Respiration and Metabolism: Biochemical Pathways in Human Physiology

Respiration and Metabolism

Overview of Metabolism

Metabolism encompasses all chemical reactions in the body, divided into anabolism (energy-requiring synthesis of large molecules) and catabolism (energy-releasing breakdown of large molecules). Catabolic reactions provide energy for ATP production, which in turn drives anabolic processes. Many metabolic reactions involve oxidation-reduction events, with aerobic cellular respiration requiring oxygen as the final electron acceptor.

Glycolysis and the Lactic Acid Pathway

Glycolysis: The First Step in Glucose Catabolism

Glycolysis is the initial pathway for glucose breakdown, occurring in the cytoplasm and not requiring oxygen (anaerobic). It involves the phosphorylation of glucose, splitting it into two molecules of pyruvic acid, and the reduction of NAD+ to NADH. The net energy gain from glycolysis is 2 ATP per glucose molecule.

• Location: Cytoplasm

• Products: 2 pyruvic acid, 2 NADH, 2 ATP

• Key enzymes: Kinases, phosphatases, isomerases, dehydrogenases

Decision Point: Fate of Pyruvic Acid

The pathway chosen by pyruvic acid depends on the presence of oxygen:

• Aerobic conditions: Pyruvic acid enters mitochondria for further oxidation.

• Anaerobic conditions: Pyruvic acid is converted to lactic acid.

Lactic Acid Pathway (Anaerobic Metabolism)

When oxygen is absent, NADH donates electrons to pyruvic acid, forming lactic acid and regenerating NAD+. This process, called fermentation, yields no additional ATP beyond glycolysis. Muscle cells and red blood cells utilize this pathway under certain conditions, but it is not favored due to low ATP yield and risk of acidosis.

• Key reaction: $\text{Pyruvic acid} + \text{NADH} + H^+ \xrightarrow{LDH} \text{Lactic acid} + \text{NAD}^+$

• Physiological significance: Allows glycolysis to continue in absence of oxygen

• Drawbacks: Low ATP yield, increased acidity

Aerobic Respiration: Citric Acid Cycle (TCA/Krebs Cycle)

Transition Step and Entry into the Citric Acid Cycle

If oxygen is present, pyruvic acid enters the mitochondrial matrix, where it is converted to acetyl CoA via the transition step, releasing CO2 and producing NADH.

• Transition reaction: $\text{Pyruvic acid} + \text{Coenzyme A} + \text{NAD}^+ \rightarrow \text{Acetyl CoA} + \text{CO}_2 + \text{NADH} + H^+$

• Location: Mitochondrial matrix

Citric Acid Cycle (Krebs/TCA Cycle)

Acetyl CoA combines with oxaloacetic acid to form citric acid, which is then metabolized through a series of reactions that regenerate oxaloacetic acid. The cycle produces ATP, NADH, FADH2, and CO2 as waste.

• Products per glucose: 2 ATP, 6 NADH, 2 FADH2, 4 CO2

• Coenzymes: NAD+, FAD

• Purpose: Complete oxidation of glucose, energy capture

Aerobic Respiration: Electron Transport Chain (ETC) and Oxidative Phosphorylation

Electron Transport Chain (ETC)

The ETC is located on the inner mitochondrial membrane. NADH and FADH2 donate electrons to a series of transporters, creating a proton gradient that drives ATP synthesis via ATP synthase. Oxygen serves as the final electron acceptor, forming water.

• Key reaction: $\text{O}_2 + 4e^- + 4H^+ \rightarrow 2\text{H}_2\text{O}$

• ATP yield: Each NADH yields ~2.5 ATP, each FADH2 yields ~1.5 ATP

• Total ATP per glucose: 30–32 (actual), 36–38 (theoretical)

Interconversion of Glucose, Lactic Acid, and Glycogen

Storing and Mobilizing Glucose

Cells cannot store free glucose due to osmotic effects. Instead, glucose is phosphorylated to glucose-6-phosphate and stored as glycogen via glycogenesis. Glycogen is found in the liver, skeletal muscle, and cardiac muscle.

• Glycogenesis: Formation of glycogen from glucose

• Glycogenolysis: Breakdown of glycogen to glucose-1-phosphate, then glucose-6-phosphate

• Liver-specific: Only the liver can release free glucose into the bloodstream due to the enzyme glucose-6-phosphatase

Cori Cycle and Gluconeogenesis

Excess lactic acid produced by muscles is transported to the liver, where it is converted back to pyruvic acid and then to glucose via gluconeogenesis. This glucose can be returned to muscles, completing the Cori cycle.

Metabolism of Lipids and Proteins

Lipid Metabolism: Lipogenesis and Lipolysis

When energy is abundant, acetyl CoA is used for lipogenesis (formation of triglycerides). When energy is needed, triglycerides are broken down via lipolysis, releasing fatty acids and glycerol. Fatty acids undergo β-oxidation to form acetyl CoA, which enters the citric acid cycle.

• β-oxidation: Each 2-carbon unit yields 1 acetyl CoA

• ATP yield: A 16-carbon fatty acid yields up to 108 ATP

Ketogenesis

When fatty acid breakdown exceeds utilization, the liver converts acetyl CoA into ketone bodies (ketogenesis). These water-soluble molecules can be used for energy but may accumulate, causing ketosis.

Amino Acid Metabolism

Excess amino acids can be converted to glucose or fat via gluconeogenesis. Amino acids are also synthesized from citric acid cycle intermediates by transamination (addition of NH2 group).

Summary: Energy Source Preferences by Organ

Relative Importance of Energy Molecules

Different organs preferentially use different energy sources, as summarized below:

Organ	Glucose	Fatty Acids	Ketone Bodies	Lactic Acid
Brain	+++	–	+	–
Skeletal muscles (resting)	+	+++	+	–
Liver	++	++	+	+
Heart	+	++	++	+

Interconversion of Energy Sources

Carbohydrates, fats, and proteins can be interconverted through metabolic pathways, allowing the body to adapt to varying energy demands.

Key Definitions

• Lipogenesis: Synthesis of lipids from acetyl CoA

• Lipolysis: Breakdown of triglycerides into fatty acids and glycerol

• Ketogenesis: Formation of ketone bodies from acetyl CoA

• Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources