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Here is a thorough explanation of the entire MED 1003 Biochemistry lecture file. It covers four major topics:
MED 1003 — Cell, Tissue and Organ System Biochemistry
TOPIC 1: Overview of Fuel Metabolism & Oxidative Phosphorylation
What is Metabolism?
Metabolism is the sum of all chemical reactions in the body. It has two directions:
| Direction | Name | What happens |
|---|---|---|
| Building up | Anabolism | Synthesizes proteins, glycogen, DNA - uses energy |
| Breaking down | Catabolism | Breaks down carbs, fats, proteins - releases energy |
All of this is coordinated to maintain a continuous supply of ATP - the cell's energy currency.
Energy and ATP
- Cells capture energy from glucose oxidation and store it as ATP (adenosine triphosphate).
- ATP ⇄ ADP + Pi powers everything: muscle contraction, nerve impulses, biosynthesis, ion pumps.
- The Na⁺/K⁺ pump depends on ATP. If ATP fails (e.g., in hypoxia), the pump stops, ions flood in, the cell swells and dies.
Hormonal Regulation
| State | Hormones Active | Effect |
|---|---|---|
| After a meal | Insulin ↑ | Store fuel: glycogen, fat, protein synthesis |
| Fasting / stress | Glucagon, cortisol, adrenaline ↑; insulin ↓ | Break down glycogen and fat; release glucose and ketones |
AMPK is an intracellular sensor - it activates when ATP is low, switching on ATP-producing pathways.
Fuel Use by Tissue
| Organ | Primary Fuel | Consequence of Failure |
|---|---|---|
| Brain | Glucose (ketones in fasting) | Confusion, coma |
| Heart | Fatty acids | Heart failure |
| Skeletal muscle | Glucose, fatty acids, amino acids | Weakness, fatigue |
| Liver | All fuels (central regulator) | Hypoglycemia, toxin build-up |
| Kidneys | Glucose, glutamine | Acidosis, urea accumulation |
Three Stages of Catabolism
- Digestion (GI tract): Carbs → sugars; proteins → amino acids; fats → fatty acids + glycerol.
- Acetyl-CoA formation (cytoplasm + mitochondria):
- Glucose → pyruvate (glycolysis) → acetyl-CoA
- Fatty acids → acetyl-CoA (β-oxidation)
- Amino acids → acetyl-CoA or Krebs cycle intermediates
- Oxidation / ATP production (mitochondria):
- Krebs cycle → CO₂ + NADH + FADH₂
- Oxidative phosphorylation → ATP
Glycolysis
- Occurs in the cytoplasm.
- Glucose is phosphorylated, split into two 3-carbon molecules, and converted to pyruvate.
- Pyruvate enters mitochondria for further oxidation, or becomes lactate when oxygen is low.
Pyruvate Oxidation
- In the mitochondria, pyruvate loses one carbon as CO₂ and combines with CoA → acetyl-CoA.
- NAD⁺ is reduced to NADH (carries electrons to the ETC).
- No ATP is made at this step, but it "prepares" the substrate for the Krebs cycle.
Krebs (TCA/Citric Acid) Cycle
- Takes place in the mitochondrial matrix.
- Acetyl-CoA is oxidized to CO₂, releasing energy.
- Generates NADH and FADH₂ (electron carriers for the ETC), plus GTP (energy equivalent of ATP).
- It is a cycle because the starting molecule (oxaloacetate) is regenerated each turn.
Oxidative Phosphorylation (OxPhos)
This is the final and most productive stage - ~90% of all ATP is made here.
The Electron Transport Chain (ETC) has four large protein complexes in the inner mitochondrial membrane:
| Complex | Name | Action |
|---|---|---|
| I | NADH Dehydrogenase | Oxidizes NADH → NAD⁺; pumps H⁺; transfers electrons to CoQ |
| II | Succinate Dehydrogenase | Oxidizes FADH₂; transfers electrons to CoQ (no H⁺ pumping) |
| III | Cytochrome bc₁ | Receives electrons from CoQ; pumps 4 H⁺; passes electrons to cytochrome c |
| IV | Cytochrome c Oxidase | Final step; reduces O₂ to water; pumps 2 H⁺ |
ATP Synthase (Complex V): H⁺ ions flow back through it down their gradient, driving rotation of its "rotor" - this mechanical motion is used to synthesize ATP from ADP + Pi.
