1. A 24-year-old woman presents with diarrhea, dysphagia, jaundice, and white transverse lines on her fingernails (Mee’s lines). She is diagnosed with arsenic poisoning. Arsenic poisoning inhibits which of the following enzymes?
A. Citrate synthase
B. Isocitrate dehydrogenase
C. Malate dehydrogenase
D. Succinate dehydrogenase
E. α-Keto glutarate dehydrogenase complex
Correct answer:
E. α-Keto glutarate dehydrogenase complex
Explanation:
Arsenic binds to lipoic acid, an essential cofactor for enzymes like α-Keto glutarate dehydrogenase complex, impairing energy production in the TCA cycle. This inhibition leads to toxic accumulation of intermediates, causing symptoms such as diarrhea, jaundice, and Mee’s lines.
Incorrect Options:
A. Citrate synthase catalyzes the formation of citrate from oxaloacetate and acetyl-CoA, but it is not affected by arsenic poisoning.
B. Isocitrate dehydrogenase converts isocitrate to α-ketoglutarate and produces NADH; it is not inhibited by arsenic.
C. Malate dehydrogenase catalyzes the conversion of malate to oxaloacetate with NADH production, but arsenic does not affect it.
D. Succinate dehydrogenase is involved in converting succinate to fumarate and produces FADH2. It is inhibited by malonate, not arsenic.
Conclusion:
The correct enzyme inhibited by arsenic poisoning is α-Ketoglutarate dehydrogenase complex, leading to energy metabolism defects and characteristic symptoms.
2. A biochemistry graduate student isolated all enzymes of the TCA cycle to produce NADH. Oxidation of which of the following substrates in the citric acid cycle is not coupled to NADH production?
A. Succinate
B. Malate
C. α-Ketoglutarate
D. Isocitrate
E. Pyruvate
Correct answer:
A. Succinate
Explanation:
Oxidation of succinate by succinate dehydrogenase is coupled to the production of FADH2, not NADH. This is a unique step in the TCA cycle, where FADH2 enters the electron transport chain via Complex II, bypassing Complex I.
Incorrect Options:
B. Malate oxidation, catalyzed by malate dehydrogenase, produces NADH.
C. α-Ketoglutarate is oxidized by the α-Ketoglutarate dehydrogenase complex, generating NADH.
D. Isocitrate is converted to α-ketoglutarate by isocitrate dehydrogenase, producing NADH.
E. Pyruvate oxidation occurs via the pyruvate dehydrogenase complex, generating NADH in preparation for entry into the TCA cycle as acetyl-CoA.
Conclusion:
Succinate oxidation stands out because it produces FADH2 rather than NADH, making it the correct answer. The other listed substrates yield NADH during their oxidation in the TCA cycle or preparatory steps.
3. A 3-year-old boy presents to the pediatric clinic with symptoms of hypotonia, lactic acidosis, and seizures. After an extensive workup, he is diagnosed with pyruvate dehydrogenase complex deficiency. Which of the following cofactors is not required by this enzyme to convert pyruvate to acetyl-CoA?
A. Thiamine
B. Lipoic acid
C. Pantothenic acid
D. Niacin
E. Ascorbic acid
Correct answer:
E. Ascorbic acid
Explanation:
The pyruvate dehydrogenase complex (PDC) requires multiple cofactors for its activity, as it catalyzes the conversion of pyruvate to acetyl-CoA, linking glycolysis to the TCA cycle. These cofactors include:
A. Thiamine (Vitamin B1): Required as thiamine pyrophosphate (TPP), a coenzyme for decarboxylation reactions.
B. Lipoic acid: Essential for the transfer of acetyl groups.
C. Pantothenic acid (Vitamin B5): Used to synthesize coenzyme A (CoA).
D. Niacin (Vitamin B3): Precursor of NAD+, which accepts electrons during the reaction.
E. Ascorbic acid (Vitamin C) is not involved in the pyruvate dehydrogenase complex reaction and thus is the correct answer.
Conclusion:
The correct answer is E. Ascorbic acid because it is not needed for the functioning of the pyruvate dehydrogenase complex. The other cofactors play critical roles in the enzyme’s catalytic activity.
4. Which of the following vitamins is required to synthesize a cofactor needed to convert succinate to fumarate?
A. Thiamine
B. Lipoic acid
C. Pantothenic acid
D. Niacin
E. Riboflavin
Correct answer:
E. Riboflavin
Explanation:
The enzyme succinate dehydrogenase catalyzes the conversion of succinate to fumarate in the TCA cycle. This reaction requires flavin adenine dinucleotide (FAD) as a cofactor, which is synthesized from riboflavin (vitamin B2). FAD serves as an electron carrier, accepting electrons from succinate and converting to FADH2.
