What Is Metabolism?

The word 'metabolism' derives from the Greek metabole — meaning 'to change'. Metabolism is the
overall process through which living systems acquire and use free energy to carry out their functions.
It encompasses two complementary processes:
• Catabolism — breakdown of nutrients and cell constituents to release energy
• Anabolism — synthesis of biomolecules from simpler components using energy
[Slide 4] Biosphere: Energy Flow in an Open System
Living systems exist as non-equilibrium steady states. Unlike isolated systems, cells continuously
exchange matter and energy with their environment.
• Energy flows in (from food/sunlight) and is dissipated as heat and work
• Matter flows through cells — nutrients enter, waste products leave
• Example of steady-state maintenance: Blood glucose levels are kept remarkably constant despite
variable intake and usage, through hormonal and enzymatic regulation
A non-equilibrium steady state is not the same as equilibrium. Equilibrium = death. Living systems are
sustained by continuous throughput of energy.
[Slide 5] Is Metabolism Really That Complicated?
Looking at the complete metabolic map (Nicholson map) can seem overwhelming — thousands of
reactions. However, the key insight is that metabolism is well-coordinated and built from a relatively
small number of interconnected reaction types and intermediates.
• Most pathways share common intermediates (acetyl-CoA, pyruvate, oxaloacetate, etc.)
• Regulation is layered — allosteric, covalent modification, gene expression
• Understanding the logic of each pathway matters more than memorising every step
[Slide 6] Catabolism vs Anabolism
Catabolism
• Nutrients and cell constituents are broken down
• Proceeds via exergonic oxidation reactions
• Releases free energy — captured as ATP, NADH, FADH₂, NADPH
• Examples: glycolysis, β-oxidation, TCA cycle
Anabolism
• Biomolecules are synthesised from simpler components
• Requires energy input (consumes ATP and NADPH)
• Examples: fatty acid synthesis, gluconeogenesis, protein synthesis
The two processes are reciprocally regulated — when catabolism is active, anabolism is suppressed, and
vice versa.
[Slide 7–9] Vitamins and Minerals Assist Metabolic Reactions
Vitamins and minerals are essential micronutrients that act as cofactors and coenzymes in metabolic
reactions. Without them, enzymes cannot function properly even if the enzyme protein itself is intact.
Key examples
• Mg²⁺ — required for ATP binding (nearly all kinases use Mg-ATP as the true substrate)
• Zn²⁺ — active site of carbonic anhydrase (catalyses CO₂ + H₂O ⇌ HCO₃⁻ + H⁺). Three
histidines + a water molecule coordinate the zinc ion. The reaction is rate-limited by
deprotonation of the zinc-bound water.
• Thiamine (B1) — cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (TCA
cycle)
• Riboflavin (B2) — precursor to FAD and FMN
• Niacin (B3) — precursor to NAD⁺/NADH and NADP⁺/NADPH
• Pantothenate (B5) — component of Coenzyme A
• Pyridoxal phosphate (B6) — cofactor for aminotransferases and amino acid metabolism
Mineral deficiencies are not merely nutritional issues — they are biochemical enzyme failures.
[Slide 10] Degradation and Biosynthesis — ATP and NADPH as Energy Currency
The flow of energy in metabolism is mediated by two central energy carriers:
ATP — Energy currency for work
• Generated primarily by catabolism (substrate-level phosphorylation and oxidative
phosphorylation)
• Used to drive endergonic biosynthetic reactions, active transport, and mechanical work
• ATP hydrolysis (→ ADP + Pi or AMP + PPi) releases ~30–46 kJ/mol under standard conditions
NADPH — Reductive biosynthetic currency
• Generated primarily by the pentose phosphate pathway (oxidative phase)
• Provides the reducing equivalents (electrons) needed for biosynthetic reductions
• Also critical for antioxidant defence (regenerating glutathione)
Complex metabolites are exergonically broken down to simple products; the free energy released is
captured in ATP and NADPH, which then fuel biosynthetic reactions.
