabolism?

Fumarate Signup and view all the answers

Which of the following is involved in the synthesis of acetyl-CoA?

Pantothenic acid as part of coenzyme A Signup and view all the answers

What kind of reactions are primarily involved in the conversion of amino acids during the citric acid cycle?

Transamination and deamination Signup and view all the answers

Which compound serves as the substrate for the phosphorylation of ADP as per the citric acid cycle?

GTP Signup and view all the answers

Which key metabolic process is linked to the buildup of oxaloacetate?

Gluconeogenesis Signup and view all the answers

What is the result of the dehydrogenation reaction catalyzed by succinate dehydrogenase?

Conversion of succinate to fumarate Signup and view all the answers

What role do dehydrogenases play in the citric acid cycle?

They catalyze the oxidation of reduced coenzymes. Signup and view all the answers

Which of the following best describes anaplerosis in the context of the citric acid cycle?

The addition of intermediates to replenish the cycle. Signup and view all the answers

Which factor influences the regulation of the citric acid cycle through energy status?

The levels of oxidized and reduced cofactors. Signup and view all the answers

Which statement best describes the citric acid cycle's role in metabolic pathways?

It provides energy and building blocks for various biosynthetic pathways. Signup and view all the answers

What is the primary consequence of a change in calcium ion concentration during muscle contraction in relation to the citric acid cycle?

Activation of dehydrogenases in the citric acid cycle. Signup and view all the answers

What is the harmful effect of fluoroacetate in the metabolic pathway?

It inhibits the enzyme aconitase. Signup and view all the answers

Which cofactor is necessary for the decarboxylation reaction of isocitrate?

Mn2+ Signup and view all the answers

What type of enzyme reduces ubiquinone in the electron transport chain?

Succinate dehydrogenase Signup and view all the answers

What is a primary function of oxaloacetate in metabolic pathways?

Substrate for gluconeogenesis. Signup and view all the answers

Which reaction results from the oxidation of malate?

Generation of oxaloacetate. Signup and view all the answers

What does the accumulation of isocitrate indicate in the citric acid cycle?

Reduced activity of aconitase. Signup and view all the answers

How does the ratio of NADH to NAD+ influence the citric acid cycle?

Affects the net flux towards oxaloacetate. Signup and view all the answers

What is an essential feature of isocitrate dehydrogenase isoenzymes found in the mitochondria?

They are dependent on NAD+ for the oxidation process. Signup and view all the answers

How does hyperammonemia affect the citric acid cycle?

It depletes citric acid cycle intermediates and inhibits enzymatic activity. Signup and view all the answers

Which of the following reactions in the citric acid cycle generates reducing equivalents?

Oxidation of isocitrate to α-ketoglutarate. Signup and view all the answers

Which aspect of the citric acid cycle is primarily affected by the availability of oxidized cofactors?

The formation of ATP. Signup and view all the answers

What is the primary consequence of impaired ATP formation from the citric acid cycle in the central nervous system?

Causes severe neurological damage. Signup and view all the answers

Which function in metabolism is NOT associated with the citric acid cycle?

Producing glucose from acetyl-CoA. Signup and view all the answers

In what way does the citric acid cycle contribute to fatty acid synthesis?

By providing intermediates that are precursors for fatty acids. Signup and view all the answers

Which process is directly linked to the regeneration of citric acid cycle intermediates?

Anaplerotic reactions. Signup and view all the answers

What does an increase in ATP levels signify for the activity of citrate synthase?

It causes inhibition of the enzyme. Signup and view all the answers

How is malate formed from oxaloacetate in the mitochondrion?

By reduction using NADH. Signup and view all the answers

What is a key characteristic of the citric acid cycle that supports both catabolism and anabolism?

Its involvement in both ATP production and biosynthetic pathways. Signup and view all the answers

What is a consequence of hyperammonemia in metabolic processes?

Loss of consciousness and convulsions. Signup and view all the answers

What role does the NADH/NAD+ ratio play in the conversion of malate to pyruvate?