Incorrect Options:
A. Thiamine (Vitamin B1) is required for enzymes such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase but is not involved in succinate dehydrogenase activity.
B. Lipoic acid acts as a cofactor for the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase, but it is not needed for succinate to fumarate conversion.
C. Pantothenic acid (Vitamin B5) is a precursor for coenzyme A (CoA), which is involved in acyl group transfer, not in this particular reaction.
D. Niacin (Vitamin B3) is required for the formation of NAD+ and NADP+, but FAD (not NAD+) is the relevant cofactor here.
Conclusion:
The correct answer is E. Riboflavin, as it is essential for the formation of FAD, the cofactor used by succinate dehydrogenase to catalyze the conversion of succinate to fumarate.
5. Pyruvate dehydrogenase complex deficiency is an autosomal recessive disorder and leads to metabolic acidosis. Which of the following accumulates to cause metabolic acidosis?
A. Beta-hydroxybutyric acid
B. Acetoacetic acid
C. Fumaric acid
D. Lactic acid
E. Hydrochloric acid
Correct answer:
D. Lactic acid
Explanation:
In pyruvate dehydrogenase complex deficiency, the conversion of pyruvate to Acetyl-CoA is impaired, causing pyruvate to accumulate. The excess pyruvate is shunted towards lactate production by the enzyme lactate dehydrogenase, leading to elevated levels of lactic acid. The accumulation of lactic acid causes metabolic acidosis, a condition characterized by decreased blood pH and increased blood lactate levels.
Incorrect Options:
A. Beta-hydroxybutyric acid and
B. Acetoacetic acid are ketone bodies that accumulate in diabetic ketoacidosis or prolonged fasting but are not the primary acids involved in pyruvate dehydrogenase deficiency.
C. Fumaric acid is an intermediate of the TCA cycle and does not accumulate in this condition.
E. Hydrochloric acid is a component of stomach acid, but it does not contribute to metabolic acidosis in pyruvate dehydrogenase complex deficiency.
Conclusion:
The correct answer is D. Lactic acid because impaired pyruvate metabolism results in excessive lactate production, causing metabolic acidosis in pyruvate dehydrogenase complex deficiency.
6. A 3-year-old child is presented with a history of recurrent rash upon sun exposure and passage of purple-colored urine. The child is diagnosed with congenital erythropoietic porphyria, a disorder of the pathway of heme biosynthesis. Which of the following intermediates of the TCA cycle is used as a precursor for heme biosynthesis?
A. Succinyl-CoA
B. Acetyl-CoA
C. Succinate
D. Malate
E. Pyruvate
Correct answer:
A. Succinyl-CoA
Explanation:
Succinyl-CoA is a critical intermediate in the TCA cycle and serves as one of the precursors in the synthesis of heme. In heme biosynthesis, succinyl-CoA combines with glycine in the first step to form δ-aminolevulinic acid (ALA), which is catalyzed by ALA synthase. This step is essential for the production of heme, which is required for hemoglobin and other heme-containing enzymes.
Incorrect Options:
B. Acetyl-CoA is involved in the synthesis of fatty acids and cholesterol but does not directly contribute to heme biosynthesis.
C. Succinate is another TCA cycle intermediate but does not serve as a precursor for heme synthesis.
D. Malate is involved in gluconeogenesis and the TCA cycle but plays no role in heme biosynthesis.
E. Pyruvate is converted to Acetyl-CoA or lactate, but it is not used in heme biosynthesis.
Conclusion:
The correct answer is A. Succinyl-CoA, as it provides the carbon backbone required for the synthesis of heme, a critical component of hemoglobin. Defects in the heme biosynthetic pathway, such as in congenital erythropoietic porphyria, lead to the accumulation of intermediates that cause photosensitivity and colored urine.
7. A 16-year-old male comes to the clinic for a routine sports physical examination. His physical examination is unremarkable except for the presence of multiple pale masses on the skin, identified as xanthomas. Xanthomas are generally associated with underlying hypercholesterolemia. Which of the following is utilized as a precursor for cholesterol biosynthesis?
