Glycolysis and PDC

Introductory Biochemistry

Glucose Metabolism

Overview

• Glucose occupies a central position in the metabolism of most cells.

Glycolysis

Definition

• Glycolysis is a catabolic pathway for the conversion of one molecule of glucose into two molecules of pyruvate.

• It generates both ATP and NADH.

• Gluconeogenesis is the opposing pathway of glycolysis.

Pathways of Glucose Metabolism

• Main Pathways:

  • Glucose

  • Glycogen

  • Pyruvate

• Intermediates: Glucose-6-phosphate

• Opposing Pathways:

  • Glycogen synthesis

  • Glycogenolysis

  • Glycolysis

  • Gluconeogenesis

Exam Scheme

• Familiarize with the various oxidation states of carbon as it relates to glycolysis.

Structures of Glucose

• Glucose is a six-carbon compound with:

  • One aldehyde group and five hydroxyl groups.

  • Formula: nC's, where n = 6, has n-1 OH groups and one carbonyl group.

• Types of Sugars:

  • Aldehyde form → Aldose

  • Ketone form (6-C sugar) → Ketohexose

Glycolysis Process

Location

• Occurs in the cytosol.

Purpose

1. Serves as the first step in the complete oxidation of glucose to CO₂ and H₂O.

2. Produces a small amount of ATP.

3. Provides building blocks for the synthesis of cellular molecules.

4. Can occur under aerobic or anaerobic conditions; typically occurs under aerobic conditions.

5. Note: Fat can only be metabolized aerobically.

Energy Dynamics

• Glycolysis includes both energy investment and energy payout phases.

• Intermediates are extensively phosphorylated throughout glycolysis.

Stages of Glycolysis

Stage 1: Energy Investment

• Activation: Glucose is activated by consuming a small amount of ATP (2 ATP consumed per glucose).

• Hexose Phase: Involves 6-carbon sugars.

Stage 2: Energy Payout

• Energy is harvested in the form of ATP and NADH.

• Involves triose (3-carbon) sugars.

Enzyme Regulation

• Each step in glycolysis is catalyzed by different enzymes, with specific enzymes highlighted as particularly important (regulation outlined in red and oxidation in purple).

Glycolytic Reactions

Activation Phase

• Conversion of Glucose to Glyceraldehyde-3-Phosphate (GAP)

  • Enzyme: Hexokinase

  • Reaction:
    $ext{Glucose} + ATP <br>ightarrow ext{Glucose-6-phosphate} + ADP + H^+$

  • Characteristics: Irreversible, Exergonic, ΔG' << 0.

• The hydrolysis of ATP occurs, coupled by the phosphorylation of glucose.

Isomerization

• Conversion between structural isomers such as Glucose-6-phosphate and Fructose-6-phosphate (aldose to ketose).

PFK-1 Reaction

• Enzyme: Phosphofructokinase-1 (PFK-1)

• Reaction Details:
  $ext{Fructose-6-phosphate} + ATP <br>ightarrow ext{Fructose-1,6-bisphosphate} + ADP + H^+$

• Characteristics: Tightly regulated and considered the committed step of glycolysis.

• Regulation involves allosteric modulation by ADP/AMP and feedback inhibition by ATP.

Lysis Phase

• Involves: The production of two molecules of GAP from Fructose-1,6-bisphosphate.

• Two pathways result in two molecules of glyceraldehyde-3-phosphate.

Summary of Glycolysis Reactions

1. Investment Phase:

   • $ext{Glucose} + ATP <br>ightarrow ext{G6P}$

   • $ext{Glucose-6-phosphate} <br>ightarrow ext{Fructose-6-phosphate}$

   • $ext{Fructose-6-phosphate} + ATP <br>ightarrow ext{Fructose-1,6-bisphosphate} + ADP + H^+$

2. Payoff Phase:

   • $ext{Glyceraldehyde-3-phosphate} + NAD^+ + Pi <br>ightarrow ext{1,3-BPG} + NADH + H^+$

   • $ext{1,3-BPG} + ADP <br>ightarrow ext{3-PG} + ATP$

   • Repeated reactions lead to two molecules of pyruvate being formed ultimately.

NET Yield of Glycolysis

• The process of glycolysis results in a net yield of 2 ATP and 2 NADH per glucose molecule, leading to:

  • Balanced equation for glycolysis:
    $ext{Glucose} + 2 ext{ATP} + 2 ext{NAD}^+ + 4 ext{ADP} + 2 ext{P}_i + 2 ext{H}^+ <br>ightarrow 2 ext{Pyruvate} + 2 ext{NADH} + 4 ext{ATP} + 2 ext{H}_2 ext{O} + 2 ext{H}^+$

• It is crucial to understand that the net yield = GROSS YIELD - INPUT: 2 ATP = 4 ATP - 2 ATP.

Regulation of Glycolysis

Importance of Regulation

• Regulation ensures:

  • Cells' energy needs are met.

  • Fuel is not wasted.

  • Intermediates maintain appropriate levels for various cellular purposes.

Major Regulatory Processes

1. Substrate Availability.

2. Alteration of enzyme activity:

   • Short-term regulation through allostery and covalent modification of enzymes.

3. Alteration of the amount of enzyme.

   • Long-term regulation, including subcellular localization or compartmentalization.

Important Regulatory Enzymes

• Hexokinase - Activated by glucose and inhibited by glucose-6-phosphate.

• PFK-1 - Regulated by ATP (high levels as an inhibitor) and allosterically activated by ADP/AMP.

• Pyruvate Kinase - Allosterically regulated, activated by fructose-1,6-bisphosphate (feedforward activation).

Pyruvate Metabolism

Under Anaerobic Conditions

• Lactate Production:

  • Lactate is produced as a 'dead-end' product and is exported from the muscle to the blood via a specific transport mechanism.

Under Aerobic Conditions

• Metabolism feeds into the Citric Acid Cycle (CAC)

  • Reaction:
    $ext{Pyruvate} + ext{CoA} + ext{NAD}^+ <br>ightarrow ext{Acetyl-CoA} + ext{NADH} + ext{CO}_2$

• Links glycolysis to the CAC and is critical for cellular respiration.

Pyruvate Dehydrogenase Complex (PDC)

Description

• PDC catalyzes the conversion of pyruvate to acetyl-CoA.

• Occurs within the mitochondrial matrix and is characterized by:

  • Mitochondrial structure facilitating transport of pyruvate via the pyruvate translocase.

  • Requires cofactors such as NAD+ and CoA.

Regulation of PDC

• Controlled through reversible phosphorylation, activated or inactivated based on energy availability within the cell focus on substrates and products.

• It exemplifies how metabolic pathways integrate signals based on the cellular energy state, e.g., ATP, ADP, NAD+, and NADH ratios.