[Slide 11–12] Metabolic Pathways — How to Read Them
A metabolic pathway is a series of connected enzymatic reactions where the product of one reaction
becomes the substrate of the next. Participants are called metabolites (reactants, intermediates, or
products).
When you encounter any pathway, ask:
• What is the INPUT and what is the OUTPUT?
• What is the net energy yield (ATP, NADH, FADH₂ made or consumed)?
• Where are the IRREVERSIBLE steps? (These are the regulatory control points)
• What signals turn the pathway ON or OFF?
• What happens if the pathway is blocked? (What accumulates? What is depleted?)
• How does this pathway connect to others?
Memorising reactions without asking these questions produces knowledge that can't be applied clinically
or experimentally.
[Slide 13] Glycolysis — Overview
Glycolysis is the universal pathway converting glucose (6C) to 2 pyruvate (3C each), occurring in the
cytosol of all cells. It proceeds in 10 enzyme-catalysed steps divided into two phases:
• Investment phase (steps 1–5): Consumes 2 ATP to phosphorylate and split glucose into two 3-
carbon units (glyceraldehyde-3-phosphate, G3P)
• Payoff phase (steps 6–10): Generates 4 ATP and 2 NADH from the two G3P molecules
• Net yield per glucose: 2 ATP + 2 NADH + 2 Pyruvate
Three irreversible (regulatory) steps: hexokinase (step 1), phosphofructokinase-1 (step 3), pyruvate
kinase (step 10).
[Slide 14] Glycolysis — The Sprint Analogy
"Glycolysis is a sprint: fast ATP, but you pay by dumping carbon and living on a thin profit margin."
Currency
• ATP — produced fast via substrate-level phosphorylation
• NAD⁺ — must be continuously regenerated to keep glycolysis running
Bottleneck
• NAD⁺ regeneration at the GAPDH step (step 6) — this enzyme requires NAD⁺ as oxidant
• If the ETC cannot oxidise NADH fast enough (e.g. hypoxia), glycolysis stalls
• Solution: lactate fermentation — lactate dehydrogenase reduces pyruvate to lactate using NADH,
regenerating NAD⁺ rapidly
Trade-off
• Speed vs efficiency: glycolysis is fast but yields only 2 ATP per glucose vs ~30 from full
oxidation
• Useful when rapid ATP is needed (exercise, hypoxia, rapidly proliferating cells)
[Slide 15] Reactions of the Citric Acid Cycle & ETC — Overview
After glycolysis, pyruvate enters the mitochondria and is converted to acetyl-CoA by pyruvate
dehydrogenase. Acetyl-CoA then enters the TCA cycle.
TCA cycle summary (per acetyl-CoA turn)
• Produces: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂
• Key regulatory enzymes: citrate synthase, isocitrate dehydrogenase, α-ketoglutarate
dehydrogenase
ETC summary
• Complex I: NADH → CoQ, pumps 4 H⁺
• Complex II: FADH₂ → CoQ, no H⁺ pumping
• Complex III: CoQ → Cyt c, pumps 4 H⁺
• Complex IV: Cyt c → O₂ → H₂O, pumps 2 H⁺
• ATP synthase (F₁F₀-ATPase): H⁺ re-entry drives ATP synthesis
[Slide 16] Respiration — The Power Plant Analogy
"Respiration is a power plant: efficient, but it needs a grid and it can black out."
Currency
 • NADH and FADH₂ are the electron currency — their oxidation drives the proton motive force
→ ATP synthesis
Bottleneck
• Electron acceptor capacity: ultimately O₂ must accept electrons at Complex IV
• If O₂ delivery is low or ETC is inhibited: NADH accumulates → NAD⁺ becomes limiting →
TCA slows → glycolysis backs up
Trade-off
• High efficiency (~30 ATP per glucose) vs infrastructural dependence
• Requires: O₂ delivery, intact mitochondria, tight coupling between ETC and ATP synthase
• Great for endurance (aerobic exercise), but fragile under hypoxia or mitochondrial poisons
(cyanide, rotenone)
[Slide 17] Convergence of Metabolism
A key conceptual principle: although cells consume enormously diverse inputs (carbohydrates, fats,
proteins), catabolism funnels them all through a small number of common intermediates.
