Biochemistry: Pyruvate Dehydrogenase
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Questions and Answers

Pyruvate can be converted to Acetyl-CoA by the Pyruvate Dehydrogenase Complex.

True

The Pyruvate Dehydrogenase Complex is a reversible reaction.

False

Acetyl-CoA and NADH can allosterically activate the Pyruvate Dehydrogenase.

False

Pyruvate Dehydrogenase Deficiency can lead to congenital lactic acidosis.

<p>True</p> Signup and view all the answers

Arsenic acts as a cofactor for the Pyruvate Dehydrogenase.

<p>False</p> Signup and view all the answers

Hexokinase has a high Km, which means it has a high affinity for glucose even at low concentrations.

<p>False</p> Signup and view all the answers

Glucokinase is primarily found in liver parenchymal cells and pancreatic islet cells.

<p>True</p> Signup and view all the answers

Phosphorylation of glucose is carried out by phosphatases.

<p>False</p> Signup and view all the answers

Pyruvate can be converted to Acetyl-CoA, which can enter the TCA Cycle.

<p>True</p> Signup and view all the answers

Pyruvate Carboxylase is responsible for converting pyruvate to ethanol.

<p>False</p> Signup and view all the answers

The regulatory enzymes in glycolysis act as metabolic 'valves' controlling irreversible reactions.

<p>True</p> Signup and view all the answers

Glyceraldehyde-3-P is a product of the conversion of dihydroxyacetone phosphate.

<p>True</p> Signup and view all the answers

Hexokinase is responsible for catalyzing the last reaction of glycolysis.

<p>False</p> Signup and view all the answers

Panthotenic acid is also known as vitamin B5.

<p>True</p> Signup and view all the answers

A deficiency in thiamine has no impact on pyruvate dehydrogenase function.

<p>False</p> Signup and view all the answers

The TCA cycle primarily occurs in the cytoplasm of the cell.

<p>False</p> Signup and view all the answers

ADP and Ca2+ activate the citrate synthase reaction.

<p>True</p> Signup and view all the answers

The oxidative decarboxylation of isocitrate is a rate-limiting step in the TCA cycle.

<p>True</p> Signup and view all the answers

Fats are converted directly into glucose in cellular respiration.

<p>False</p> Signup and view all the answers

Succinyl CoA acts as an inhibitor in the α-ketoglutarate dehydrogenase complex.

<p>True</p> Signup and view all the answers

NADH is produced during the conversion of α-ketoglutarate to succinyl CoA.

<p>True</p> Signup and view all the answers

Succinyl CoA is converted to Succinate and produces one GTP.

<p>True</p> Signup and view all the answers

The enzyme succinate dehydrogenase is found in the cytoplasm.

<p>False</p> Signup and view all the answers

FADH2 is produced from the conversion of fumarate to malate.

<p>False</p> Signup and view all the answers

The total theoretical ATP yield from one Acetyl CoA in the TCA cycle is 12.

<p>True</p> Signup and view all the answers

NADH and FADH2 produced in the TCA cycle are used in oxidative phosphorylation to generate ATP.

<p>True</p> Signup and view all the answers

Citrate synthase is activated by ATP.

<p>False</p> Signup and view all the answers

A total of 4 electron pairs are transferred from the TCA cycle to generate 3 NADH and 2 FADH2.

<p>False</p> Signup and view all the answers

Malate dehydrogenase converts malate to oxaloacetate and produces NADH.

<p>True</p> Signup and view all the answers

Anaerobic metabolism is more efficient than aerobic metabolism.

<p>False</p> Signup and view all the answers

Aerobic glycolysis produces a maximum of 38 ATP from one glucose molecule.

<p>True</p> Signup and view all the answers

The direct production of ATP occurs via oxidative phosphorylation.

<p>False</p> Signup and view all the answers

Anaerobic glycolysis yields 2 ATP per glucose molecule.

<p>True</p> Signup and view all the answers

NADH can produce 3 ATP when converted in the electron transport chain.

<p>True</p> Signup and view all the answers

The TCA cycle produces more NADH than FADH2 per glucose metabolized.

<p>True</p> Signup and view all the answers

Anaerobic metabolism results in the production of lactate.

<p>True</p> Signup and view all the answers

Aerobic metabolism can convert glucose into pyruvate without using oxygen.

