Basics of metabolism

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Basics of Metabolism

Metabolism is the totality of all chemical reactions occurring within a living organism to sustain life. It has two fundamental, interlinked components: catabolism and anabolism.

1. What Is Metabolism?

Metabolism is composed of two components:

Catabolism - processes that harvest energy from the breakdown of complex molecules (e.g., glucose, fatty acids, proteins), using that energy to synthesize ATP.
Anabolism (biosynthesis) - processes that use the energy stored in ATP to synthesize and assemble the building blocks of macromolecules (proteins, nucleic acids, lipids, carbohydrates).

In a weight-stable person, anabolism and catabolism are in net balance - zero energy balance. Most people cycle between the two: net anabolism after meals (storing glycogen and triacylglycerol) and net catabolism during fasting (mobilizing those stores).

Harper's Illustrated Biochemistry, 32nd Ed, p. 145 | Jawetz Melnick & Adelberg's Medical Microbiology, 28e

2. Metabolic Fuels

The three major fuel substrates are:

Fuel	Primary Store	When Used
Carbohydrates (glucose)	Glycogen (liver, muscle)	Fed state, high-intensity exercise
Fats (fatty acids)	Triacylglycerol (adipose)	Fasting, prolonged exercise
Proteins (amino acids)	Muscle protein	Prolonged starvation

The resting (basal) metabolic rate accounts for approximately 60% of daily energy expenditure. Physical activity can raise metabolic rate 40-50% above basal. The mix of fuel being oxidized depends on diet composition, fed/fasting state, and exercise intensity (you burn what you eat).

Harper's Illustrated Biochemistry, 32nd Ed, p. 145

3. The Three Stages of Cellular Respiration

All three macronutrients ultimately converge on a common pathway to produce ATP. This is best illustrated by the classic three-stage model:

Catabolism of proteins, fats, and carbohydrates in three stages of cellular respiration

Fig. 5.4 - Three stages of cellular respiration: Stage 1 = Acetyl-CoA production; Stage 2 = Citric acid cycle; Stage 3 = Electron transport and oxidative phosphorylation. (Brenner and Rector's The Kidney)

Stage 1 - Acetyl-CoA Production (Cytosol + Mitochondria)

Glycolysis (occurs in the cytosol):

Glucose (6-carbon) is split into 2 molecules of pyruvate (3-carbon) through 10 enzyme-catalyzed steps
Net yield: 2 ATP per glucose (4 ATP produced, 2 consumed in activation)
Also produces 2 NADH

Pyruvate to Acetyl-CoA (mitochondria):

Pyruvate enters the mitochondria and is converted to acetyl-CoA by the pyruvate dehydrogenase complex
CO2 is released; NADH is generated
This reaction is irreversible - acetyl-CoA cannot be converted back to pyruvate in humans

Similarly, fatty acids undergo beta-oxidation and amino acids are deaminated to yield acetyl-CoA.

Guyton and Hall Textbook of Medical Physiology, p. 835

Stage 2 - Citric Acid Cycle / Krebs Cycle (Mitochondrial Matrix)

Acetyl-CoA (2-carbon) combines with oxaloacetate (4-carbon) to form citrate (6-carbon). Through a series of 8 reactions involving dehydrogenases and decarboxylases, per turn of the cycle:

Product	Quantity	Downstream ATP
NADH	3	~7.5 ATP (each NADH ~ 2.5 ATP)
FADH2	1	~1.5 ATP
GTP	1	1 ATP

Total: ~10 ATP per acetyl-CoA (modern estimates) or 12 by older accounting.

The Krebs cycle also serves as a metabolic hub - its intermediates feed into gluconeogenesis, lipogenesis, and amino acid synthesis depending on the cell's energy status.