Major convergence points
• Pyruvate — receives carbon from glucose (glycolysis), some amino acids, and lactate
• Acetyl-CoA — receives carbon from pyruvate, fatty acids (β-oxidation), ketogenic amino acids
• TCA intermediates — receive carbon from glucogenic amino acids, odd-chain fatty acids
Conversely, anabolism diverges from these same few intermediates to produce the enormous variety of
biomolecules in the cell. This economy of design is a fundamental feature of metabolism.
[Slide 18] Compartmentalisation of Metabolism
In eukaryotes, metabolic pathways are physically separated into distinct compartments, preventing futile
cycles and allowing independent regulation.
• Cytosol: glycolysis, gluconeogenesis, pentose phosphate pathway, fatty acid synthesis
• Mitochondrial matrix: TCA cycle, β-oxidation, pyruvate dehydrogenase, urea cycle (partly)
• Inner mitochondrial membrane: ETC, ATP synthase, metabolite transporters
• Peroxisomes: very long chain fatty acid oxidation, glyoxylate cycle (in plants/fungi)
• Endoplasmic reticulum: lipid synthesis, protein glycosylation
Transport across the inner mitochondrial membrane is tightly controlled (e.g. malate-aspartate shuttle for
NADH, carnitine shuttle for fatty acyl-CoA). This compartmentalisation means you cannot simply run
two opposing pathways simultaneously in the same space.
[Slide 20] Thought: Did Metabolism Precede the Central Dogma?
A profound evolutionary question: if DNA is the blueprint of life, can it function without metabolism?
• Transcription requires ATP (nucleotide synthesis, RNA polymerase)
• Translation requires GTP, amino acids, and ribosomes
• DNA replication requires dNTPs, ATP, and a reducing environment
Conclusion: metabolism must have preceded and enabled the central dogma. The earliest life forms
likely had primitive metabolic chemistry before they had stable genetic molecules. This supports the
RNA world hypothesis and the idea that metabolic networks are older than the genetic code.
[Slide 21] Opposing Glycogen Pathways: Synthesis & Degradation
Glycogen serves as the primary glucose storage polymer in animals (liver and muscle). Its synthesis and
degradation are opposing pathways that are reciprocally regulated to prevent futile cycling.
Glycogen synthesis (glycogenesis)
• Glucose-1-phosphate + UTP → UDP-glucose (UDP-glucose pyrophosphorylase)
• UDP-glucose added to growing glycogen chain by glycogen synthase
• Branching enzyme creates α-1,6 branch points
• Activated by: insulin, glucose-6-phosphate
• Inhibited by: glucagon, epinephrine (via PKA → phosphorylation inactivates glycogen synthase)
Glycogen degradation (glycogenolysis)
• Glycogen phosphorylase cleaves glucose-1-phosphate from the chain (phosphorolysis)
• Debranching enzyme removes α-1,6 branches
• Activated by: glucagon, epinephrine, AMP
• Inhibited by: insulin, ATP, glucose-6-phosphate
The liver releases free glucose into blood; muscle retains glucose-6-phosphate for its own use (lacks
glucose-6-phosphatase).
[Slide 22] β-Oxidation of Fatty Acyl-CoA
β-oxidation is the mitochondrial pathway for degrading fatty acids to acetyl-CoA. The process requires
activation to acyl-CoA (in cytosol), transport into mitochondria via the carnitine shuttle, and then
repeated cycles of four reactions.