<p>False</p> Signup and view all the answers

Glucose is a non-polar molecule and can easily cross cell membranes without transport proteins.

<p>False</p> Signup and view all the answers

The body must maintain glucose levels in circulation between 4.5 - 5.6 mmol/L during fasting.

<p>True</p> Signup and view all the answers

Anaerobic metabolism yields more ATP per glucose molecule than aerobic metabolism.

<p>False</p> Signup and view all the answers

Certain tissues, such as the brain and erythrocytes, can only use glucose as a metabolic fuel.

<p>True</p> Signup and view all the answers

The TCA cycle is primarily located in the nucleus of the cell.

<p>False</p> Signup and view all the answers

Hexokinase is inhibited by its product, glucose-6-phosphate, indicating its regulatory role in glycolysis.

<p>True</p> Signup and view all the answers

Glucokinase operates with a high affinity for glucose, making it effective at low glucose concentrations.

<p>False</p> Signup and view all the answers

Phosphofructokinase (PFK1) is the rate-limiting step in glycolysis and is activated by ATP.

<p>False</p> Signup and view all the answers

Fructose 2,6-bisphosphate acts as an inhibitor of gluconeogenesis.

<p>True</p> Signup and view all the answers

The Pyruvate Dehydrogenase Complex consists of four distinct enzyme activities.

<p>False</p> Signup and view all the answers

Pyruvate kinase is activated by fructose-1,6-bisphosphate, allowing for efficient glycolysis.

<p>True</p> Signup and view all the answers

Pyruvate is converted to Lactic acid in the case of Pyruvate Dehydrogenase Deficiency.

<p>True</p> Signup and view all the answers

The mitochondrial membrane is permeable to charged molecules, allowing pyruvate to freely enter the mitochondria.

<p>False</p> Signup and view all the answers

AMP acts as an allosteric activator of phosphofructokinase, indicating low energy status in the cell.

<p>True</p> Signup and view all the answers

Acetyl-CoA can be converted back into glucose through the actions of the Pyruvate Dehydrogenase Complex.

<p>False</p> Signup and view all the answers

Glucose-6-phosphate serves as a signal to the cell that additional glucose is required.

<p>False</p> Signup and view all the answers

Arsenic poisoning inhibits enzymes that rely on lipoic acid as a cofactor, including pyruvate dehydrogenase.

<p>True</p> Signup and view all the answers

The association of the three enzymes in the Pyruvate Dehydrogenase Complex allows intermediates to be released into the cytoplasm.

<p>False</p> Signup and view all the answers

Hexokinase has a high Vmax, allowing it to handle high glucose levels effectively.

<p>False</p> Signup and view all the answers

Glucokinase operates efficiently at high glucose concentrations due to its low Km.

<p>False</p> Signup and view all the answers

Phosphorylation of glucose prevents its exit from the cell by converting it to Glucose-6-phosphate.

<p>True</p> Signup and view all the answers

The conversion of pyruvate to Acetyl-CoA is catalyzed by Pyruvate Kinase.

<p>False</p> Signup and view all the answers

Hexokinase, phosphofructokinase, and pyruvate kinase are considered regulatory enzymes in glycolysis.

<p>True</p> Signup and view all the answers

Dihydroxyacetone phosphate (DHAP) and Glyceraldehyde-3-P are inter-convertible C3 molecules.

<p>True</p> Signup and view all the answers

Acetyl-CoA can enter the TCA Cycle and also serves as a precursor for fatty acid synthesis.

<p>True</p> Signup and view all the answers

The irreversible reaction catalyzed by pyruvate kinase occurs at the end of glycolysis.

<p>True</p> Signup and view all the answers

Aerobic metabolism allows for the complete oxidation of fuel molecules to CO2 and H2O.

<p>True</p> Signup and view all the answers

Anaerobic metabolism produces 8 ATP for every glucose molecule processed.

<p>False</p> Signup and view all the answers

Oxidative phosphorylation produces the most ATP in aerobic respiration.

<p>True</p> Signup and view all the answers

Anaerobic glycolysis recycles NADH by converting pyruvate to ethanol.

<p>False</p> Signup and view all the answers

The TCA cycle generates a maximum of 6 ATP from one glucose molecule.

<p>False</p> Signup and view all the answers

Each NADH can contribute to the generation of 2.5 ATP in the electron transport chain.

<p>True</p> Signup and view all the answers

FADH2 produces more ATP than NADH in oxidative phosphorylation.

<p>False</p> Signup and view all the answers

Aerobic glycolysis yields both ATP and NADH per glucose molecule.

<p>True</p> Signup and view all the answers

Glucose is a polar molecule and does not require transport proteins to move through membranes.

<p>False</p> Signup and view all the answers

Certain tissues, such as the brain and erythrocytes, can exclusively utilize glucose as their primary metabolic fuel.

<p>True</p> Signup and view all the answers

The body aims to maintain glucose levels between 3.0 - 4.0 mmol/L during fasting.

<p>False</p> Signup and view all the answers

Anaerobic metabolism produces no ATP when glucose is metabolized.

<p>False</p> Signup and view all the answers

The TCA cycle occurs primarily in the cytoplasm of the cell.

<p>False</p> Signup and view all the answers

Arsenic acts as a catalyst in the pyruvate dehydrogenase reaction.

<p>False</p> Signup and view all the answers

The Pyruvate Dehydrogenase Complex is reversible, allowing acetyl-CoA to convert back to pyruvate.

<p>False</p> Signup and view all the answers

Lactic acid is produced when pyruvate is converted due to a deficiency in pyruvate dehydrogenase.

<p>True</p> Signup and view all the answers

Pyruvate dehydrogenase requires three distinct coenzymes for its catalytic activities.

<p>False</p> Signup and view all the answers

Acetyl-CoA acts as an allosteric inhibitor of the Pyruvate Dehydrogenase Complex.

<p>True</p> Signup and view all the answers

Glucokinase has a low Km, which means it operates efficiently at low glucose concentrations.

<p>False</p> Signup and view all the answers

Hexokinase has a high Vmax, allowing it to handle high glucose levels efficiently.

<p>False</p> Signup and view all the answers

The conversion of glucose to fructose 1,6-bisphosphate requires both an isomerization and two phosphorylation steps.

<p>True</p> Signup and view all the answers

Pyruvate can be converted to oxaloacetate, which serves as a precursor for fatty-acid synthesis.

<p>False</p> Signup and view all the answers

Regulatory enzymes in glycolysis act as metabolic valves, controlling reversible reactions.

<p>False</p> Signup and view all the answers

Triose phosphate isomerase converts glyceraldehyde-3-phosphate into dihydroxyacetone phosphate.

<p>False</p> Signup and view all the answers

Phosphorylation of glucose is catalyzed by kinases like glucokinase, hexokinase, and phosphofructokinase.

<p>False</p> Signup and view all the answers

During glycolysis, ATP is generated when 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate.

<p>True</p> Signup and view all the answers

The rate-limiting step of the TCA cycle occurs during the conversion of citrate to isocitrate.

<p>False</p> Signup and view all the answers

Thiamine pyrophosphate is a coenzyme used in the conversion of α-ketoglutarate to succinyl CoA.

<p>True</p> Signup and view all the answers

Activated by ATP, the citrate synthase reaction combines acetyl CoA with oxaloacetate to form citrate.

<p>False</p> Signup and view all the answers

Pyruvate dehydrogenase deficiency has no connection to lactate levels in the body.

<p>False</p> Signup and view all the answers

The mitochondrial matrix is the primary location for the TCA cycle.

<p>True</p> Signup and view all the answers

Oxidative phosphorylation and the TCA cycle are both crucial for generating ATP from fatty acids.

<p>True</p> Signup and view all the answers

Isocitrate dehydrogenase operates independently of any allosteric regulators.

<p>False</p> Signup and view all the answers

NADH is produced during the conversion of succinate to fumarate in the TCA cycle.

<p>True</p> Signup and view all the answers

Aerobic metabolism produces a maximum of 38 ATP from one glucose molecule during oxidative phosphorylation.

<p>True</p> Signup and view all the answers

Anaerobic glycolysis results in the complete oxidation of glucose to CO2 and H2O.

<p>False</p> Signup and view all the answers

The conversion of NADH to ATP in the electron transport chain yields more ATP than FADH2.

<p>True</p> Signup and view all the answers

Anaerobic metabolism involves the conversion of glucose to lactate, resulting in a total yield of 8 ATP per glucose.

<p>False</p> Signup and view all the answers

Glycolysis yields the same amount of ATP whether oxygen is present or not.