A. Succinyl-CoA
B. Acetyl-CoA
C. Succinate
D. Malate
E. Pyruvate
Correct answer:
B. Acetyl-CoA
Explanation:
Cholesterol biosynthesis begins with acetyl-CoA, which is a crucial building block for many biological molecules. In this pathway, acetyl-CoA is first converted into HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) and then reduced to mevalonate by HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This pathway continues through a series of reactions that eventually lead to the formation of cholesterol.
Incorrect Options:
A. Succinyl-CoA is involved in the TCA cycle and heme biosynthesis, but it does not participate in cholesterol synthesis.
C. Succinate is another intermediate of the TCA cycle but plays no role in cholesterol biosynthesis.
D. Malate is involved in gluconeogenesis and energy production but is not relevant to cholesterol formation.
E. Pyruvate serves as a precursor for Acetyl-CoA but is not directly involved in cholesterol synthesis itself.
Conclusion:
The correct answer is B. Acetyl-CoA. Acetyl-CoA is the key precursor for cholesterol biosynthesis, which is essential for cell membranes, steroid hormones, and bile acids. Elevated cholesterol levels are associated with conditions like xanthomas, a hallmark of hypercholesterolemia.
8. A 2-year-old child is brought to the pediatric emergency with convulsions. The child is diagnosed with ammonia intoxication due to a urea cycle disorder. Reduced formation of GABA is identified as the critical cause of the convulsions, stemming from glutamate depletion, as GABA is synthesized through the decarboxylation of glutamate. Which of the following TCA cycle intermediates is involved in the formation of glutamate?
A. Succinate
B. Malate
C. α-Ketoglutarate
D. Isocitrate
E. Pyruvate
Correct answer:
C. α-Ketoglutarate
Explanation:
α-Ketoglutarate is a key intermediate in the TCA cycle and plays a pivotal role in amino acid metabolism. It is converted to glutamate through a transamination reaction, where an amino group is transferred to α-ketoglutarate, forming glutamate. Glutamate is then decarboxylated by glutamate decarboxylase to produce GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter. In conditions like ammonia intoxication, the depletion of glutamate affects GABA synthesis, leading to convulsions.
Incorrect Options:
A. Succinate is involved in the conversion of succinate to fumarate in the TCA cycle but does not participate in amino acid metabolism or glutamate formation.
B. Malate is part of the TCA cycle and gluconeogenesis but does not contribute to glutamate synthesis.
D. Isocitrate is converted to α-ketoglutarate during the TCA cycle but does not directly participate in the formation of glutamate.
E. Pyruvate can be converted to alanine via transamination, but it is not involved in the formation of glutamate.
Conclusion:
The correct answer is C. α-Ketoglutarate. This intermediate plays a crucial role in amino acid metabolism by serving as the precursor for glutamate, which is essential for the synthesis of GABA. A disruption in this pathway, as seen in ammonia intoxication, leads to glutamate depletion and results in convulsions.
9. In the TCA cycle, GTP is produced at one step by substrate-level phosphorylation, which is subsequently utilized in gluconeogenesis. Which of the following enzymes is involved in the formation of GTP from GDP?
A. Succinate thiokinase
B. Succinate dehydrogenase
C. Citrate synthase
D. Isocitrate dehydrogenase
E. Malate dehydrogenase
Correct answer:
A. Succinate thiokinase
Explanation:
Succinate thiokinase (also called succinyl-CoA synthetase) catalyzes the conversion of succinyl-CoA to succinate in the TCA cycle, releasing GTP through substrate-level phosphorylation. This GTP can later be utilized in gluconeogenesis, specifically for the conversion of oxaloacetate to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase (PEPCK).
Incorrect Options:
B. Succinate dehydrogenase catalyzes the oxidation of succinate to fumarate, producing FADH2, but it is not involved in GTP formation.
C. Citrate synthase catalyzes the formation of citrate from acetyl-CoA and oxaloacetate but does not produce GTP.
D. Isocitrate dehydrogenase converts isocitrate to α-ketoglutarate, generating NADH, not GTP.
E. Malate dehydrogenase catalyzes the conversion of malate to oxaloacetate, producing NADH, but it is not involved in GTP synthesis.
Conclusion:
The correct answer is A. Succinate thiokinase, as it is the enzyme responsible for producing GTP during the TCA cycle via substrate-level phosphorylation. This GTP plays an important role in supporting gluconeogenesis.
10. A 5-year-old child was rushed to the pediatric emergency after accidentally consuming fluoroacetate, a known inhibitor of the TCA cycle. Which of the following enzymes is inhibited by fluoroacetate?