One cycle of β-oxidation (removes 2 carbons)
• Step 1: Acyl-CoA → trans-Δ²-Enoyl-CoA (acyl-CoA dehydrogenase, produces FADH₂)
• Step 2: trans-Δ²-Enoyl-CoA + H₂O → L-3-Hydroxyacyl-CoA (enoyl-CoA hydratase)
• Step 3: L-3-Hydroxyacyl-CoA → 3-Ketoacyl-CoA (3-hydroxyacyl-CoA dehydrogenase,
produces NADH)
• Step 4: 3-Ketoacyl-CoA + CoA → Acetyl-CoA + shorter Acyl-CoA (thiolase)
Yield (for palmitate C16:0)
• 7 cycles → 7 FADH₂ + 7 NADH + 8 Acetyl-CoA
• Total ATP ≈ 106 ATP (minus 2 for activation)
Fatty acid oxidation yields far more ATP per carbon than glucose — but is slower and requires O₂. This
is why endurance athletes rely on fat oxidation.
[Slide 23] The Urea Cycle
Amino acids cannot be stored like glycogen or triglycerides. When amino acids are catabolised, their
nitrogen must be safely excreted. In mammals, this is accomplished via the urea cycle in the liver.
Why urea?
• Free ammonia (NH₃) is highly toxic — even low concentrations damage the brain
• Urea (H₂N–CO–NH₂) is non-toxic, water-soluble, and easily excreted in urine
Urea cycle steps (partly mitochondrial, partly cytosolic)
 • 1. NH₃ + CO₂ + 2 ATP → Carbamoyl phosphate (carbamoyl phosphate synthetase I,
mitochondria)
• 2. Carbamoyl phosphate + Ornithine → Citrulline (ornithine transcarbamoylase, mitochondria)
• 3. Citrulline + Aspartate + ATP → Argininosuccinate (argininosuccinate synthetase, cytosol)
• 4. Argininosuccinate → Arginine + Fumarate (argininosuccinate lyase)
• 5. Arginine + H₂O → Urea + Ornithine (arginase) — ornithine re-enters mitochondria
Net: 2 NH₃ + CO₂ + 3 ATP → Urea. Fumarate produced links urea cycle to TCA cycle (aspartate-
argininosuccinate shunt).
[Slide 24] Metabolism — Not Just Energy Production
A critical conceptual reframe: metabolism is far broader than simply generating ATP.
• Controls growth: biosynthetic pathways supply the building blocks for cell division
• Controls disease: metabolic reprogramming is a hallmark of cancer; metabolic errors cause
inherited metabolic disorders
• Controls adaptation: cells rewire their metabolism in response to nutrient availability, oxygen
levels, and stress
• Relevant to medicine: most drugs target metabolic enzymes or their regulators
• Relevant to biotechnology: engineering metabolic pathways in microbes for biofuel, drug, and
chemical production
• Relevant to origins of life: primitive metabolic chemistry may have preceded genetics
Metabolism is a dynamic system constantly sensing and responding to the environment.
[Slide 25–26] Biochemistry Functional Groups and Linkages
Understanding functional groups is essential for following the chemistry of metabolic reactions. Each
group has characteristic reactivity.
