Metabolism Study Guide

📖 Core Concepts Metabolism – the full set of chemical reactions that keep an organism alive; it converts food into energy, building blocks, and waste. Intermediary metabolism – the network of reactions that occurs inside cells (glycolysis, TCA cycle, etc.). Catabolism vs. Anabolism Catabolic pathways break down molecules (e.g., glucose → pyruvate) and release energy. Anabolic pathways build up molecules (e.g., amino acids → protein) and consume energy. Enzymes – protein catalysts that speed up each step, allow non‑spontaneous reactions, and provide regulation. Energy currencies ATP – primary “energy‑money” molecule; transfers a phosphate group: $$\text{ATP} + \text{H}2\text{O} \rightarrow \text{ADP} + \text{P}\text{i} + \text{energy}$$ NAD⁺ / NADH – catabolic electron carrier; NADH feeds the electron transport chain (ETC). NADP⁺ / NADPH – anabolic electron carrier; NADPH supplies reducing power for biosynthesis (e.g., fatty‑acid synthesis, PPP). Basal Metabolic Rate (BMR) – energy used by all metabolic reactions when the organism is at rest. Open‑system thermodynamics – living cells exchange matter/energy with the environment, increasing the entropy of surroundings while keeping internal order. Coupling – spontaneous catabolic reactions (ΔG < 0) supply the free energy that drives non‑spontaneous anabolic reactions (ΔG > 0). --- 📌 Must Remember Glycolysis net: 2 ATP, 2 NADH, 2 pyruvate per glucose. Oxidative phosphorylation: Each NADH ≈ 2.5 ATP, each FADH₂ ≈ 1.5 ATP (via ETC & ATP synthase). β‑oxidation per 2‑C unit: 1 NADH + 1 FADH₂ + 1 acetyl‑CoA →  12 ATP (including downstream TCA). Pentose Phosphate Pathway (PPP): Produces NADPH and ribose‑5‑phosphate; up‑regulated when cells need reducing power or nucleotides. Key irreversible steps (different enzymes in gluconeogenesis): Hexokinase → Phosphofructokinase‑1 (PFK‑1) → Pyruvate kinase (glycolysis) Fructose‑1,6‑bisphosphatase, PEP carboxykinase, glucose‑6‑phosphatase (gluconeogenesis). Allosteric regulators (example: PFK‑1) – inhibited by ATP & citrate, activated by AMP & fructose‑2,6‑bisphosphate. Insulin → ↑ glucose uptake, ↑ glycogen & fatty‑acid synthesis, ↓ glycogenolysis & lipolysis. Glucogenic vs. ketogenic amino acids – some (e.g., leucine) yield only acetyl‑CoA → ketogenic; many yield TCA intermediates → glucogenic. --- 🔄 Key Processes Glycolysis (cytosol) Glucose → Glucose‑6‑P (hexokinase) → Fructose‑6‑P → Fructose‑1,6‑bisP (PFK‑1) → Glyceraldehyde‑3‑P → 1,3‑bisP (produces NADH) → 2 ATP (substrate‑level) → Pyruvate (produces 2 ATP). Conversion of Pyruvate → Acetyl‑CoA (mitochondrial matrix) Pyruvate dehydrogenase complex releases CO₂, produces NADH, attaches CoA. Citric Acid Cycle (TCA) Acetyl‑CoA + Oxaloacetate → Citrate → … → Oxaloacetate + 3 NADH + 1 FADH₂ + 1 GTP per turn. Oxidative Phosphorylation NADH/FADH₂ → Complex I–IV → Proton gradient → ATP synthase → ATP. β‑Oxidation (mitochondria) Fatty‑acid + CoA → Acyl‑CoA → (repeated) → Acetyl‑CoA + NADH + FADH₂. Gluconeogenesis (mainly liver) Pyruvate → Oxaloacetate (PC) → PEP (PEPCK) → … → Glucose‑6‑P (different enzymes). Fatty‑Acid Synthesis (cytosol) Acetyl‑CoA → Malonyl‑CoA (ACC) → Repeated condensation, reduction, dehydration, reduction → Palmitate (16 C). Protein Synthesis Amino acid + tRNA + ATP → aminoacyl‑tRNA (synthetase). Ribosome reads mRNA codons → peptide bond formation → polypeptide chain. Nucleotide De‑novo Synthesis Purines: Build on PRPP → IMP → AMP/GMP (requires glycine, glutamine, aspartate, formate). Pyrimidines: Build on carbamoyl phosphate → Orotate → UMP → CTP/UTP. --- 🔍 Key Comparisons Catabolism vs. Anabolism – “break‑down & release energy” vs. “build‑up & use energy”. NAD⁺ vs. NADP⁺ – NAD⁺ shuttles electrons to the ETC (catabolic); NADP⁺ supplies electrons for biosynthetic reductions (anabolic). Glycolysis vs. Gluconeogenesis – Same substrates, opposite directions; distinct enzymes at the three irreversible steps. β‑Oxidation vs. Fatty‑Acid Synthesis – Oxidation occurs in mitochondria, yields NADH/FADH₂; synthesis occurs in cytosol, consumes NADPH. Allosteric vs. Hormonal Regulation – Immediate, metabolite‑level feedback vs. slower, signal‑transduction cascades (e.g., insulin). --- ⚠️ Common Misunderstandings “ATP is the only energy source.” – NADH, FADH₂, and NADPH also carry usable energy. Lactate is just waste. – It regenerates NAD⁺ under anaerobic conditions, allowing glycolysis to continue. NADH can cross the mitochondrial inner membrane directly. – It uses shuttles (malate‑aspartate, glycerol‑3‑P). All amino acids are glucogenic. – Leucine and lysine are strictly ketogenic. Oxidative phosphorylation occurs in the cytosol. – It is confined to the inner mitochondrial (or bacterial plasma) membrane. --- 🧠 Mental Models / Intuition Energy‑flow waterfall: Catabolism = downhill flow (releases energy); Anabolism = uphill climb (spends that energy). Currency analogy: ATP = cash, NADH/NADPH = “checks” used for different purchases (ATP for work, NADPH for building). Assembly line: Each enzymatic step adds a specific part; missing or faulty steps halt the whole line (e.g., enzyme deficiency → metabolic disease). Bow‑tie architecture: Diverse nutrients (inputs) converge on a few “currency” metabolites (acetyl‑CoA, NADH, ATP) and diverge into many products. --- 🚩 Exceptions & Edge Cases Anaerobic glycolysis: Pyruvate → lactate (via lactate dehydrogenase) to recycle NAD⁺. Fatty‑acid synthesis uses NADPH, not NADH. Mitochondrial entry of long‑chain fatty acids requires the carnitine shuttle. Amino acids that are both glucogenic & ketogenic (e.g., isoleucine, phenylalanine). High‑energy phosphate bonds can be stored as phosphocreatine in muscle – not covered in outline but a known exception. --- 📍 When to Use Which Fuel choice: Glucose preferred when oxygen is abundant & insulin high. Fatty acids dominate during fasting or prolonged exercise (low insulin, high glucagon). Coenzyme selection: Use NAD⁺ for catabolic redox reactions (e.g., glycolysis, TCA). Use NADP⁺ for anabolic reductions (e.g., fatty‑acid synthesis, PPP). Pathway activation: Insulin → activate glycolysis, glycogen synthesis, lipogenesis. Glucagon/epinephrine → activate gluconeogenesis, glycogenolysis, lipolysis. Regulatory mode: Allosteric control for rapid, local flux changes (e.g., PFK‑1). Hormonal control for longer‑term, organism‑wide adjustments. --- 👀 Patterns to Recognize Repeated 2‑C units (acetyl‑CoA) feeding both the TCA cycle and fatty‑acid synthesis. High‑energy phosphate transfer always involves ATP → ADP + Pi (look for kinases). Feedback inhibition at the first irreversible step of a pathway (e.g., end‑product inhibits its own synthesis). NADPH production spikes when the cell needs biosynthesis (PPP activation). “Bow‑tie” signature: Many diverse substrates → few common intermediates (acetyl‑CoA, NADH, ATP) → many end products. --- 🗂️ Exam Traps Confusing NADH ↔ NADPH – remember NADH = catabolism/ETC; NADPH = biosynthesis/PPP. Choosing the wrong irreversible enzyme – e.g., picking pyruvate kinase for gluconeogenesis (incorrect; the reverse step uses PEP carboxykinase). Assuming lactate formation only occurs in pathology – it’s a normal anaerobic response. Attributing insulin’s effect to glycogen breakdown – insulin inhibits glycogenolysis, it stimulates glycogen synthesis. Believing all fatty acids enter mitochondria freely – long‑chain fatty acids need the carnitine shuttle; omission leads to over‑estimation of ATP yield. Mixing up allosteric vs. hormonal regulation – a metabolite (e.g., ATP) can inhibit an enzyme directly, whereas insulin works through signaling cascades. ---