ATP

STRUCTURE: Adenine (purine base) + ribose + 3 phosphate groups (α, β, γ). The two terminal phosphoanhydride bonds are high-energy. Hydrolysis to ADP + Pi (or AMP + PPi) releases free energy that is coupled to unfavorable reactions.

PRODUCTION: - Glycolysis (cytosol): net 2 ATP per glucose by substrate-level phosphorylation (phosphoglycerate kinase, pyruvate kinase). This is the only ATP source in RBCs, which lack mitochondria. Anaerobic glycolysis yields 2 ATP per glucose. - TCA cycle (mitochondrial matrix): 1 GTP/ATP per turn (succinyl-CoA synthetase), plus NADH/FADH2 that feed the ETC. - Oxidative phosphorylation (inner mitochondrial membrane): the ETC pumps protons into the intermembrane space, creating a proton gradient. ATP synthase (Complex V, F0F1) uses this gradient to make ATP. Approximate yield is ~2.5 ATP per NADH and ~1.5 ATP per FADH2, for ~30–32 ATP per glucose (older texts say 36–38). - Creatine phosphate in muscle rapidly regenerates ATP (creatine kinase). - Fatty acid β-oxidation yields more ATP per carbon than carbohydrate.

ETC INHIBITORS AND UNCOUPLERS (high-yield): - Complex I: rotenone. Complex III: antimycin A. Complex IV: cyanide, CO, azide (H2S too). ATP synthase: oligomycin. - Oligomycin blocks the proton channel, so ATP synthesis stops and the ETC backs up. - Uncouplers (2,4-dinitrophenol, aspirin overdose, thermogenin/UCP-1 in brown fat) dissipate the proton gradient. ETC activity and O2 consumption rise, ATP falls, and heat is produced (hyperthermia). - Adenine nucleotide translocase (ANT) exchanges ATP for ADP across the inner membrane. Atractyloside inhibits it.

FUNCTIONS: Active transport (Na+/K+-ATPase, Ca2+-ATPase, H+/K+-ATPase), muscle contraction (myosin head ATPase; ATP binding causes detachment from actin, which is why rigor mortis occurs when ATP is depleted), biosynthesis, phosphorylation by kinases, and cAMP production (adenylyl cyclase). ATP is also a substrate for RNA synthesis and a purinergic signaling molecule.

REGULATION: High ATP/ADP ratio inhibits PFK-1 (key glycolytic regulatory enzyme), pyruvate dehydrogenase, isocitrate dehydrogenase, and the ETC (respiratory control). High AMP activates AMPK, which turns on catabolism and turns off anabolism.

CLINICAL CORRELATES: - Mitochondrial diseases (maternal inheritance, heteroplasmy; e.g., MELAS, MERRF, Leber hereditary optic neuropathy, Leigh syndrome) cause impaired ATP production. They affect high-energy tissues (brain, muscle, heart, retina) and often show lactic acidosis, ragged red fibers, and myopathy. - Ischemia/hypoxia: ATP depletion causes failure of Na+/K+-ATPase, cell swelling, and failure of Ca2+ pumps. Reversible injury progresses to irreversible injury/necrosis (mitochondrial permeability, membrane damage). - Apoptosis requires ATP, whereas necrosis occurs with ATP depletion. - Pyruvate kinase deficiency: decreased RBC ATP leads to hemolytic anemia (rigid RBCs, echinocytes). - McArdle disease (muscle glycogen phosphorylase deficiency): no glycogen-derived glucose, so exercise intolerance, myoglobinuria, and no lactate rise. - Malignant hyperthermia and uncoupling agents: excessive ATP consumption/heat. - Cardiac: ATP-sensitive K+ channels (KATP) link metabolism to excitability. In pancreatic β-cells, increased ATP closes KATP, causing depolarization, Ca2+ influx, and insulin release (sulfonylureas close the channel). - Arsenic poisoning: arsenate substitutes for phosphate in glycolysis (1,3-BPG step), so net ATP is 0 in glycolysis. Arsenite inhibits lipoic acid (PDH, α-KG dehydrogenase). - Drugs: ATPase inhibitors include digoxin (Na+/K+-ATPase), PPIs (H+/K+-ATPase), and ouabain.

ATP vs. related terms: GTP is used in protein synthesis (translation), gluconeogenesis (PEPCK), and G-protein signaling. CTP is used in phospholipid synthesis, and UTP in glycogen synthesis.