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Questions and Answers
Which organ is primarily responsible for gluconeogenesis?
What inhibits the fructose bisphosphatase reaction in gluconeogenesis?
Which of the following substrates can be converted into glucose through gluconeogenesis?
What is the primary effect of glucagon during fasting?
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Which statement about the pyruvate carboxylase reaction is true?
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Which type of glycogen storage disorder is most commonly associated with a deficiency in glucose-6-phosphatase?
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Which of the following clinical manifestations is NOT commonly associated with glycogen storage disorders?
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What is the estimated incidence of glycogen storage disorders in live births?
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Which type of glycogen storage disease is specifically noted to have a higher incidence among Jews in northern Africa?
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Which enzyme deficiency is associated with Pompe's disease?
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What type of glycosidic bonds are formed at the branch points of glycogen?
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Which enzyme phosphorylates glucose to initiate glycolysis?
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What is the main hormone active during the synthesis of glycogen?
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Which step in the glycogenesis pathway is considered the rate-limiting step?
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What is produced at the end of the glycogenesis pathway?
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Which enzyme is responsible for the conversion of isocitrate to α-ketoglutarate in the Kreb's cycle?
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In the Kreb's cycle, which end product is generated alongside 3 NADH and 1 FADH2?
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Which of the following statements about citrate in the Kreb's cycle is NOT true?
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Which factor does NOT activate isocitrate dehydrogenase in the Kreb's cycle?
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What is the primary location of the Kreb's cycle in eukaryotic cells?
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What is the primary reaction catalyzed by Isocitrate Dehydrogenase in the TCA cycle?
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Which of the following statements about Succinyl-CoA Synthetase is correct?
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What inhibits the α-ketoglutarate Dehydrogenase Complex?
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Which enzyme is responsible for the hydration of Fumarate to Malate?
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What is a characteristic result of the reaction catalyzed by Malate Dehydrogenase?
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What is a primary characteristic of the Krebs cycle?
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Which compound is identified as the central molecule of biochemistry in the context of the Krebs cycle?
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During fasting, from where does acetyl CoA primarily originate?
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What factors regulate the rate of the Krebs cycle?
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Which of the following accurately describes transamination and deamination in relation to the Krebs cycle?
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What is the role of glucokinases in glucose metabolism?
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Which step of glycolysis is identified as both the rate-limiting and the second irreversible step?
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What intermediate is formed during glycolysis that affects oxygen dissociation from hemoglobin?
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Which molecule is produced during substrate-level phosphorylation in glycolysis?
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During the oxidation of glyceraldehyde phosphate, what is reduced?
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What is the primary function of glycolysis in glucose metabolism?
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Which enzyme is responsible for the first irreversible step of glycolysis?
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Under which condition do tissues like the brain continue to utilize glucose despite low blood glucose levels?
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What occurs to glucose-6-phosphate in the first step of glycolysis?
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How does the activity of glucokinase change in response to elevated postprandial blood glucose levels?
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What is the main product of glycolysis under aerobic conditions?
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What is required for the transport of NADH across the inner mitochondrial membrane?
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When is glycolysis activated?
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Which of the following is NOT a step in glycolysis?
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Under which condition does anaerobic glycolysis occur?
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Study Notes
Gluconeogenesis
- Converts non-carbohydrates to glucose/glycogen to prevent hypoglycemia during fasting.
- Predominantly occurs in liver (90%) and kidneys (10%), not in muscle or adipose tissue.
- Reversed by glucose-6-phosphate; hexokinase is the first irreversible step in glycolysis but not committed.
- Substrates include glucogenic amino acids, lactate (via the Cori cycle), and glycerol.
Regulation of Gluconeogenesis
- Pyruvate carboxylase is inactive without acetyl CoA.
- Fructose bisphosphatase is inhibited by AMP.
- Glucagon is the hormone active during fasting.
Glycogen Structure and Function
- Glycogen exists as granules in the cytosol and serves as an important fuel reserve.
- Functions to buffer blood-glucose levels, especially via glucose-6-phosphate.