A. Citrate synthase
B. Aconitase
C. Succinate dehydrogenase
D. Isocitrate dehydrogenase
E. Malate dehydrogenase
Correct answer:
B. Aconitase
Explanation:
Fluoroacetate is metabolized to fluorocitrate within cells. Fluorocitrate acts as a potent inhibitor of aconitase, an enzyme that catalyzes the conversion of citrate to isocitrate. Inhibiting aconitase disrupts the flow of the TCA cycle, leading to the accumulation of citrate and a depletion of downstream intermediates, impairing energy production. This can result in severe metabolic disturbances, which are particularly dangerous in pediatric patients.
Incorrect Options:
A. Citrate synthase catalyzes the condensation of oxaloacetate and acetyl-CoA to form citrate. However, it is not affected by fluoroacetate.
C. Succinate dehydrogenase converts succinate to fumarate and generates FADH2. It is inhibited by malonate, not fluoroacetate.
D. Isocitrate dehydrogenase catalyzes the conversion of isocitrate to α-ketoglutarate, generating NADH. It is not directly inhibited by fluoroacetate.
E. Malate dehydrogenase catalyzes the conversion of malate to oxaloacetate, producing NADH. It is unaffected by fluoroacetate poisoning.
Conclusion:
The correct answer is B. Aconitase. Fluoroacetate’s toxic effects arise from its conversion to fluorocitrate, which inhibits aconitase, leading to a block in the TCA cycle and subsequent energy failure.
11. Malonate is an inhibitor of which of the following enzymes?
A. Citrate synthase
B. Aconitase
C. Succinate dehydrogenase
D. Isocitrate dehydrogenase
E. Malate dehydrogenase
Correct answer:
C. Succinate dehydrogenase
Explanation:
Malonate is a competitive inhibitor of succinate dehydrogenase, the enzyme that catalyzes the oxidation of succinate to fumarate in the TCA cycle. Malonate resembles succinate structurally and competes for the active site of the enzyme, inhibiting the conversion of succinate to fumarate. This inhibition decreases FADH2 production and disrupts the electron transport chain, leading to impaired cellular respiration.
Incorrect Options:
A. Citrate synthase catalyzes the condensation of oxaloacetate and acetyl-CoA to form citrate but is not inhibited by malonate.
B. Aconitase converts citrate to isocitrate but is inhibited by fluorocitrate, not malonate.
D. Isocitrate dehydrogenase catalyzes the conversion of isocitrate to α-ketoglutarate with NADH production but is not affected by malonate.
E. Malate dehydrogenase catalyzes the conversion of malate to oxaloacetate, producing NADH, and it is not inhibited by malonate.
Conclusion:
The correct answer is C. Succinate dehydrogenase. Malonate inhibits this enzyme by competing with succinate for the active site, disrupting the TCA cycle and energy production.
12. A 56-year-old chronic alcoholic has been brought to the medical emergency in a semiconscious state. Blood biochemistry reveals hypoglycemia with a blood glucose level of 45 mg/dL. Which of the following intermediates of the TCA cycle can be directly converted to phosphoenolpyruvate to trigger the pathway of gluconeogenesis?
A. Succinate
B. Malate
C. α-Ketoglutarate
D. Oxaloacetate
E. Pyruvate
Correct answer:
D. Oxaloacetate
Explanation:
In gluconeogenesis, oxaloacetate is directly converted to phosphoenolpyruvate (PEP) by the enzyme phosphoenolpyruvate carboxykinase (PEPCK). This is a key step in gluconeogenesis, which is essential for producing glucose during fasting or in states of hypoglycemia, such as those often seen in chronic alcoholics. Alcohol consumption disrupts gluconeogenesis by depleting key substrates and cofactors, worsening hypoglycemia.
Incorrect Options:
A. Succinate is involved in the TCA cycle but does not participate in gluconeogenesis.
B. Malate can be transported to the cytoplasm from mitochondria and converted to oxaloacetate, but it is not directly converted to phosphoenolpyruvate.
C. α-Ketoglutarate is involved in the TCA cycle and amino acid metabolism but does not directly contribute to gluconeogenesis.
E. Pyruvate is a precursor for oxaloacetate, but it must first be carboxylated to oxaloacetate by pyruvate carboxylase before entering gluconeogenesis.