Proton Motive Force (PMF): The H⁺ gradient across the inner membrane (matrix = alkaline/negative; intermembrane space = acidic/positive) is the driving force.
Disruption of OxPhos (Clinical)
| Cause | Mechanism | Consequence |
|---|---|---|
| Hypoxia / ischemia | No O₂ → electron flow stops | NADH accumulates, ATP drops, cell swells and dies |
| Cyanide / CO | Block Complex IV | Histotoxic hypoxia; bright red venous blood, lactic acidosis |
| Oligomycin | Blocks ATP synthase | No ATP synthesis |
| 2,4-Dinitrophenol (DNP) | Uncoupler - collapses H⁺ gradient | Heat instead of ATP - fatal hyperthermia |
| Thermogenin (UCP1) | Physiological uncoupler in brown fat | Non-shivering thermogenesis in newborns |
Reactive Oxygen Species (ROS)
- ~1-2% of electrons "leak" during OxPhos → form ROS (superoxide O₂⁻•, H₂O₂, hydroxyl radical •OH).
- Controlled ROS: signaling, immunity (respiratory burst in neutrophils/macrophages).
- Excess ROS: DNA damage, lipid peroxidation, protein damage = oxidative stress.
Antioxidant enzymes:
- SOD: superoxide → H₂O₂
- Catalase: H₂O₂ → H₂O + O₂
- Glutathione peroxidase: H₂O₂ → H₂O (uses glutathione)
Clinical example: After a myocardial infarction, sudden re-oxygenation causes a ROS burst → membrane damage and calcium overload.
Mitochondrial Disorders
| Disease | Defect | Symptoms |
|---|---|---|
| LHON | Complex I mutation | Optic nerve degeneration, vision loss |
| MELAS | tRNA gene mutation | Lactic acidosis, stroke-like episodes |
| MERRF | tRNA mutation | Myoclonic epilepsy, ragged red fibers |
| Kearns-Sayre | mtDNA deletion | Eye muscle paralysis, cardiac block |
- Mitochondria are maternally inherited (from the oocyte).
- mtDNA is especially vulnerable to ROS damage (no histones, weak repair).
TOPIC 2: Vitamins and Minerals
Vitamins: Overview
Vitamins are organic compounds required in tiny amounts, acting mainly as coenzymes or gene regulators for metabolic enzymes.
Fat-Soluble Vitamins (A, D, E, K)
Stored in liver/adipose; absorbed with fats; deficiency develops slowly; excess can be toxic.
| Vitamin | Key Functions | Deficiency |
|---|---|---|
| A (Retinol) | Vision (rhodopsin), cell differentiation, gene regulation | Night blindness, growth defects |
| D (Cholecalciferol) | Ca²⁺ and phosphate metabolism; synthesized in skin from UV | Rickets (children), osteomalacia (adults) |
| E (Tocopherol) | Lipid antioxidant; protects membranes from ROS | Rare; oxidative membrane damage |
| K (Phylloquinone) | Cofactor for clotting factor activation | Bleeding; warfarin antagonizes it |
Water-Soluble Vitamins: B-group (Energy Metabolism)
Not stored; must be consumed daily; excess excreted by kidneys.