- More glycogen is stored in muscle compared to liver, correlating with tissue mass.
Glycogenesis
- Occurs in energy-excess states, primarily in liver and muscles.
- Involves the conversion of glucose to glycogen:
- Glycogen synthase forms α-(1→4) glycosidic bonds.
- Activated glucose is in the form of UDP-glucose.
- Rate-limiting step may involve enzyme deficiency or dysfunction affecting glucose-to-glycogen conversion.
Glycogen Storage Disorders (GSD)
- Incidence of GSDs estimated at 1 in every 20,000-43,000 live births; no significant ethnic differences.
- Von Gierke’s disease (GSD Type I) - Glucose-6-phosphatase deficiency, causing fasting hypoglycemia and lactic acidosis. Affects liver, intestinal mucosa, and kidneys.
- Pompe’s disease (GSD Type II) - Deficiency of lysosomal acid α-1,4 glucosidase leads to glycogen accumulation in lysosomes.
Other Glycogen Storage Disorders
- McArdle’s disease (GSD Type V) - Phosphorylase deficiency in skeletal muscle causing myoglobinuria, fatigue, and exercise intolerance.
- Cori’s disease (GSD Type III) - Glycogen debranching enzyme deficiency, leading to abnormally structured glycogen.
- Andersen’s disease (GSD Type IV) - Branching enzyme deficiency results in abnormal glycogen with fewer branch points.
- Hers disease (GSD Type VI) - Liver glycogen phosphorylase deficiency leading to enlarged liver.
- Tarui’s disease (GSD Type VII) - Muscle phosphofructokinase deficiency causing exercise-related symptoms.
Clinical Manifestations and Treatment
- Symptoms of GSDs vary by type; common issues include fatigue, exercise intolerance, and lactic acidosis.
- Treatment approaches may involve high-protein diets and controlled exercise.
Kreb's Cycle Overview
- Also known as the tricarboxylic acid (TCA) cycle, it is the final common pathway for aerobic oxidation of carbohydrates, lipids, and proteins.
- Known as an amphibolic pathway, functioning in both catabolic and anabolic processes.
Function and Importance
- Major source for ATP production.
- Provides key substrates for gluconeogenesis, amino acid synthesis, and fatty acid synthesis.
Location
- Occurs within the mitochondrial matrix of all cells containing mitochondria.
- Exception: succinate dehydrogenase is located on the inner mitochondrial membrane.
Substrate and End Products
- Main substrate is Acetyl-CoA.
- Produces: 2 CO2, 1 GTP, 3 NADH, and 1 FADH2 per cycle.
Rate-Limiting Step
- Isocitrate to α-ketoglutarate is the rate-limiting step, catalyzed by isocitrate dehydrogenase.
Key Enzymes and Reactions
- Citrate Synthase: Condenses Acetyl-CoA with oxaloacetate to form citrate.
- Aconitase: Converts citrate to isocitrate; inhibited by fluoroacetate.
- Isocitrate Dehydrogenase: Catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate.
- α-Ketoglutarate Dehydrogenase Complex: Converts α-ketoglutarate to succinyl-CoA, yielding CO2 and NADH.
- Succinyl-CoA Synthetase: Associated with substrate-level phosphorylation producing GTP (or ATP).
- Succinate Dehydrogenase: Oxidizes succinate to fumarate, yielding FADH2.
- Fumarase: Hydrates fumarate to malate.
- Malate Dehydrogenase: Oxidizes malate to oxaloacetate, yielding NADH.
CO2 and Energy Production
- Key steps that produce CO2: oxidative decarboxylation reactions.
- Key steps that yield NADH and FADH2 accompany the generation of energy through electron transport.
Inhibition and Regulation
- Inhibitors include arsenite, fluoroacetate, and malonate, affecting different enzymes in the cycle.
- Regulation depends on energy requirements and the need for carbon precursors.
Additional Pathways
- Kreb’s cycle intermediates support other pathways:
- Gluconeogenesis: Key for producing glucose precursors.