<p>True</p> Signup and view all the answers

The TCA cycle yields a total of 2 NADH and 2 GTP per glucose metabolized.

<p>False</p> Signup and view all the answers

Oxygen is essential for both substrate-level phosphorylation and oxidative phosphorylation.

<p>False</p> Signup and view all the answers

ATP is generated indirectly in anaerobic metabolism through oxidative phosphorylation.

<p>False</p> Signup and view all the answers

Study Notes

Sodium-Dependent Unidirectional Transporter

  • SGLT1 is a protein that facilitates the active uptake of glucose against a concentration gradient in both the small intestine and kidneys.

Glucose Retention in Cells

  • Once inside the cell, glucose is trapped through phosphorylation, converting it to glucose-6-phosphate.
  • This phosphorylation is catalyzed by hexokinase, present in all cells, and glucokinase, mainly in liver parenchymal and pancreatic islet cells.

Hexokinase vs. Glucokinase

  • Hexokinase has a low Km (high affinity for glucose) and a low Vmax (limited capacity), operating effectively at low glucose concentrations.
  • Glucokinase has a high Km (only operates efficiently at high glucose levels) and a high Vmax (high capacity), allowing it to handle high glucose levels post-prandially.

Stages of Glycolysis

  • Glycolysis is the breakdown of glucose into pyruvate, generating ATP.
  • It involves a series of enzymatic reactions, starting with the phosphorylation of glucose, followed by a series of complex steps that ultimately lead to the formation of two pyruvate molecules.
  • During glycolysis, glucose is converted to two 3-carbon molecules, ultimately producing two ATP.

Generation of ATP

  • ATP is generated through substrate-level phosphorylation during glycolysis, with key reactions involving:
    • Glyceraldehyde-3-phosphate (G3P) to 1,3-bisphosphoglycerate (1,3-BPG), catalyzed by G3P dehydrogenase.
    • 1,3-BPG to 3-phosphoglycerate (3-PG), catalyzed by phosphoglycerate kinase.
    • Phosphoenolpyruvate (PEP) to pyruvate, catalyzed by pyruvate kinase.

Alternative Metabolic Uses of Pyruvate

  • Pyruvate can be converted to Acetyl-CoA by pyruvate dehydrogenase complex, entering the TCA cycle or serving as a precursor for fatty acid synthesis.
  • Pyruvate can also be converted to oxaloacetate by pyruvate carboxylase, entering the TCA cycle or serving as a precursor for gluconeogenesis.
  • Pyruvate can be reduced to ethanol by pyruvate decarboxylase.

Regulatory Processes in Glycolysis

  • Irreversible reactions in glycolysis are controlled by regulatory enzymes, acting as metabolic "valves". These enzymes include:
    • Hexokinase: controls entry into glycolysis.
    • Phosphofructokinase: controls a key step in the pathway.
    • Pyruvate kinase: controls the last step in glycolysis.

Control of Glycolysis - Hexokinase

  • This enzyme catalyzes the first reaction of glycolysis, regulating entry into the pathway.
  • Hexokinase activity can be influenced by the concentration of glucose within the cell.

Pyruvate Dehydrogenase Complex

  • This multi-enzyme complex catalyzes the irreversible conversion of pyruvate to Acetyl-CoA.
  • It comprises three distinct enzyme activities: pyruvate decarboxylase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase.
  • The complex utilizes five coenzymes: thiamine pyrophosphate (TPP), lipoic acid, CoA, NAD+, and FAD.
  • It can be allosterically inhibited by Acetyl-CoA and NADH.

Pyruvate Dehydrogenase Deficiency

  • This inherited X-linked genetic defect leads to congenital lactic acidosis.
  • The body is unable to convert pyruvate to Acetyl-CoA, resulting in its conversion to lactic acid.
  • Symptoms include developmental defects, muscle spasticity, and early death.
  • There is no effective therapy available.

Pyruvate Dehydrogenase Inhibition by Arsenic Poisoning

  • Arsenic, an inhibitor of enzymes utilizing lipoic acid as a cofactor, inhibits pyruvate dehydrogenase.
  • This can lead to neurological disturbances and death.