| Vitamin | Coenzyme Form | Key Role | Deficiency |
|---|---|---|---|
| B₁ (Thiamine) | TPP | Pyruvate → acetyl-CoA; links glycolysis to Krebs | Beriberi, Wernicke-Korsakoff |
| B₂ (Riboflavin) | FMN, FAD | Redox in Krebs cycle and ETC | Glossitis, angular stomatitis (rare) |
| B₃ (Niacin) | NAD⁺, NADP⁺ | Central energy metabolism | Pellagra (dermatitis, diarrhea, depression) |
| B₅ (Pantothenic acid) | CoA, ACP | Fatty acid metabolism | Very rare |
| B₉ (Folate) | THF (tetrahydrofolate) | DNA synthesis (C1 unit transfer) | Megaloblastic anemia; neural tube defects in pregnancy |
Water-Soluble Vitamins: B-group (Amino Acid Metabolism & Biosynthesis)
| Vitamin | Key Role | Deficiency |
|---|---|---|
| B₆ (Pyridoxal) | PLP: transamination, neurotransmitter synthesis (serotonin, dopamine, GABA) | Irritability, neuropathy, anemia |
| B₇ (Biotin) | Carboxylation: gluconeogenesis, fatty acid synthesis | Rare; raw egg whites can cause it |
| B₁₂ (Cobalamin) | Homocysteine → methionine; connects folate metabolism | Megaloblastic anemia + neurological damage (pernicious anemia) |
| C (Ascorbic acid) | Collagen synthesis (keeps Fe²⁺ for prolyl hydroxylase); antioxidant | Scurvy (bleeding, connective tissue fragility) |
Minerals
Macroelements (>100 mg/day needed)
| Mineral | Key Roles | Deficiency / Excess |
|---|---|---|
| Ca²⁺ | Bones/teeth (hydroxyapatite), muscle contraction, clotting | Hypocalcemia → tetany; hypercalcemia → kidney stones |
| Phosphate | ATP, nucleic acids, bone mineral, pH buffering | Hypophosphatemia → muscle weakness |
| Mg²⁺ | Cofactor for >300 enzymes; stabilizes ATP | Deficiency in alcoholism → arrhythmias, cramps; used in preeclampsia |
| Na⁺/K⁺/Cl⁻ | Membrane potential, nerve/muscle function, fluid balance | Low K⁺ → arrhythmias; excess Na⁺ → hypertension |
Trace Elements (<100 mg/day)
| Element | Key Role | Deficiency |
|---|---|---|
| Fe | Hemoglobin, cytochromes (O₂ transport, ETC) | Microcytic anemia |
| Cu | Cytochrome c oxidase, SOD, connective tissue | Anemia, weak connective tissue (Menkes/Wilson diseases) |
| Zn | >300 enzymes; zinc finger transcription factors; immune defense | Dermatitis, poor wound healing |
| Se | Glutathione peroxidase (antioxidant); thyroid hormone activation | Keshan disease (cardiomyopathy) |
| I | Thyroid hormones T₃ and T₄ | Goiter, hypothyroidism, developmental delay |
| Co | Central atom of vitamin B₁₂ | Manifests as B₁₂ deficiency |
TOPIC 3: Nucleic Acids
Nucleotide Structure
- Nucleoside = nitrogenous base + sugar (ribose or deoxyribose)
- Nucleotide = nucleoside + phosphate group
- Bases:
- Purines: Adenine (A), Guanine (G) - 2 rings
- Pyrimidines: Cytosine (C), Thymine (T in DNA), Uracil (U in RNA) - 1 ring
DNA vs RNA
| Feature | DNA | RNA |
|---|---|---|
| Sugar | Deoxyribose | Ribose |
| Unique base | Thymine (T) | Uracil (U) |
| Strands | Double-stranded helix | Single-stranded |
| Function | Stores genetic information | Gene expression, protein synthesis |
DNA Double Helix
- Two antiparallel strands (5'→3' and 3'→5'), held by hydrogen bonds: A=T (2 H-bonds), G≡C (3 H-bonds).
- B-DNA is the predominant right-handed helix in cells.
- Supercoiling compacts DNA inside the nucleus; controlled by topoisomerases.
- Ciprofloxacin inhibits bacterial topoisomerase (DNA gyrase) - the basis of its antibiotic action.
DNA Replication
- Each strand acts as a template; DNA polymerases build the new strand.
- Powered by hydrolysis of dNTPs (dATP, dCTP, dGTP, dTTP).
- Polymerases have proofreading (exonuclease) activity → high fidelity.
DNA Damage & Repair
- Damaged by ROS (oxidizes guanine → 8-oxoguanine), radiation (thymine dimers), and alkylating agents.
- Repaired by excision, resynthesis, and ligation.
- Xeroderma pigmentosum: defect in nucleotide excision repair → UV damage accumulates → high skin cancer risk.
- Lynch syndrome: mismatch repair gene mutation → hereditary colorectal cancer.
Types of RNA
| Type | Function |
|---|---|
| mRNA | Carries genetic code from DNA to ribosomes |
| tRNA | Matches codons to amino acids during translation; cloverleaf structure; anticodon + amino acid attachment at 3' CCA end |
| rRNA | Structural and catalytic scaffold of ribosomes |
| snRNA | Splicing of pre-mRNA (in spliceosomes) |
| ncRNA | Various regulatory functions |
Nucleotide Metabolism - Clinical Links
- Gout / Lesch-Nyhan syndrome: deficiency of HGPRT (salvage enzyme) → uric acid accumulates → gout, neurological damage, self-mutilation. Treated with allopurinol (xanthine oxidase inhibitor).