- Fatty Acid Synthesis: Acetyl-CoA is a major building block.
- Heme Synthesis: Succinyl-CoA combines with glycine in heme formation.
ATP Yield
- Complete oxidation from one Acetyl-CoA molecule results in approximately 10 ATP.
- Complete oxidation of glucose yields around 30 to 32 ATP, depending on shuttle systems.
Summary of Key Facts
- Kreb’s cycle plays a crucial role in metabolism and energy production.
- Central molecule is Acetyl-CoA, with various pathways determined by the nutritional state (well-fed vs fasting).
- Takes place in mitochondrial matrix, barring the succinate dehydrogenase step in the inner mitochondrial membrane.
Glycolysis Overview
- Major pathway for glucose metabolism, converting glucose to 3-carbon compounds for energy.
- Occurs in the cytosol, primarily through the Embden-Meyerhof-Parnas pathway.
- Substrate is glucose; end products are two molecules of either pyruvate or lactate.
- Key regulation point is Step 1: Phosphorylation of glucose by phosphofructokinase-1.
ATP Yield in Glycolysis
- ATP produced through substrate-level phosphorylation, generating 2 ATP molecules per glucose molecule during glycolysis.
- Formation of pyruvate is the primary outcome of glycolysis, while lactate is produced under anaerobic conditions.
Aerobic vs. Anaerobic Glycolysis
- Aerobic glycolysis occurs in cells with mitochondria and adequate O2; yields pyruvate.
- Anaerobic glycolysis occurs in cells without mitochondria or with insufficient O2; reduces pyruvate to lactate.
- NADH is recycled to NAD+ via lactate formation under anaerobic conditions, crucial for maintaining glycolytic flux.
Key Steps of Glycolysis
- Step 1: Phosphorylation of glucose to glucose-6-phosphate (irreversible).
- Step 2: Isomerization of glucose-6-phosphate to fructose-6-phosphate.
- Step 3: Phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate (ratelimit step).
- Step 4-5: Cleavage of fructose-1,6-bisphosphate into two 3-carbon units.
- Step 6: Oxidation of glyceraldehyde phosphate to 1,3-bisphosphoglycerate, involves reduction of NAD+.
- Step 10: Formation of pyruvate from phosphoenolpyruvate (PEP), also a substrate-level phosphorylation step.
Regulation of Glycolysis
- Glucokinase operates in the liver, actively trapping glucose during hyperglycemia, and is not inhibited by G6P.
- Hexokinases (I, II, III) are allosterically inhibited by G6P, regulating glucose usage in peripheral tissues.
- Fructose-1,6-bisphosphate activates pyruvate kinase, while glucagon inhibits glucose metabolism.
Pyruvate Dehydrogenase Complex
- Pyruvate is oxidized to acetyl-CoA in the mitochondria if oxygen is present.
- Key cofactors for the complex include NAD+ and coenzyme A; NADH generated enters the electron transport chain.
Luebering-Rapoport Pathway (RBCs)
- Metabolic bypass in red blood cells that produces 2,3-bisphosphoglycerate (2,3-BPG).
- 2,3-BPG lowers hemoglobin's affinity for oxygen, facilitating oxygen release in tissues.
- Involves two enzymes: Bisphosphoglycerate mutase and 2,3-BPG phosphatase.
Importance of Regulation
- Ensures efficient management of glucose based on energy demands and availability.
- Blood glucose levels influence liver and peripheral tissue usage through glucokinase and hexokinase activity.
Clinical Relevance
- Lactic acidosis can result from intense exercise, septic shock, and impaired oxygen delivery.
- Anaerobic metabolism becomes prominent in conditions where oxygen is scarce, leading to lactate accumulation.
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Description
Explore the key concepts and mechanisms involved in gluconeogenesis, including the conversion of non-carbohydrates into glucose or glycogen. This quiz covers the roles of enzymes such as glucose-6-phosphate and emphasizes the physiological importance of gluconeogenesis in the liver and kidneys.
