Metabolism tricks that make pathways click

Glycolysis: 1 glucose → 2 pyruvate, net 2 ATP, 2 NADH. In cytoplasm. No oxygen.

Glycolysis — Invest 2 ATP early, gain 4 → net 2 ATP. Also produces 2 NADH. Occurs in cytoplasm, no oxygen needed. With oxygen → pyruvate enters mitochondria. Without → fermentation.

Krebs cycle (per glucose): 2 acetyl-CoA → 6 CO₂, 2 ATP, 6 NADH, 2 FADH₂

Krebs Cycle — Runs twice per glucose (one turn per pyruvate). Carbon atoms leave as CO₂. NADH and FADH₂ carry electrons to the Electron Transport Chain (ETC) where most ATP is made. Occurs in mitochondrial matrix.

ETC: electrons flow NADH → Complex I → CoQ → III → Cyt c → IV → O₂. H⁺ pumped out → ATP synthase.

Electron Transport Chain — Electrons from NADH and FADH₂ move through protein complexes. Energy pumps H⁺ into intermembrane space. H⁺ flows back through ATP synthase → ~32 ATP. O₂ is final electron acceptor → becomes H₂O.

Total ATP per glucose: ~36-38 (2 glycolysis + 2 Krebs + ~32-34 ETC)

ATP Yield — Glycolysis: 2 net ATP. Krebs: 2 ATP. ETC: ~32-34 ATP. Total theoretical maximum: ~36-38 ATP per glucose. Actual yield slightly lower due to membrane proton leakage.

Gluconeogenesis: makes glucose from non-carbohydrate sources (amino acids, lactate, glycerol) — liver

Gluconeogenesis — Occurs in fasting, starvation, and prolonged exercise. Substrates: amino acids (from muscle breakdown), lactate (from red blood cells (RBCs) and anaerobic muscle), glycerol (from fat breakdown). Mostly in liver, some in kidney.

Anabolism: building molecules (requires energy). Catabolism: breaking molecules (releases energy).

Anabolism vs Catabolism — Anabolism: synthesis reactions — build complex molecules from simple ones. Requires ATP. Protein synthesis, fatty acid synthesis, gluconeogenesis. Catabolism: degradation reactions — break complex molecules into simple ones. Releases ATP. Glycolysis, beta-oxidation, protein digestion. Metabolism = anabolism + catabolism.

Pyruvate dehydrogenase complex: pyruvate → acetyl-CoA + CO₂ + NADH. Bridge between glycolysis and Krebs.

Pyruvate Oxidation — Pyruvate (3 carbons) enters mitochondria → pyruvate dehydrogenase complex removes one carbon as CO₂ → acetyl-CoA (2 carbons) + NADH. This step is irreversible — acetyl-CoA cannot be converted back to glucose (unlike pyruvate). Why alcohol can't be converted to glucose: ethanol → acetaldehyde → acetyl-CoA (irreversible).

Fatty acid synthesis: in cytoplasm. Beta-oxidation: in mitochondria. Opposite processes, opposite compartments.

Fatty Acid Synthesis vs Oxidation — Beta-oxidation (catabolism): mitochondria, uses FAD and NAD⁺, produces acetyl-CoA and NADH. Fatty acid synthesis (anabolism): cytoplasm, uses NADPH, uses malonyl-CoA building blocks, requires biotin. They cannot run simultaneously — when one is active, the other is inhibited. Malonyl-CoA inhibits carnitine shuttle (blocks beta-oxidation).

Pentose phosphate pathway: produces NADPH (for biosynthesis and antioxidant) and ribose-5-phosphate (for nucleotides)

Pentose Phosphate Pathway — Runs parallel to glycolysis. Two products: NADPH (reduced glutathione, fatty acid synthesis, keeps red blood cells (RBCs) from oxidative damage) and ribose-5-phosphate (nucleotide synthesis). G6PD deficiency: can't make NADPH → RBCs vulnerable to oxidative stress → hemolytic anemia triggered by certain foods (fava beans) and drugs.

Glycogen synthesis: in liver (blood glucose buffer) and muscle (local energy). Glycogen phosphorylase breaks it down.

Glycogen Metabolism — Glycogen: branched polymer of glucose — rapid glucose storage. Liver glycogen: maintains blood glucose levels during fasting. Muscle glycogen: fuel for muscle contraction only. Glycogen synthase: builds glycogen. Glycogen phosphorylase: breaks it down, regulated by glucagon (liver), epinephrine (muscle and liver).

Metabolic regulation: allosteric control (fast), covalent modification (phosphorylation/dephosphorylation), gene expression (slow)

AllostericImmediate — feedback molecules

Covalent modificationMinutes — phosphorylation

Gene expressionHours/days — change enzyme amounts

Insulin lowers blood glucose: promotes glucose uptake, glycolysis, glycogen synthesis, fat storage. Glucagon raises it: promotes gluconeogenesis, glycogenolysis.

InsulinFed state — store glucose, build glycogen

GlucagonFasting — release glucose, gluconeogenesis