Pyruvate Dehydrogenase and Vitamin Deficiencies

  • Coenzymes require vitamins for their synthesis:
    • CoA: requires pantothenic acid (B5).
    • NAD: requires niacin (B3).
    • FAD: requires riboflavin (B2).
    • TPP: requires thiamine (B1).
  • Deficiency in any of these vitamins can impair pyruvate dehydrogenase function, leading to increased levels of pyruvate, lactate, and alanine, lethargy, fatigue, and complications affecting various systems.

The Tricarboxylic Acid (TCA) Cycle

  • It occurs primarily in the mitochondrial matrix.
  • It plays a central role in cellular respiration, contributing significantly to energy production and supplying metabolic intermediates.
  • The cycle is a series of reactions involving the oxidation of Acetyl-CoA, generating energy in the form of ATP, NADH, and FADH2.

TCA Cycle Reactions

  • Citrate Synthase: Acetyl-CoA and oxaloacetate combine to form citrate.
  • Aconitase: Citrate is converted to isocitrate.
  • Isocitrate Dehydrogenase: Isocitrate is oxidized to α-ketoglutarate, generating CO2 and NADH.
    • This is a rate-limiting step in the TCA cycle.
  • α-ketoglutarate Dehydrogenase Complex: α-ketoglutarate is oxidized to succinyl CoA, generating CO2 and NADH.
    • This multi-enzyme complex requires coenzymes: TPP, lipoic acid, FAD, NAD+, and CoA.
  • Succinate Thiokinase: Succinyl CoA is converted to succinate, generating GTP.
  • Succinate Dehydrogenase: Succinate is oxidized to fumarate, generating FADH2.
  • Fumarase: Fumarate is converted to malate.
  • Malate Dehydrogenase: Malate is oxidized to oxaloacetate, generating NADH.

Energy Generation in the TCA Cycle

  • The TCA cycle yields one GTP molecule directly.
  • It generates four electron pairs, producing three NADH and one FADH2 molecules, which will ultimately generate ATP through oxidative phosphorylation.

Regulation of the TCA Cycle

  • Various factors influence the activity of the TCA cycle enzymes, including:
    • Inhibitors: NADH, ATP, succinyl CoA.
    • Activators: ADP, Ca2+

Energy Yield from Glucose Catabolism

  • Glycolysis can be viewed as having two stages, based on energy generation and consumption.
  • Anaerobic metabolism:
    • Glucose is broken down to pyruvate.
    • Yields a net of 2 ATP per glucose.
  • Aerobic metabolism:
    • Glucose is completely oxidized to CO2 and H2O.
    • Yields a net of 30-38 ATP per glucose.
  • This higher efficiency of aerobic metabolism is due to the complete oxidation of fuel molecules.

ATP Production

  • ATP is produced through two methods:
    • Substrate-level phosphorylation: direct generation of ATP from specific reactions, e.g., phosphoglycerate kinase in glycolysis.
    • Oxidative phosphorylation: indirect generation of ATP from NADH+H+ and FADH2, which act as carriers of reducing power (electrons) during the electron transport chain.

Aerobic vs. Anaerobic Glycolysis

  • Anaerobic glycolysis:
    • Occurs in the absence of oxygen.
    • Produces lactate as a byproduct.
  • Aerobic glycolysis:
    • Occurs in the presence of oxygen.
    • Produces pyruvate, which enters the TCA cycle.

Energy from Aerobic Glycolysis

  • Yields 8 ATP (2 from glycolysis and 6 from oxidative phosphorylation of NADH produced during glycolysis).
  • Includes the conversion of 2 NADH to 6 ATP.

Energy from Anaerobic Glycolysis

  • Yields 2 ATP (from glycolysis only).
  • Includes the conversation of pyruvate to lactate.

ATP Production Comparison

  • Anaerobic metabolism: 1 glucose produces 2 ATP (8 from glycolysis - 6 from lactate production).
  • Aerobic metabolism: 1 glucose produces 38 ATP.

Energy Yield from Cellular Respiration

  • Anaerobic glycolysis: 2 ATP per glucose.
  • Aerobic glycolysis: 2 ATP and 2 NADH per glucose.
  • Pyruvate Dehydrogenase: 2 NADH per glucose.
  • TCA cycle: 6 NADH, 2 FADH2, and 2 GTP per glucose.
  • Oxidative phosphorylation: 2.5 ATP per NADH, 2 ATP per FADH2.
  • Total yield from 1 glucose for aerobic respiration: 33 ATP* (30-38).