Mulholland and Greenfield's Surgery, p. 89

Stage 3 - Oxidative Phosphorylation / Electron Transport Chain (Inner Mitochondrial Membrane)

The NADH and FADH2 from stages 1-2 donate electrons to the electron transport chain (ETC):

Complex I (NADH-CoQ reductase) - accepts electrons from NADH
Complex II (Succinate dehydrogenase) - accepts electrons from FADH2
Complex III (Q-cytochrome c oxidoreductase)
Complex IV (Cytochrome c oxidase) - O2 accepts the final electrons → reduced to H2O

As electrons move down the chain, protons (H+) are pumped across the inner mitochondrial membrane, creating the proton motive force (pH gradient + voltage gradient). ATP synthase uses this force to phosphorylate ADP → ATP.

Total ATP yield from one glucose molecule:

Glycolysis: ~2 ATP
Pyruvate decarboxylation: ~5 ATP
Citric acid cycle: ~20 ATP
Total: ~30-32 ATP per glucose (aerobic)

Mulholland and Greenfield's Surgery, p. 89-91

4. Three Key Metabolic Crossroads

Three metabolites act as master regulators, orchestrating the switch between catabolism and anabolism:

Metabolite	Anabolic fates	Catabolic fates
Glucose-6-phosphate (G6P)	Glycogen synthesis, ribose-5-P (nucleotides)	Glycolysis, pentose phosphate pathway
Pyruvate	Gluconeogenesis, alanine synthesis	Acetyl-CoA, lactate, oxaloacetate
Acetyl-CoA	Fatty acid/cholesterol synthesis, ketogenesis	Krebs cycle → CO2 + ATP

Mulholland and Greenfield's Surgery, p. 89

5. Fasting vs. Fed State

Fasting:

Liver provides glucose (~9 g/hr) via glycogenolysis and gluconeogenesis
Brain and RBCs are the priority glucose consumers
Adipose releases free fatty acids (FFA) as fuel for heart, muscle, liver
Liver synthesizes ketone bodies from fatty acids for muscle and brain

Fed state:

Intestine becomes the glucose source (dietary carbohydrate)
Liver switches from glucose producer to glucose consumer
Excess glucose stored as glycogen or converted to fat
Insulin promotes glucose uptake, glycogen synthesis, lipogenesis

Harper's Illustrated Biochemistry, 32nd Ed, p. 145

6. Compartmentalization of Metabolism

Pathway	Location
Glycolysis	Cytosol
Fatty acid synthesis (lipogenesis)	Cytosol
Citric acid cycle	Mitochondrial matrix
Beta-oxidation of fatty acids	Mitochondrial matrix
Oxidative phosphorylation (ETC)	Inner mitochondrial membrane
Gluconeogenesis	Cytosol + mitochondria

Substrates freely cross the outer mitochondrial membrane through porins but require specific transporters to cross the inner membrane, driven by concentration gradients or the H+ gradient from the ETC.

Brenner and Rector's The Kidney

7. Key Regulatory Principles

Enzymes are the gatekeepers - pathways are regulated by controlling either the amount or activity of enzymes
Allosteric regulation - metabolites act as effectors to modulate enzyme activity (e.g., ATP inhibits phosphofructokinase-1; AMP activates it)
Hormonal control - insulin promotes anabolism; glucagon and epinephrine promote catabolism
Energy charge - the ATP/ADP/AMP ratio is a cell-wide signal: high ATP suppresses catabolism, low ATP (high AMP) activates catabolic pathways via AMPK (AMP-activated protein kinase)

Summary Flowchart

FOOD (Carbohydrates, Fats, Proteins)
         |
    [STAGE 1] Glycolysis / Beta-oxidation / Deamination
         |
     Acetyl-CoA  ←→  2 ATP (glycolysis net)
         |
    [STAGE 2] Citric Acid Cycle
         |
     NADH + FADH₂ + GTP
         |
    [STAGE 3] Electron Transport Chain
         |
     ~28-30 ATP + H₂O + CO₂

Metabolism is not just about energy production - it is a tightly regulated network where the balance between building up (anabolism) and breaking down (catabolism) determines growth, maintenance, and survival of every cell.

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