ADP

**Biochemistry / Bioenergetics** - Structure: adenine + ribose + 2 phosphate groups. Formed when ATP is hydrolyzed (ATP → ADP + Pi) to release energy (~ -7.3 kcal/mol), or from AMP via adenylate kinase (2 ADP ⇌ ATP + AMP; myokinase reaction). - Regeneration to ATP: (1) Oxidative phosphorylation: ATP synthase (Complex V, F0F1) uses the proton gradient to phosphorylate ADP. (2) Substrate-level phosphorylation: glycolysis (1,3-BPG → 3-phosphoglycerate via phosphoglycerate kinase; phosphoenolpyruvate → pyruvate via pyruvate kinase), TCA cycle (succinyl-CoA → succinate; GTP/ATP via succinyl-CoA synthetase). (3) Creatine kinase: phosphocreatine + ADP → creatine + ATP (muscle, brain). - Regulation: A high ADP/ATP ratio (or high AMP) signals low energy and allosterically activates key catabolic enzymes: PFK-1 (glycolysis), isocitrate dehydrogenase (TCA), and AMPK (via AMP). ADP availability is the main determinant of respiratory control: electron transport is tightly coupled to ADP availability (acceptor control). Without ADP, the proton gradient is not dissipated and the ETC slows. - Uncouplers (2,4-DNP, thermogenin/UCP-1, aspirin overdose) dissipate the proton gradient, so oxygen consumption rises without ADP phosphorylation, with heat production and hyperthermia. ATP synthase inhibitors (oligomycin) block ADP→ATP and the ETC backs up. Atractyloside/bongkrekic acid inhibit the adenine nucleotide translocase (ANT), which exchanges mitochondrial ATP for cytosolic ADP. - ADP-ribosylation: NAD+ is the donor of ADP-ribose in bacterial toxin mechanisms: diphtheria toxin and Pseudomonas exotoxin A ADP-ribosylate EF-2 (inhibit protein synthesis); cholera toxin ADP-ribosylates Gs (↑cAMP, rice-water diarrhea); pertussis toxin ADP-ribosylates Gi (↑cAMP); E. coli LT acts like cholera toxin. PARP also uses ADP-ribosylation in DNA repair (PARP inhibitors, e.g., olaparib, for BRCA-mutated cancers). - Related: GDP/GTP in G-protein signaling is analogous; ADP-ribosylation factor (ARF) is a small GTPase involved in vesicle trafficking.

**Hematology / Pharmacology (high-yield)** - ADP is stored in platelet dense (delta) granules together with Ca2+, serotonin, and ATP. After platelet activation (e.g., by collagen exposure or thrombin), ADP is released and acts on P2Y12 (Gi-coupled; ↓cAMP, which promotes GP IIb/IIIa activation) and P2Y1 (Gq-coupled; shape change and Ca2+ mobilization). This causes GP IIb/IIIa expression/activation, fibrinogen binding, and platelet aggregation (secondary wave). - P2Y12 inhibitors: clopidogrel, prasugrel, ticlopidine (irreversible; thienopyridine prodrugs requiring hepatic CYP activation, with clopidogrel needing CYP2C19; omeprazole and poor-metabolizer alleles reduce effect), and ticagrelor (reversible, direct-acting, cyclopentyltriazolopyrimidine; adverse effect: dyspnea), cangrelor (IV, reversible). Uses: ACS, post-PCI/stent, stroke/TIA, peripheral artery disease. Adverse effects: bleeding; ticlopidine → neutropenia and TTP; clopidogrel → rare TTP. - Dense granule deficiency (storage pool disease) as in Hermansky-Pudlak and Chediak-Higashi syndromes → impaired secondary aggregation and mucocutaneous bleeding with normal platelet count. - Lab: ADP is one of the agonists in platelet aggregometry (along with collagen, epinephrine, arachidonic acid, ristocetin). Glanzmann thrombasthenia (GP IIb/IIIa deficiency) shows absent aggregation to ADP, collagen, and epinephrine, with normal ristocetin response. Bernard-Soulier (GP Ib deficiency) shows absent aggregation with ristocetin only.

**Other uses of the abbreviation** - ADP can also stand for autosomal dominant polycystic (kidney disease), which is more commonly abbreviated ADPKD, or for ADP ribosylation. Context determines meaning. Nucleotide/platelet meaning is the most common on boards.

**Exam pearls** - ATP → ADP + Pi releases energy; ADP + Pi → ATP requires energy (ATP synthase). - High ADP = low energy state → stimulates glycolysis, TCA, and oxidative phosphorylation. - Platelet ADP → P2Y12 → ↓cAMP → GP IIb/IIIa activation: blocked by clopidogrel, prasugrel, ticagrelor. - Aspirin blocks COX-1 (↓TXA2), not ADP; the two are often combined as dual antiplatelet therapy (DAPT).