GDP

**Structure and role:** GDP is a guanine nucleoside with two phosphate groups. It is the product of GTP hydrolysis and the resting-state ligand of GTP-binding proteins.

**G-protein cycle (GPCR signaling):** 1. In the inactive state, the heterotrimeric G protein (αβγ) has GDP bound to Gα. 2. Ligand binding to the GPCR makes the receptor act as a GEF (guanine nucleotide exchange factor). GDP is released and GTP binds Gα. 3. Gα-GTP dissociates from βγ and activates effectors: Gαs activates adenylyl cyclase (↑cAMP), Gαi inhibits it (↓cAMP), and Gαq activates phospholipase C (↑IP3/DAG/Ca²⁺). 4. Gα's intrinsic GTPase activity hydrolyzes GTP to GDP, and the trimer reassembles. RGS proteins speed this up.

**Small monomeric GTPases (Ras, Rho, Rab, Ran, Arf):** - Ras-GDP is inactive and Ras-GTP is active. GEFs (e.g., SOS) promote the switch to GTP. GAPs (e.g., neurofibromin, an NF1 gene product) promote GTP hydrolysis back to GDP. - Oncogenic RAS mutations impair GTPase activity, so Ras stays locked in the GTP-bound state. This causes constitutive MAPK signaling and is common in colon, pancreatic, and lung cancers. - Neurofibromin loss (NF1) removes a GAP, so Ras-GTP persists.

**Toxins that alter the GDP/GTP cycle:** - Cholera toxin ADP-ribosylates Gαs, which inhibits GTP hydrolysis. Gαs stays active, so cAMP rises and causes secretory diarrhea. - Pertussis toxin ADP-ribosylates Gαi, which prevents GDP-to-GTP exchange. Gαi stays inactive, so cAMP rises.

**Other high-yield contexts:** - Translation: EF-Tu (prokaryotes) and eEF1α (eukaryotes) deliver aminoacyl-tRNA as GTP-bound forms. EF-G and eEF2 drive translocation. Diphtheria toxin and Pseudomonas exotoxin A inactivate eEF2. - Tubulin: GTP-bound β-tubulin favors polymerization (the GTP cap), and GDP-bound tubulin favors depolymerization (dynamic instability). - Krebs cycle: succinyl-CoA synthetase (succinate thiokinase) makes GTP (GDP + Pi → GTP) by substrate-level phosphorylation. This is the only substrate-level phosphorylation step in the TCA cycle. - Gluconeogenesis: PEPCK uses GTP to convert oxaloacetate to PEP. - Purine synthesis and salvage: IMP → GMP → GDP → GTP. Mycophenolate and ribavirin inhibit IMP dehydrogenase, which depletes guanine nucleotides. - Ras/MAPK, mTOR (Rheb), and nuclear transport (Ran-GTP) also use GDP/GTP switching.

**Memory aid:** "GDP = Gone/Dormant/Paused (off); GTP = Go/Turned on/Primed (on)."

**Non-clinical meaning:** GDP can also mean gross domestic product, a macroeconomic measure sometimes used in health economics (e.g., health spending as a % of GDP). It is not a high-yield term for boards.