Glucose Metabolism

  • Glucose metabolism is the process by which organisms break down glucose for energy. It is critical for the normal functioning of the brain, red blood cells, and other tissues.
  • Glucose is the primary energy source for the human body.
  • The body must maintain a constant supply of glucose in the bloodstream, maintained within a narrow range of 4.5-5.6 mmol/L.
  • Two main metabolic pathways: glycolysis and the tricarboxylic acid (TCA) cycle.
  • Glycolysis is the breakdown of glucose into pyruvate. This process occurs in the cytoplasm of cells.
  • The TCA cycle occurs in the mitochondria of cells and oxidizes pyruvate further to carbon dioxide.

Glucose Entry into Cells

  • Glucose is a polar molecule, so special transporters are required to move it across cell membranes.
  • SGLT1 transporter facilitates glucose uptake against a concentration gradient, found in the small intestine and kidney.
  • Once glucose enters the cell, it is trapped inside by phosphorylation, converting it to glucose-6-phosphate.
  • Hexokinase and glucokinase are the enzymes that catalyze phosphorylation.

Hexokinase vs. Glucokinase

  • Hexokinase is an enzyme present in all cells, while glucokinase is found in liver and pancreatic cells.
  • Hexokinase has a low Km and high affinity for glucose, meaning it is very efficient at low glucose concentrations.
  • Glucokinase has a high Km and low affinity for glucose, it only operates efficiently at high glucose concentrations. This makes it particularly relevant after a meal.

Stages of Glycolysis

  • Steps 1-3: Glucose is trapped and destabilized in preparation for splitting. This involves a series of phosphorylation and isomerization reactions.
  • Step 4: The 6-carbon glucose molecule is split into two 3-carbon molecules.
  • Steps 5-10: The two 3-carbon molecules are further modified and converted into pyruvate, generating ATP molecules.

Regulation of Glycolysis

  • Hexokinase: inhibited by its product, glucose-6-phosphate.
  • Glucokinase: not inhibited by glucose-6-phosphate.
  • Phosphofructokinase (PFK): the most important control point; allosterically inhibited by ATP and citrate, activated by AMP.
  • Pyruvate kinase: Activated by fructose-1,6-bisphosphate, inactivated by glucagon mediated phosphorylation.

Alternative Metabolic Fates of Pyruvate

  • Pyruvate can be converted to:
    • Acetyl-CoA: enters the TCA cycle or is used for fatty acid synthesis.
    • Oxaloacetate: enters the TCA cycle or is used for gluconeogenesis.
    • Ethanol: during fermentation by some organisms.

Pyruvate Dehydrogenase Complex

  • This enzyme complex converts pyruvate to Acetyl-CoA.
  • It is located in the mitochondrial matrix.
  • It is a multi-enzyme complex with 3 distinct enzyme activities.
  • This complex requires 5 coenzymes for function.
  • It is an irreversible reaction, meaning Acetyl-CoA can't be used for glucose synthesis.
  • It is inhibited by Acetyl-CoA and NADH.

Clinical Significance of Pyruvate Dehydrogenase Complex

  • Pyruvate Dehydrogenase Deficiency: A genetic disorder resulting in lactic acidosis due to pyruvate being converted to lactate instead of Acetyl-CoA. Causes developmental issues, muscular spasticity, and early death.
  • Arsenic Poisoning: Arsenic inhibits enzymes using lipoic acid, including pyruvate dehydrogenase, leading to neurological disturbances and death

ATP Production

  • Substrate-level phosphorylation: Directly generates ATP; for example, in the phosphoglycerate kinase reaction in glycolysis.
  • Oxidative phosphorylation: Indirectly generates ATP by utilizing NADH and FADH2 as electron carriers. NADH yields 3 ATP per molecule, FADH2 yields 2 ATP.

Anaerobic vs. Aerobic Glycolysis

  • Anaerobic glycolysis: occurs when oxygen is limited, resulting in the production of lactate.
  • Aerobic glycolysis: when oxygen is present, pyruvate enters the TCA cycle for further breakdown.

Energy Yield from Cellular Respiration

  • Anaerobic glycolysis: only yields 2 ATP per glucose molecule.
  • Aerobic glycolysis: yields 2 ATP and 2 NADH per glucose.
  • Pyruvate dehydrogenase complex: yields 2 NADH per glucose.
  • TCA cycle yields 6 NADH, 2 FADH2, and 2 GTP per glucose.
  • Oxidative phosphorylation: converts NADH (2.5 ATP) and FADH2 (2 ATP) into ATP.
  • Total ATP yield for aerobic respiration is typically around 30-38 molecules per glucose molecule.

