Cellular Respiration: Glycolysis, Gluconeogenesis, and the Citric Acid Cycle

Cellular Respiration Overview

Introduction to Cellular Respiration

Cellular respiration is a series of metabolic pathways that convert biochemical energy from nutrients into adenosine triphosphate (ATP), and release waste products. It is essential for energy production in both aerobic and anaerobic conditions.

• Aerobic respiration involves glycolysis, the citric acid (Krebs/TCA) cycle, and the electron transport chain.

• Anaerobic respiration (fermentation) occurs when oxygen is not present, resulting in less ATP production.

Glycolysis and Gluconeogenesis

Glycolysis: Steps and Regulation

Glycolysis is the metabolic pathway that converts glucose into pyruvate, generating ATP and NADH. It occurs in the cytoplasm and is the first step in both aerobic and anaerobic respiration.

• Reactants: Glucose, 2 NAD+, 2 ATP, 2 Pi

• Products: 2 Pyruvate, 2 NADH, 2 H+, 2 ATP

• Key regulatory steps: Steps 1 (hexokinase), 3 (phosphofructokinase), and 10 (pyruvate kinase)

• Allosteric regulation: ATP, citrate, and other metabolites regulate these enzymes to control the pathway's flux.

Gluconeogenesis: Bypass Reactions

Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors, essentially reversing glycolysis with a few bypass steps catalyzed by unique enzymes.

• Reactants: Lactate or pyruvate, 4 ATP, 2 NADH, 2 GTP

• Products: Glucose, 2 NAD+

• Key enzymes for bypass reactions:

Enzyme	Reaction Catalyzed
Pyruvate carboxylase (PC)	Pyruvate to oxaloacetate
Phosphoenolpyruvate carboxykinase (PEPCK)	Oxaloacetate to phosphoenolpyruvate
Fructose-1,6-bisphosphatase (FBPase)	Fructose-1,6-bisphosphate to fructose-6-phosphate
Glucose-6-phosphatase (GPase)	Glucose-6-phosphate to glucose

Fermentation Pathways

Lactic Acid Fermentation

When oxygen is not present, cells convert pyruvate to lactate to regenerate NAD+, allowing glycolysis to continue. This process is catalyzed by lactate dehydrogenase.

• Reaction: Pyruvate + NADH + H+ → L-Lactate + NAD+

• ΔG'°: -25.1 kJ/mol (exergonic)

The Citric Acid Cycle (Krebs/TCA Cycle)

Overview and Location

The citric acid cycle is a series of eight enzyme-catalyzed reactions that occur in the mitochondrial matrix. It oxidizes acetyl CoA to CO2 and reduces NAD+ and FAD to NADH and FADH2, which are used in the electron transport chain.

• First product: Citrate (hence, citric acid cycle)

• Location: Mitochondrial matrix

• ATP yield: 1 ATP (or GTP) per cycle

• Electron carriers produced: 3 NADH, 1 FADH2 per cycle

• CO2 released: 2 per cycle

Pyruvate to Acetyl CoA (Link Reaction)

Before entering the TCA cycle, pyruvate is converted to acetyl CoA by the pyruvate dehydrogenase complex. This reaction produces NADH and CO2 and is a key regulatory point.

• Reactants: Pyruvate, Coenzyme A, NAD+

• Products: Acetyl CoA, CO2, NADH

• Enzyme: Pyruvate dehydrogenase

Coenzyme A Structure and Function

Coenzyme A is a large, complex molecule derived from pantothenic acid (a B vitamin). It forms high-energy thioester bonds with acyl groups, facilitating their transfer in metabolic reactions.

• Key feature: Thioester bond (S–C=O) stores significant energy

• Role: Transfers acetyl group into the TCA cycle

Steps of the Citric Acid Cycle

The TCA cycle consists of eight steps, each catalyzed by a specific enzyme. The cycle regenerates oxaloacetate and produces high-energy electron carriers and GTP/ATP.

1. Acetyl CoA + Oxaloacetate → Citrate (citrate synthase)

2. Citrate → Isocitrate (aconitase)

3. Isocitrate → α-Ketoglutarate (isocitrate dehydrogenase; produces NADH, CO2)

4. α-Ketoglutarate → Succinyl CoA (α-ketoglutarate dehydrogenase; produces NADH, CO2)

5. Succinyl CoA → Succinate (succinyl CoA synthetase; produces GTP/ATP)

6. Succinate → Fumarate (succinate dehydrogenase; produces FADH2)

7. Fumarate → Malate (fumarase)

8. Malate → Oxaloacetate (malate dehydrogenase; produces NADH)

Summary of TCA Cycle Yields

• Per pyruvate: 3 NADH, 1 FADH2, 1 ATP (or GTP), 2 CO2

• Per glucose (2 cycles): 6 NADH, 2 FADH2, 2 ATP (or GTP), 4 CO2

Regulation of Glycolysis and the TCA Cycle

Both glycolysis and the TCA cycle are tightly regulated to meet cellular energy demands. Key enzymes are regulated by allosteric effectors and feedback inhibition.

Pathway	Regulatory Enzyme/Step	Positive (+) Effectors	Negative (-) Effectors
Glycolysis	Hexokinase (1)	—	Glucose 6-phosphate
Glycolysis	Phosphofructokinase-1 (3)	AMP	Citrate
Glycolysis	Pyruvate kinase (10)	Fructose 1,6-bisphosphate	ATP
TCA Cycle	Pyruvate dehydrogenase (0)	Pyruvate, NAD+	Acetyl CoA, NADH, ATP
TCA Cycle	Isocitrate dehydrogenase (3)	ADP	NADH

Key Concepts and Applications

• Be able to draw and name the reactants and products of glycolysis and the TCA cycle.

• Identify the number of carbons and high-energy bonds in intermediates.

• Indicate which steps consume or produce ATP, NADH, FADH2, CO2, GTP, and H2O.

• Understand the regulation and integration of glycolysis, gluconeogenesis, and the TCA cycle.