It drives the reaction forwards, favoring formation of pyruvate. Signup and view all the answers

What happens to citrate when both ATP and long-chain fatty acyl-CoA levels are high?

Its synthesis is inhibited. Signup and view all the answers

Which component is crucial in determining the rate of citrate formation?

Concentration of oxaloacetate. Signup and view all the answers

How does citrate synthase activity change with varying availability of oxaloacetate?

Activity decreases if oxaloacetate levels drop significantly. Signup and view all the answers

What metabolic functions does the pyruvate carboxylase enzyme perform?

It carboxylates pyruvate to produce oxaloacetate using ATP. Signup and view all the answers

What is the direct entry point for propionate into gluconeogenesis?

Succinyl-CoA Signup and view all the answers

Which enzyme is inhibited by its product, thereby influencing the transport of citrate?

Aconitase Signup and view all the answers

Which metabolic cycle is responsible for the production of cytosolic acetyl-CoA for fatty acid synthesis?

Citric acid cycle Signup and view all the answers

What reaction must occur for citrate to be available for transport out of the mitochondrion?

Cleavage by citrate lyase Signup and view all the answers

Which of the following substances is formed as a result of the reaction catalyzed by pyruvate carboxylase?

Oxaloacetate Signup and view all the answers

Which pathway uses both the products from glycolysis and citric acid cycle for energy metabolism?

Gluconeogenesis Signup and view all the answers

What limits the availability of citrate for exporting from the mitochondrion?

Inhibition of aconitase Signup and view all the answers

Which product of the citric acid cycle plays a role in fatty acid synthesis?

Citrate Signup and view all the answers

During which reaction is acetyl-CoA specifically utilized in the citric acid cycle?

Formation of citrate from oxaloacetate Signup and view all the answers

Which enzyme facilitates the conversion of malate to oxaloacetate in the cytosol?

Malate dehydrogenase Signup and view all the answers

Match the following components of the citric acid cycle with their respective functions:

Acetyl-CoA = Enters the cycle and forms citrate Citrate = Converted to isocitrate Isocitrate = Oxidized to produce CO2 Succinyl-CoA = Converted to succinate, generating ATP Signup and view all the answers

Match the following terms related to the citric acid cycle with their definitions:

Anaplerosis = The process of adding carbon to the cycle Cataplerosis = The process of removing carbon from the cycle Oxidative phosphorylation = Generation of ATP via electron transport Substrate-level phosphorylation = Direct conversion of ADP to ATP within the cycle Signup and view all the answers

Match the following enzymes with their reactions in the citric acid cycle:

Citrate synthase = Condenses Acetyl-CoA and oxaloacetate Aconitase = Isomerizes citrate to isocitrate Isocitrate dehydrogenase = Oxidizes isocitrate to alpha-ketoglutarate Succinate dehydrogenase = Oxidizes succinate to fumarate Signup and view all the answers

Match the following metabolic processes to their descriptions:

Gluconeogenesis = Conversion of pyruvate to oxaloacetate Lipogenesis = Utilizes NADPH for fatty acid synthesis Beta-oxidation = Breakdown of fatty acids to Acetyl-CoA Respiratory chain = Reoxidation of coenzymes to generate ATP Signup and view all the answers

Match the following coenzymes with their related functions in the citric acid cycle:

NAD+ = Accepts electrons during dehydrogenation FAD = Participates in the oxidation of succinate Coenzyme A = Involved in the formation of Acetyl-CoA GDP = Couples with a substrate-level phosphorylation to form GTP Signup and view all the answers

Match the following substances with their roles in metabolism:

Citrate = Source of acetyl-CoA for fatty acid synthesis Fluoroacetate = Inhibitor of aconitase Oxaloacetate = Substrate for gluconeogenesis Isocitrate = Intermediate in the citric acid cycle Signup and view all the answers

Match the following enzymes with their respective reactions:

Aconitase = Catalyzes the isomerization of citrate to isocitrate Isocitrate dehydrogenase = Converts isocitrate to α-ketoglutarate Fumarase = Catalyzes the hydration of fumarate to malate Malate dehydrogenase = Oxidizes malate to oxaloacetate Signup and view all the answers

Match the following compounds with their metabolic functions:

NAD+ = Electron acceptor in oxidation reactions NADH = Produced during isocitrate dehydrogenation Acetyl-CoA = Entry point for fatty acid synthesis Fumarate = Intermediary in the citric acid cycle Signup and view all the answers

Match the following ions with their roles in the citric acid cycle:

Mg2+ = Required for decarboxylation of isocitrate Mn2+ = Co-factor for isocitrate dehydrogenase Iron-sulfur proteins = Part of the electron transport chain Calcium ions = Influence regulation of the citric acid cycle Signup and view all the answers

Match the following reactions with their corresponding products:

Citrate synthesis = Formation of citrate from acetyl-CoA Isocitrate dehydrogenation = Conversion of isocitrate to α-ketoglutarate Fumarate hydration = Conversion of fumarate to malate Malate oxidation = Formation of oxaloacetate from malate Signup and view all the answers

Study Notes

The Citric Acid Cycle: A Metabolic Hub

The citric acid cycle, also known as the Krebs cycle or the tricarboxylic acid cycle, is a vital metabolic pathway occurring within mitochondria.
This cycle is the final common pathway for the oxidation of carbohydrates, lipids, and proteins.
The cycle oxidizes the acetyl moiety of acetyl-CoA to CO2, coupling this oxidation to the reduction of coenzymes such as NAD+ and FAD.
These reduced coenzymes (NADH and FADH2) are then reoxidized in the mitochondrial electron transport chain, ultimately leading to the generation of ATP.
The cycle also provides essential intermediates for various metabolic processes, including gluconeogenesis, amino acid synthesis, and fatty acid synthesis.

Citric Acid Cycle Reactions:

The citric acid cycle begins with the condensation of acetyl-CoA with oxaloacetate, forming citrate.
Citrate is then isomerized to isocitrate.
Isocitrate undergoes oxidative decarboxylation to α-ketoglutarate, generating the first NADH.
α-ketoglutarate is also oxidatively decarboxylated to succinyl-CoA, producing the second NADH.
Succinyl-CoA is converted to succinate, generating GTP through substrate-level phosphorylation.
Succinate is oxidized to fumarate, generating FADH2.
Fumarate is hydrated to malate.
Finally, malate is oxidized to oxaloacetate, producing the third NADH.
The cycle completes a full turn with the regeneration of oxaloacetate.

The Citric Acid Cycle and Energy Production:

Each turn of the citric acid cycle produces nine molecules of ATP via oxidative phosphorylation, and one ATP (or GTP) through substrate-level phosphorylation.

Regulation:

The citric acid cycle is tightly regulated to ensure efficient energy production and cellular function.
Key regulatory enzymes include citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase.
ATP, NADH, and long-chain fatty acyl-CoA act as allosteric inhibitors of citrate synthase and isocitrate dehydrogenase, reflecting an energy-rich state.
Conversely, ADP and Ca2+ act as allosteric activators, indicating an energy-demanding state.

Hyperammonemia and Implications:

Hyperammonemia, an excess of ammonia in the blood, can severely impair citric acid cycle function.
Hyperammonemia can occur due to liver disease or genetic defects in amino acid metabolism.
High ammonia levels deplete citric acid cycle intermediates, such as α-ketoglutarate, by diverting them towards glutamate and glutamine synthesis.
Ammonia also inhibits the oxidative decarboxylation of α-ketoglutarate.
These effects lead to a decrease in ATP production and can cause severe neurologic deficits, including coma, convulsions, and even death.

Citric Acid Cycle

The citric acid cycle is a key metabolic pathway located in the mitochondria
It oxidizes the acetyl group of Acetyl-CoA to carbon dioxide
This process is coupled to the reduction of coenzymes, which are then reoxidized in the electron transport chain
This process is linked to the production of ATP
The citric acid cycle is the final common pathway for the oxidation of carbohydrates, lipids, and proteins.
The citric acid cycle can be regulated by the availability of certain vitamins and the energy status of a cell
Hyperammonemia, a condition associated with advanced liver disease, can impair the citric acid cycle
Hyperammonemia can be fatal due to impaired ATP production.

Citric Acid Cycle Reactions

Acetyl-CoA joins with oxaloacetate to form citrate: Catalyzed by citrate synthase.
Citrate is isomerized to isocitrate: Catalyzed by aconitase.
Isocitrate is oxidized and decarboxylated to α-ketoglutarate: Catalyzed by isocitrate dehydrogenase.
α-ketoglutarate is oxidized and decarboxylated to succinyl-CoA: Catalyzed by α-ketoglutarate dehydrogenase complex
Succinyl-CoA is converted to succinate: Catalyzed by succinyl-CoA synthetase.
Succinate is oxidized to fumarate: Catalyzed by succinate dehydrogenase.
Fumarate is hydrated to malate: Catalyzed by fumarase.
Malate is oxidized to oxaloacetate: Catalyzed by malate dehydrogenase.

Citric Acid Cycle - Regulation

Citrate synthase is inhibited by ATP and long-chain fatty acyl-CoA.
Isocitrate dehydrogenase is activated by ADP and inhibited by ATP and NADH.
α-ketoglutarate dehydrogenase complex is regulated in the same way as pyruvate dehydrogenase.
Succinate dehydrogenase is inhibited by oxaloacetate.
The availability of oxaloacetate is controlled by malate dehydrogenase and depends on the [NADH]/[NAD+] ratio.

Citric Acid Cycle - Importance

The citric acid cycle provides a pathway for the catabolism of amino acids.
The citric acid cycle provides a pathway for the synthesis of certain amino acids.
It is essential for gluconeogenesis.
It is the major pathway for the formation of ATP.
It is required for fatty acid synthesis.

Anaplerosis and Cataplerosis

Anaplerosis refers to the replenishment of citric acid cycle intermediates.
Cataplerosis refers to the removal of citric acid cycle intermediates.
These processes are critical for maintaining the balance of the cycle.

Medical Importance

Fluoroacetate poisoning: This poison is found in some plants and can be fatal to animals.
Hyperammonemia: A condition associated with advanced liver disease, can impair the citric acid cycle leading to neurological damage.
Impaired ATP Formation: Hyperammonemia leads to reduced formation of ATP, which is essential for energy production in the brain and other tissues.

Fatty Acid Synthesis

The citric acid cycle provides citrate for the synthesis of fatty acids.
Citrate is transported from the mitochondria to the cytosol where it is used for fatty acid synthesis.
This pathway is essential for providing acetyl-CoA for fatty acid synthesis.

Vitamin Requirements

Biotin: Required as a coenzyme for pyruvate carboxylase.
Niacin: Required for NAD+-dependent isocitrate dehydrogenase.
Riboflavin: Required for succinate dehydrogenase.
Thiamine: Required for α-ketoglutarate dehydrogenase complex.

Citric Acid Cycle Location

Enzymes of the citric acid cycle are found in the mitochondrial matrix, either free or attached to the inner mitochondrial membrane and the crista membrane.

Citric Acid Cycle Function

It serves as a central pathway for carbohydrate, lipid, and protein catabolism.
The cycle must maintain a balance in the number of carbons entering and leaving.
Acetyl-CoA (two carbon molecule) combines with oxaloacetate (four carbon molecule) to form citrate (six carbon molecule).
During each turn of the cycle, citrate is converted back to oxaloacetate, and two carbons are released as CO2.
Anaplerosis refers to the addition of carbon to the cycle, like pyruvate to oxaloacetate for gluconeogenesis.
Cataplerosis is the removal of carbon from the cycle, such as oxaloacetate to phosphoenolpyruvate.
Anaplerosis must equal cataplerosis to sustain the citric acid cycle.

