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Page 1: Kreb's Cycle (TCA Cycle) Overview

Definition

  • Second stage of mitochondrial pathway for glucose oxidation.

  • Follows oxidative decarboxylation of pyruvate to form acetyl CoA.

  • Acetyl CoA is oxidized into CO2 and H2O.

Site

  • Occurs in the mitochondria of every cell in the body.

Biochemical Steps

  1. Citrate Synthase: Combines acetyl CoA with citric acid to form isocitrate.

  2. Aconitase: Converts isocitrate to other forms.

  3. Isocitrate Dehydrogenase: Oxidizes isocitrate, yielding NADH and CO2.

  4. α-Ketoglutarate Dehydrogenase: Converts isocitrate into α-ketoglutarate.

  5. Succinate Thiokinase: Involves substrate-level phosphorylation.

  6. Succinate Dehydrogenase: Converts succinate into fumarate, producing FADH2.

  7. Fumarase: Hydrates fumarate to malate.

  8. Malate Dehydrogenase: Oxidizes malate to oxaloacetate, producing NADH.

Energy Yield

  • Total energy produced per molecule of acetyl CoA: 12 ATP.

    • Breakdown: 3 NADH (9 ATP) + 1 FADH2 (2 ATP) + 1 ATP = 12 ATP.

Page 2: Carbohydrate Metabolism and Kreb's Cycle Regulation

Complete Oxidation of Glucose

  • Complete oxidation yields either 36 or 38 ATP.

  • Breakdown process includes glycolysis and conversion of pyruvic acid to acetyl CoA followed by TCA cycle.

    • Glycolysis: 2 ATP

    • Pyruvic acid: 3 ATP to Acetyl CoA.

    • TCA Cycle: 12 ATP from TCA.

Regulation of Kreb's Cycle

  • Key regulators: ADP, ATP, AMP, NAD, NADH, and products such as citrate and oxaloacetate.

  • Enzymatic Regulation:

    • Citrate synthase, aconitase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase affected by covalent modifications such as phosphorylation.

Page 3: Biochemical Importance of Kreb's Cycle

Amphibolic Nature

  • Performs both anabolic and catabolic functions.

Functions

Catabolic Functions

  1. Oxidation of carbohydrates, lipids, proteins.

  2. Energy production: 12 ATP.

Anabolic Functions

a. Synthesis of fatty acids and cholesterol from acetyl CoA. b. Gluconeogenesis: Intermediates such as α-ketoglutarate and oxaloacetate convert into glucose. c. Synthesis of amino acids (e.g., glutamic acid and aspartic acid from intermediates).

Other Important Functions

  1. Heme synthesis, detoxification reactions, activation of ketone bodies.

  2. CO2 fixation reactions.

  3. Production of glucose and ammonia-related compounds.

Page 4: Glycogen Metabolism

Glycogen Structure

  • Highly branched homopolysaccharide of glucose units.

  • Contains 1,4 and 1,6 glucosidic linkages, with branches consisting of 12-14 glucose units.

Locations

  • Stored mainly in liver and muscle cells:

    • Liver: 120 gm (6% of weight)

    • Muscle: 350 gm (1% of weight).

Functions of Glycogen

In the Liver

  • Maintains blood glucose levels during fasting (depleted in 12-18 hours).

In Muscles

  • Provides glucose-6-P for glycolysis, crucial for muscle contraction and lactate production.

Glycogenesis (Glycogen Synthesis)

  • Formation from glucose and amino acids.

    • Sites: Primarily in liver and muscles.

  • Enzymatic steps involve glycogen synthase and branching enzyme.

Page 5: Glycogenolysis (Glycogen Breakdown)

Definition

  • Breakdown of glycogen into glucose in the liver or glucose-6-P in muscles.

Site

  • Occurs mainly in the cytoplasm of liver and muscle cells.

Steps of Glycogenolysis

  1. Glycogen phosphorylase breaks down 1,4 glucosidic linkages producing glucose-1-P.

  2. Debranching enzyme acts on 1,6 linkages, releasing glucose.

  3. Glucose-1-P is converted to glucose-6-P.

In the Liver

  • Glucose-6-P is converted to glucose by glucose-6-phosphatase, then released into the bloodstream.

In the Muscles

  • Enters glycolysis, providing energy for contracting muscles.

Page 6: Glycogen Storage Diseases

Types of Glycogen Storage Diseases

  • Type II (Pompe's Disease): Deficiency in acid maltases; leads to muscle weakness and cardiomegaly.

  • Type III (Cori Disease): Deficiency of the debranching enzyme.

  • Type IV (Andersen Disease): Deficiency of branching enzyme.

  • Type V (McArdle's Disease): Deficiency of muscle glycogen phosphorylase.

  • Type VI (Her's Disease): Deficiency of liver glycogen phosphorylase.

  • Type VII (Tarui Disease): Deficiency of phosphofructokinase in muscle and red blood cells.

  • Type VIII: Deficiency of phosphorylase b kinase in liver.