Key functional groups in biochemistry
• Hydroxyl (–OH): found in alcohols, sugars; can be phosphorylated, oxidised
• Carbonyl (C=O): ketone or aldehyde — reactive toward nucleophiles, oxidation/reduction
• Carboxyl (–COOH): acidic; forms esters (with alcohols) and amide bonds (with amines)
• Amino (–NH₂): basic; forms peptide bonds; donates/accepts protons; involved in transamination
• Phosphate (–OPO₃²⁻): high-energy transfer potential; central to ATP, NADH, DNA/RNA
backbone
• Thiol (–SH): in cysteine; forms disulfide bonds; thioester bonds (e.g. Acyl-CoA) are high-energy
• Methyl (–CH₃): added by SAM in methylation reactions; regulates epigenetics
Key linkages
• Ester bonds: between carboxyl and hydroxyl (e.g. triglycerides, phospholipids)
• Amide/peptide bonds: between carboxyl and amino group (proteins)
• Glycosidic bonds: between sugars (polysaccharides)
• Phosphodiester bonds: backbone of DNA and RNA
[Slide 27] Bond Cleavage — Homolytic vs Heterolytic
Two fundamentally different ways a covalent bond can break, with completely different chemistry:
Homolytic cleavage
• Bond electrons are split equally between the two atoms: A:B → A• + B•
• Produces radicals (highly reactive, unpaired electrons)
• Relevant in radical reactions, lipid peroxidation, some vitamin B12-dependent reactions
Heterolytic cleavage
• Bond electrons go entirely to one atom: A:B → A⁺ + B⁻ (or A⁻ + B⁺)
• Produces ions (cation and anion)
• Most common in biochemistry — enzyme-catalysed reactions use heterolytic mechanisms
• Produces nucleophiles (electron-rich) and electrophiles (electron-poor)
Understanding which type of cleavage occurs determines the reaction mechanism and explains enzyme
specificity.
[Slide 28–30] Nucleophiles and Electrophiles in Biochemical Reactions
The chemistry of metabolism is fundamentally about electron-rich species (nucleophiles) attacking
electron-poor species (electrophiles).
Nucleophiles (electron donors, seek positive centres)
• Water (H₂O) — weak nucleophile, involved in hydrolysis
• Hydroxyl ion (OH⁻) — strong nucleophile
• Thiolate (–S⁻) — excellent nucleophile (soft base); cysteine in enzyme active sites
• Amino groups (–NH₂/–NH₃⁺) — moderate nucleophile; attacks carbonyl carbons
• Imidazole of histidine — versatile nucleophile in enzyme mechanisms
Electrophiles (electron acceptors, seek negative centres)
• Carbonyl carbon (C=O) — polarised, δ+ carbon is attacked by nucleophiles
• Phosphorus in phosphate esters — electrophilic centre in phosphoryl transfer
• Acyl carbons in thioesters (Acyl-CoA) — highly reactive electrophiles
Most enzyme mechanisms can be described as a nucleophile in the active site attacking an electrophilic
substrate — this framework unifies reaction mechanisms across all of biochemistry.
[Slide 32]Metabolic Hooks — Abstract Concepts Made Concrete
The slide introduces the pedagogical principle underlying this course: metabolism should not be taught
as a series of abstract pathways but as a connected, logical system with real-world relevance.
A 'metabolic hook' is a clinical case, analogy, or thought experiment that gives an entry point into
understanding a pathway:
• Why does a drunk person get hypoglycaemic? → Alcohol metabolism and NADH/NAD⁺ ratio
• Why can't you synthesise glucose from fat? → Acetyl-CoA cannot be converted to oxaloacetate
(net)
• Why does cancer prefer glycolysis? → Warburg effect and biosynthetic demands
• How does the body survive starvation? → Ketogenesis and gluconeogenesis
Each hook is a gateway into the deeper biochemistry.
[Slide 33–35]Chronic Alcoholics and Thiamine — From Bar to Coma
Clinical scenario: A chronic alcoholic with cirrhosis presents with confusion, ataxia, and
ophthalmoplegia. Blood glucose is slightly low but not alarmingly so. What is happening
biochemically?