Conclusion:
The correct answer is D. Oxaloacetate. It plays a pivotal role in gluconeogenesis by being converted directly to phosphoenolpyruvate, which helps restore blood glucose levels in hypoglycemic states. Chronic alcoholics are prone to hypoglycemia due to impaired gluconeogenesis, making oxaloacetate crucial for recovery.
13. A 78-year-old male is brought to the emergency with an acute myocardial infarction. Blood chemistry reveals lactic acidosis. How much is the energy yield (ATP) per mole of glucose expected in such a condition?
A. 32
B. 2
C. 34
D. 36
E. 38
Correct answer:
B. 2
Explanation:
In conditions like acute myocardial infarction, oxygen delivery to tissues is impaired, leading to anaerobic metabolism. Under anaerobic conditions, glycolysis is the primary source of ATP production. During glycolysis, one mole of glucose produces only 2 ATP molecules (net gain). The pyruvate formed in glycolysis is converted to lactate, resulting in lactic acidosis. Without sufficient oxygen, the TCA cycle and oxidative phosphorylation cannot operate efficiently, severely limiting ATP production.
Incorrect Options:
A. 32 ATP is the theoretical yield under aerobic conditions, but this is not achieved during hypoxia or lactic acidosis.
C. 34 ATP and
D. 36 ATP are reported variations of aerobic ATP yield due to differences in NADH shuttling efficiency, but these are also only achieved under aerobic conditions.
E. 38 ATP is another theoretical maximum yield for one mole of glucose via glycolysis, the TCA cycle, and oxidative phosphorylation, but this is not possible under anaerobic conditions.
Conclusion:
The correct answer is B. 2. In lactic acidosis, only 2 ATP molecules are generated per mole of glucose through anaerobic glycolysis, since oxidative phosphorylation is impaired by insufficient oxygen. This reduced ATP production contributes to the energy crisis seen in ischemic tissues during myocardial infarction.
14. Which of the following allosteric modulators is not effective in influencing the rate of the TCA cycle?
A. NADH
B. FADH2
C. Ca++
D. ADP
E. ATP
Correct answer:
B. FADH2
Explanation:
FADH2 is produced in the TCA cycle during the oxidation of succinate to fumarate by succinate dehydrogenase. However, it acts as an electron carrier and is involved in the electron transport chain (ETC), not in the direct regulation of the TCA cycle. FADH2 itself does not have any known allosteric regulatory effects on enzymes of the TCA cycle.
Incorrect Options:
A. NADH inhibits key enzymes of the TCA cycle, including isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, reducing the cycle’s rate during high energy states.
C. Ca++ stimulates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, enhancing the cycle’s rate during times of increased energy demand, such as muscle contraction.
D. ADP is a positive allosteric regulator of isocitrate dehydrogenase, increasing the TCA cycle’s rate when energy demand is high.
E. ATP acts as a negative regulator of the TCA cycle by inhibiting isocitrate dehydrogenase, slowing down the cycle when energy levels are sufficient.
Conclusion:
The correct answer is B. FADH2. While FADH2 plays a role in the electron transport chain, it does not influence the allosteric regulation of the TCA cycle. Other modulators such as NADH, Ca++, ADP, and ATP are directly involved in regulating the cycle’s activity based on the cell’s energy needs.
15. How many molecules of CO₂ are produced per mole of acetyl-CoA in the TCA cycle?
A. 2
B. 1
C. 3
D. 0
E. 4
Correct answer:
A. 2
Explanation:
In the TCA cycle (Krebs cycle), for every mole of Acetyl-CoA that enters the cycle, two molecules of CO₂ are released. This happens during two decarboxylation reactions:
- Isocitrate dehydrogenase converts isocitrate to α-ketoglutarate, releasing the first molecule of CO₂.
- α-Ketoglutarate dehydrogenase complex converts α-ketoglutarate to succinyl-CoA, releasing the second molecule of CO₂. These two CO₂ molecules account for the carbon atoms originally derived from acetyl-CoA.
Incorrect Options:
B. 1 CO₂: This is incorrect, as two molecules are released per Acetyl-CoA.
C. 3 CO₂: The TCA cycle produces exactly two CO₂ per Acetyl-CoA, not three.
D. 0 CO₂: CO₂ release is a key part of the TCA cycle, contributing to carbon removal.
E. 4 CO₂: Only two CO₂ molecules are produced per mole of Acetyl-CoA, not four.
Conclusion:
The correct answer is A. 2. For each mole of Acetyl-CoA that enters the TCA cycle, two molecules of CO₂ are produced, representing the complete oxidation of the carbons from the acetyl group.