Citric Acid Cycle Reactions

Citrate Synthesis: Acetyl-CoA reacts with oxaloacetate catalyzed by citrate synthase to form citryl-CoA, which is hydrolyzed, releasing citrate and CoASH.
Isomerization: Citrate is isomerized to isocitrate by aconitase through dehydration to cis-aconitate and rehydration to isocitrate.
Oxidative Decarboxylation of Isocitrate: Isocitrate is dehydrogenated to oxalosuccinate, which is enzyme-bound and undergoes decarboxylation to α-ketoglutarate, catalyzed by isocitrate dehydrogenase.
Oxidative Decarboxylation of α-ketoglutarate: α-ketoglutarate is converted to succinyl-CoA in a reaction catalyzed by α-ketoglutarate dehydrogenase complex, which requires cofactors like thiamin diphosphate, lipoate, NAD+, FAD, and CoA.
Succinyl-CoA to Succinate: Succinyl-CoA is converted to succinate by succinate thiokinase, generating ATP or GTP through substrate-level phosphorylation.
Succinate to Fumarate: Succinate is oxidized to fumarate by succinate dehydrogenase, reducing FAD to FADH2.
Fumarate to Malate: Fumarate is hydrated to malate by fumarase.
Malate to Oxaloacetate: Malate is oxidized to oxaloacetate by malate dehydrogenase, reducing NAD+ to NADH.

ATP Production

One turn of the citric acid cycle generates a total of 10 ATPs.
The cycle produces three NADH and one FADH2 molecules per acetyl-CoA oxidized.
During oxidative phosphorylation, reoxidation of NADH yields ~2.5 ATP, and reoxidation of FADH2 yields ~1.5 ATPs.
Substrate-level phosphorylation in the conversion of succinyl-CoA to succinate generates 1 ATP.

Regulation of the Citric Acid Cycle

The citric acid cycle is primarily regulated by the availability of oxidized cofactors (NAD+).
Regulation of individual enzymes:
- Citrate synthase is allosterically inhibited by ATP and long-chain fatty acyl-CoA.
- Isocitrate dehydrogenase is allosterically activated by ADP, counteracted by ATP and NADH.
- α-ketoglutarate dehydrogenase is regulated similarly to pyruvate dehydrogenase.
- Succinate dehydrogenase is inhibited by oxaloacetate.

Vitamins and the Citric Acid Cycle

Four B vitamins are essential for the citric acid cycle:
- Riboflavin (as FAD) is a cofactor for succinate dehydrogenase.
- Niacin (as NAD+) is an electron acceptor for isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase.
- Thiamin (as thiamin diphosphate) is a cofactor for α-ketoglutarate dehydrogenase.
- Biotin is a coenzyme for pyruvate carboxylase, which carboxylates pyruvate to oxaloacetate.

Citric Acid Cycle and Fatty Acid Synthesis

Citrate, as a source of acetyl-CoA, can be transported to the cytosol for fatty acid synthesis.
The accumulation of isocitrate inhibits aconitase, making citrate "free" to be transported to the cytosol.
Malic enzyme, which converts malate to pyruvate, utilizes NADPH, a co-substrate in fatty acid synthesis.

Hyperammonemia

Hyperammonemia, elevated ammonia levels in the blood, can occur in liver disease or genetic diseases of amino acid metabolism.
Hyperammonemia depletes citric acid cycle intermediates by removing α-ketoglutarate for the synthesis of glutamate and glutamine.
This depletion further decreases citric acid cycle flux and ATP generation.
Ammonia inhibits the α-ketoglutarate dehydrogenase complex, further reducing the citric acid cycle flux.

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Test your knowledge on the Citric Acid Cycle, a crucial metabolic pathway that plays a key role in cellular respiration. Learn about its reactions, the conversion of acetyl-CoA, and its importance in energy production and metabolic processes. This quiz covers essential concepts and steps within the cycle.