The problem: thiamine (Vitamin B1) deficiency
• Chronic alcohol consumption → poor diet, impaired intestinal absorption, reduced liver storage
of thiamine
• Cirrhosis further impairs thiamine storage and activation
Why thiamine matters biochemically
• Thiamine pyrophosphate (TPP) is the cofactor for: pyruvate dehydrogenase (pyruvate → acetyl-
CoA), α-ketoglutarate dehydrogenase (TCA step 4), transketolase (pentose phosphate pathway)
• Without TPP: pyruvate accumulates → cannot enter TCA cycle → lactic acidosis
• Without TPP: α-ketoglutarate cannot be oxidised → TCA cycle partially blocked
• Without TPP: transketolase fails → NADPH production drops → oxidative stress in neurons
Clinical consequences: Wernicke-Korsakoff Syndrome
• Acute phase (Wernicke's encephalopathy): confusion, ophthalmoplegia, ataxia — caused by
energy failure in metabolically demanding brain regions
• Chronic phase (Korsakoff's psychosis): irreversible memory impairment, confabulation
Treatment
• IV thiamine (before any glucose — giving glucose first worsens TPP depletion and can
precipitate acute Wernicke's)
[Slide 36–37]Naked Mole-Rat: Surviving Without Oxygen
The naked mole-rat (Heterocephalus glaber) is a remarkable mammal that can survive extreme hypoxia
and even brief complete anoxia — conditions that kill most mammals within minutes.
The metabolic twist
• Under anoxia: the mole-rat switches its primary fuel from glucose to fructose
• Fructose enters glycolysis via fructokinase → fructose-1-phosphate → bypasses the rate-limiting
phosphofructokinase-1 (PFK-1) step
• PFK-1 is allosterically inhibited under low ATP/high AMP conditions in most mammals — this
is a classic choke point; fructose sidesteps it entirely
• This allows ATP production to continue even when the normal glycolytic regulatory checkpoints
would stall
• Lactate rises (anaerobic) but tissues tolerate this better than other mammals
Why this matters
• Demonstrates that metabolic flexibility (substrate switching) is a survival adaptation
• Has implications for understanding ischaemia tolerance in cardiac and brain tissue
• Fructose metabolism in cancer cells uses a similar bypass of PFK-1 regulation
[Slide 38]Ketone Bodies — Alternative Fuel in Fasting and Starvation
During prolonged fasting, starvation, or a ketogenic diet, the liver produces ketone bodies from acetyl-
CoA. These are exported to peripheral tissues as an alternative fuel, especially important for the brain
(which cannot use fatty acids directly).
Three ketone bodies
• Acetoacetate — primary ketone body synthesised in liver
• β-Hydroxybutyrate (3-hydroxybutyrate) — reduced form; quantitatively the most abundant in
blood
• Acetone — spontaneous decarboxylation of acetoacetate; exhaled (ketone breath)
Ketogenesis (in liver mitochondria)
• 2 Acetyl-CoA → Acetoacetyl-CoA → HMG-CoA → Acetoacetate → β-Hydroxybutyrate
• Driven by high acetyl-CoA (from β-oxidation) and low oxaloacetate (OAA diverted to
gluconeogenesis)
Ketolysis (in peripheral tissues — not liver)
• β-Hydroxybutyrate → Acetoacetate → Acetoacetyl-CoA → 2 Acetyl-CoA → TCA cycle →
ATP
The liver cannot use its own ketone bodies — it lacks succinyl-CoA transferase. This division of labour
(liver produces, brain/muscle consumes) is a key metabolic principle.
[Slide 39–40] GLUT1 Deficiency — Inborn Metabolic Disorder
Clinical scenario: A young child presents with seizures, developmental delay, and hypoglycorrhachia
(low CSF glucose) despite normal blood glucose.
The diagnosis: GLUT1 deficiency syndrome
• GLUT1 (SLC2A1) is the primary glucose transporter at the blood-brain barrier and on
erythrocytes
• Loss-of-function mutations in SLC2A1 → glucose cannot cross the BBB efficiently
• Brain behaves as if glucose-starved even when blood glucose is normal
Why seizures?
• Brain depends almost entirely on glucose for ATP under normal conditions
• Energy failure in neurons → abnormal neuronal excitability → seizures
Treatment: Ketogenic diet
• High fat, low carbohydrate diet → liver produces ketone bodies (β-hydroxybutyrate,
acetoacetate)
• Ketone bodies cross the BBB via monocarboxylate transporters (MCT1) — independent of
GLUT1
• Ketones provide an alternative fuel for the brain
Key insight: Brain failure here is a fuel delivery problem, not a fuel supply problem. This teaches the
distinction between circulating fuel availability and cellular fuel access — critically important in
medicine.