Why Glucose Metabolism is Important

  • Glucose and related sugars are important components of the diet, including the breakdown product of carbohydrates like starch.
  • Some tissues rely solely on glucose for metabolic fuel, including the brain, erythrocytes, renal medulla, cornea, testes, and exercising muscle.
  • The body must maintain constant glucose levels in circulation, typically between 4.5 and 5.6 mmol/L during fasting.

Glucose Entry into Cells

  • Glucose uptake into cells requires transport proteins due to its polar nature.
  • The Sodium-dependent Unidirectional Transporter (SGLT1) actively transports glucose against a concentration gradient, found in the small intestine and kidney.
  • Once inside the cell, glucose is trapped by phosphorylation, becoming Glucose-6-phosphate. This prevents it from leaving the cell as there are no membrane transporters for phosphorylated sugars.
  • Phosphorylation is catalyzed by kinases: hexokinase in all cells and glucokinase in liver parenchymal cells and pancreatic islet cells.
  • Hexokinase has a low Km (high affinity for glucose even at low concentrations) and low Vmax (limited capacity).
  • Glucokinase (hexokinase-D) has a high Km (only efficient at high glucose concentrations) and high Vmax (high capacity to handle post-prandial glucose levels).

Metabolism of Glucose: Glycolysis

  • Glycolysis is the breakdown of glucose into pyruvate, a ten-step process in the cytoplasm.
  • It can be divided into two phases:
    • Investment Phase: Requires two ATP molecules to phosphorylate glucose and destabilize it. This results in two C3 molecules from the original C6 molecule.
    • Payoff Phase: Generates four ATP molecules, two NADH molecules, and two pyruvate molecules.
  • Key enzymes in glycolysis include:
    • Hexokinase: Phosphorylates glucose to glucose-6-phosphate.
    • Phospho-fructokinase: Phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate. A key regulatory step.
    • Pyruvate kinase: Converts phosphoenolpyruvate to pyruvate, generating ATP.
  • Glycolysis produces a net gain of 2 ATP molecules, 2 NADH molecules, and 2 pyruvate molecules per glucose molecule.

Alternative Metabolic Uses of Pyruvate

  • Pyruvate can be converted to Acetyl-CoA, entering the TCA cycle or serving as a precursor for fatty acid synthesis. This conversion is catalyzed by the Pyruvate Dehydrogenase complex.
  • Pyruvate can be converted to Oxaloacetate, entering the TCA cycle or serving as a precursor for gluconeogenesis. This conversion is catalyzed by Pyruvate Carboxylase.
  • Pyruvate can be reduced to Ethanol, a process found in yeast and some bacteria. This conversion is catalyzed by Pyruvate Decarboxylase.

Pyruvate Dehydrogenase Complex

  • A multi-enzyme complex composed of three distinct enzyme activities:
    • Pyruvate decarboxylase (“dehydrogenase”)
    • Dihydrolipoyl transacetylase
    • Dihydrolipoyl dehydrogenase
  • Contains five coenzymes:
    • Coenzyme A (CoA)
    • Nicotinamide adenine dinucleotide (NAD)
    • Flavin adenine dinucleotide (FAD)
    • Thiamine pyrophosphate (TPP)
    • Lipoic acid
  • Pyruvate Dehydrogenase is an irreversible reaction, meaning glucose cannot be made from Acetyl-CoA.
  • It's allosterically inhibited by Acetyl-CoA, NADH, and ATP.
  • Clinically relevant due to deficiencies and poisoning:
    • Pyruvate Dehydrogenase Deficiency: An inherited genetic defect causing congenital lactic acidosis, characterized by developmental defects, muscular spasticity, and early death.
    • Arsenic Poisoning: Arsenic inhibits enzymes using lipoic acid as a cofactor, leading to neurological disturbances and death.
    • Vitamin Deficiencies: Coenzymes require vitamins for synthesis: CoA requires Panthotenic acid (B5), NAD requires Niacin (B3), FAD requires Riboflavin (B2), and TPP requires Thiamine (B1). Deficiencies impair pyruvate dehydrogenase function, leading to elevated pyruvate, lactate, and alanine levels, lethargy, fatigue, and complications affecting various organ systems.