- Cancer therapy: methotrexate and 5-fluorouracil block thymidylate synthesis → slow tumor cell division.
- Antiviral therapy: acyclovir (guanosine analog) incorporates into viral DNA → chain termination.
- Diagnostics: PCR amplifies DNA for detecting HIV, hepatitis, COVID-19.
TOPIC 4: Signal Transduction Mechanisms
General Principle
Cells communicate through signals (hormones, neurotransmitters) that bind to receptors, triggering internal cascades that change metabolism, gene expression, growth, or secretion.
Types of Receptors
-
Receptor Tyrosine Kinases (RTK) - single-pass (1-helix) membrane receptors
- Ligand binding → receptor dimerization → autophosphorylation → kinase cascade.
- Example: HER2 receptor in breast cancer (overactive). Treated with trastuzumab (Herceptin).
-
Ion Channel-Linked Receptors
- Ligand binds → channel opens → ion flow → electrical change.
- Example: Acetylcholine receptor at neuromuscular junction.
- In myasthenia gravis: autoantibodies block these receptors → muscle weakness.
-
G Protein-Coupled Receptors (GPCRs) - 7-helix transmembrane receptors
- Most common receptor class.
- Ligand → receptor activates G protein → α subunit swaps GDP for GTP → activates enzymes → second messengers.
- Cholera toxin locks Gα in the "on" state → permanent adenylate cyclase activation → excess cAMP → massive Cl⁻/water loss → life-threatening diarrhea.
Second Messengers
Small intracellular molecules that amplify and transmit signals:
| Messenger | Made from | Effect |
|---|---|---|
| cAMP | ATP (by adenylate cyclase) | Activates PKA → phosphorylates enzymes and transcription factors |
| cGMP | GTP (by guanylate cyclase) | Vision; NO signaling |
| Ca²⁺ | Released from ER or enters from outside | Activates calmodulin; muscle contraction; secretion |
| IP₃ | From PIP₂ (by phospholipase C) | Releases Ca²⁺ from the ER |
| DAG | Made with IP₃ | Activates PKC |
| NO (nitric oxide) | From arginine | Vasodilation (smooth muscle relaxation) |
cAMP signaling detail:
- Adenylate cyclase makes cAMP; phosphodiesterase (PDE) degrades it.
- Caffeine inhibits PDE → prolongs cAMP action.
- Theophylline (PDE inhibitor) used in asthma.
- Insulin lowers cAMP via PDE activation.
Signaling Cascades (Phosphorylation Cascades)
One signal triggers a chain of kinases - each activates the next (like falling dominoes) - amplifying the signal enormously.
Example - Growth factor pathway:
Growth factor → RTK → Ras-MAPK cascade → nucleus → new proteins → cell division.
Dysregulation causes disease: cancer (uncontrolled growth), diabetes (impaired insulin signaling), immune disorders.
Summary Table of Key Clinical Connections
| Condition | Biochemical Basis | Drug / Mechanism |
|---|---|---|
| Gout / Lesch-Nyhan | ↓ HGPRT → uric acid accumulation | Allopurinol (xanthine oxidase inhibitor) |
| Xeroderma pigmentosum | Defective nucleotide excision repair | - |
| HER2 breast cancer | Overactive RTK (HER2) | Trastuzumab (blocks HER2) |
| Cholera | Gs locked "on" → ↑ cAMP | Rehydration |
| Myasthenia gravis | Autoantibodies block ACh receptors | AChE inhibitors |
| Pernicious anemia | B₁₂ malabsorption (no intrinsic factor) | B₁₂ injections |
| Beriberi / Wernicke-Korsakoff | B₁ (thiamine) deficiency | Thiamine supplementation |
| Pellagra | B₃ (niacin) deficiency | Niacin supplementation |
| Scurvy | Vitamin C deficiency | Ascorbic acid |
| Rickets | Vitamin D deficiency | Vitamin D + calcium |
| MELAS / MERRF | mtDNA mutation | Supportive care |
| Myocardial infarction + ischemia-reperfusion | ROS burst on re-oxygenation | Antioxidant strategies |
This covers all 74 pages of the lecture slides. The four major units build on each other logically: nutrients are metabolized to produce ATP via OxPhos (Topic 1); vitamins and minerals act as essential cofactors in those pathways (Topic 2); nucleic acids carry and express the genetic code that encodes all enzymes (Topic 3); and signal transduction coordinates how cells respond to their environment and regulate all of the above (Topic 4).
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