Raises the question: if ketosis helps here, what does this imply about neuronal mitochondrial capacity
and substrate flexibility?
[Slide 41–45] Gollum — A Metabolic Case Study in Chronic Fasting Physiology
The lecturer uses Gollum (from Tolkien's Lord of the Rings) as a creative metabolic hook to illustrate
chronic fasting/ketosis physiology.
"Why are you so emaciated, Precious?"
• Gollum's diet: primarily fish (protein + fat), living underground away from sunlight
• Effectively a forced ketogenic diet — high fat/protein, minimal carbohydrate
Metabolic interpretation
• Baseline fuel: ketone bodies (from fat oxidation) — ketone-driven baseline metabolism
• Glucose protection: gluconeogenesis maintains blood glucose for obligate glucose tissues
(RBCs, renal medulla)
• Glycolysis: reserved for emergency high-intensity bursts only
• Emaciation: chronic negative energy balance → skeletal muscle wasting (gluconeogenesis uses
amino acids), loss of adipose
• Neurological changes: micronutrient deficits (B vitamins, minerals) over centuries would impair
enzymatic function
• Stress hormones: chronically elevated cortisol/glucagon → promotes catabolism, muscle
breakdown
Gollum is what happens when a hominin is forced into permanent fasting physiology. A memorable case
study for integrating gluconeogenesis, ketogenesis, protein catabolism, and micronutrient biochemistry.
[Slide 46–49] The Tragically Adaptive Cancer Metabolism
Cancer cells undergo dramatic metabolic reprogramming to support their survival, rapid proliferation,
and evasion of the immune system.
Altered nutrient uptake
• Massive upregulation of glucose transporters (GLUT1, GLUT3) and glycolytic enzymes
• Increased glutamine uptake — glutamine is the primary nitrogen and carbon source for
biosynthesis
• Enhanced uptake of lipids, acetate, and other non-glucose fuels
Opportunistic modes of nutrition
• Macropinocytosis — bulk engulfment of extracellular fluid (including proteins) for nutrient
scavenging
• Autophagy — self-digestion of cellular components to release amino acids and lipids under
nutrient stress
• Lipid scavenging — uptake of exogenous lipids from the tumour microenvironment
• Lactate recycling — some cancer cells consume lactate from neighbouring glycolytic cells
(metabolic symbiosis)
The metabolic reprogramming of cancer is not random — it is adaptive, serving the demands of
proliferation, survival, and invasion.
[Slide 50–51] Moonlighting of Metabolic Enzymes
Enzyme moonlighting: a single enzyme performs two or more distinct, physiologically relevant
functions using the same polypeptide chain. This adds a new dimension to the diversity of enzyme
function beyond simple catalysis.
Classic examples
• Aconitase/IRP1 (ACO1): TCA cycle enzyme (citrate → isocitrate) when iron-replete; becomes
Iron Regulatory Protein 1 (IRP1) when iron is low — regulates ferritin and transferrin receptor
mRNA (discussed in Lecture 10)
• Phosphoglucose isomerase (PGI): inside the cell, catalyses G6P ↔ F6P in glycolysis; when
secreted, functions as Autocrine Motility Factor (AMF) — a cytokine that promotes tumour cell
motility
• GAPDH: normally catalyses step 6 of glycolysis; under oxidative stress or in the nucleus, acts in
DNA repair and transcriptional regulation
• Enolase: glycolytic enzyme; also found on the cell surface acting as a plasminogen receptor
Moonlighting functions are often revealed under specific conditions (low iron, oxidative stress,
secretion) and are increasingly recognised as clinically relevant. Cancer cells often exploit the
moonlighting functions of glycolytic enzymes.