The Tricarboxylic Acid (TCA) Cycle

  • The TCA cycle is a series of enzymatic reactions that oxidize acetyl-CoA to CO2, generating energy in the form of ATP, NADH, and FADH2.
  • It occurs in the mitochondrial matrix.
  • Key functions:
    • Generates energy through oxidative phosphorylation.
    • Provides essential intermediates for biosynthesis pathways.
  • Reactions in sequence:
    • Citrate Synthase: Acetyl-CoA + oxaloacetate  citrate (Activated by Ca2+, ADP; Inhibited by ATP, NADH, succinyl CoA).
    • Aconitase: Citrate  isocitrate.
    • Isocitrate Dehydrogenase: Isocitrate  α-ketoglutarate (+ CO2 + NADH). Rate limiting step in the TCA cycle (Activated by ADP, Ca2+; Inhibited by ATP, NADH).
    • α-ketoglutarate Dehydrogenase Complex: α-ketoglutarate  succinyl CoA (+ CO2 + NADH). Uses the same coenzymes as the Pyruvate Dehydrogenase complex (Activated by Ca2+; Inhibited by ATP, NADH, GTP, Succinyl CoA).
    • Succinate Thiokinase: Succinyl CoA  succinate (+ GTP). Regenerates GTP from GDP (Inhibited by ATP).
    • Succinate Dehydrogenase: Succinate  fumarate (+ FADH2). Bound to the inner mitochondrial membrane (Inhibited by malonate).
    • Fumarase: Fumarate  malate.
    • Malate Dehydrogenase: Malate  oxaloacetate (+ NADH). This step regenerates oxaloacetate, completing the cycle.

Energy Yield from Cellular Respiration

  • ATP is produced directly through substrate-level phosphorylation during specific reactions like the phosphoglycerate kinase reaction in glycolysis.
  • ATP is produced indirectly through oxidative phosphorylation, where NADH+H+ and FADH2 are generated and act as carriers of reducing power (electrons), which is ultimately converted to ATP in the electron transport chain.
  • NADH+H+ yields 3 ATP molecules.
  • FADH2 yields 2 ATP molecules.
  • Anaerobic glycolysis: Yields 2 ATP per glucose by converting pyruvate to lactate, which regenerates NAD+.
  • Aerobic glycolysis: Yields 2 ATP and 2 NADH per glucose.
  • Pyruvate Dehydrogenase: Generates 2 NADH per glucose.
  • TCA Cycle: Generates 6 NADH, 2 FADH2, and 2 GTP per glucose.
  • Oxidative Phosphorylation: Yields 2.5 ATP per NADH and 2 ATP per FADH2.
  • *Total yield from one glucose molecule undergoing aerobic respiration is approximately 33 ATP molecules (30-38 ATP).

Regulation of Glycolysis and TCA Cycle

  • Key regulatory enzymes act as metabolic “valves,” controlling the flow of metabolites through the pathways.
  • In glycolysis, these irreversible reactions are regulated:
    • Hexokinase: Controls entry into glycolysis.
    • Phosphofructokinase: A key regulatory point, controlling the rate of glycolysis (Activated by AMP, ADP, fructose-2,6-bisphosphate; Inhibited by ATP, citrate).
    • Pyruvate Kinase: Converts phosphoenolpyruvate to pyruvate (Activated by fructose-1,6-bisphosphate; Inhibited by ATP, alanine).
  • In the TCA cycle, key regulation points include:
    • Citrate Synthase: Controls the entry of acetyl-CoA into the cycle (Activated by Ca2+, ADP; Inhibited by ATP, NADH, succinyl CoA).
    • Isocitrate Dehydrogenase: A rate-limiting step in the TCA cycle (Activated by ADP, Ca2+; Inhibited by ATP, NADH).
    • α-ketoglutarate Dehydrogenase Complex: Another rate-limiting step (Activated by Ca2+; Inhibited by ATP, NADH, GTP, Succinyl CoA).

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Glycolysis_TCA 2022 Past Paper PDF

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This quiz covers the function and importance of the Pyruvate Dehydrogenase Complex in metabolic processes. Test your knowledge on its mechanisms, regulation, and clinical implications such as deficiencies and associated conditions. Suitable for students studying biochemistry.

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