GTP

**Structure:** Guanine + ribose + 3 phosphates. Synthesized from IMP → GMP (IMP dehydrogenase; inhibited by mycophenolate and ribavirin) → GDP → GTP (nucleoside diphosphate kinase).

**Key functions (high-yield):** 1. **G-protein–coupled receptor (GPCR) signaling:** Inactive G protein is bound to GDP. Ligand binding to the GPCR makes the receptor act as a GEF, so GDP is exchanged for GTP and the α subunit dissociates from βγ. The α subunit has intrinsic GTPase activity, so hydrolysis of GTP to GDP terminates the signal. - Gs: stimulates adenylyl cyclase, which raises cAMP and activates PKA. - Gi: inhibits adenylyl cyclase. - Gq: activates phospholipase C, which makes IP3/DAG and raises Ca²⁺ and PKC. - **Cholera toxin:** ADP-ribosylates Gs and locks it in the GTP-bound (active) state, causing massive cAMP-driven Cl⁻ and water secretion (rice-water diarrhea). - **Pertussis toxin:** ADP-ribosylates Gi and prevents its inactivation of adenylyl cyclase, so cAMP rises. - **McCune-Albright syndrome:** Activating GNAS (Gsα) mutation causes polyostotic fibrous dysplasia, café-au-lait spots, and precocious puberty or other endocrine hyperfunction. It is a postzygotic somatic mosaic mutation. - **Pseudohypoparathyroidism type 1a (Albright hereditary osteodystrophy):** Inactivating Gsα mutation causes PTH resistance, with short 4th/5th metacarpals and hypocalcemia. 2. **Small monomeric GTPases (e.g., Ras):** Ras is active when GTP-bound and inactive when GDP-bound. GAPs enhance GTP hydrolysis, and GEFs promote GDP-to-GTP exchange. Mutations that impair GTPase activity cause constitutive activation and oncogenesis (KRAS, HRAS, NRAS). Neurofibromin (NF1) is a Ras-GAP, so loss of NF1 causes unchecked Ras activity. 3. **Protein synthesis:** - **Initiation:** IF2 (prokaryotes) and eIF2 (eukaryotes) are GTP-dependent. Phosphorylation of eIF2α inhibits translation (integrated stress response). - **Elongation:** Aminoacyl-tRNA delivery to the A site by EF-Tu (prokaryotes) or eEF1α (eukaryotes) uses GTP. Translocation uses EF-G (prokaryotes) or eEF2 (eukaryotes) and GTP. - **Diphtheria toxin** and *Pseudomonas* exotoxin A ADP-ribosylate eEF2 and inhibit translocation. - ATP is used for tRNA charging (aminoacyl-tRNA synthetase). GTP is used for initiation, elongation, and translocation (**4 high-energy phosphates per peptide bond:** 2 ATP-equivalents for charging, 1 GTP for A-site delivery, 1 GTP for translocation). 4. **TCA cycle:** Succinyl-CoA synthetase converts succinyl-CoA to succinate, generating GTP (or ATP in some tissues) by substrate-level phosphorylation. 5. **Gluconeogenesis:** PEP carboxykinase (PEPCK) requires GTP to convert oxaloacetate to PEP. 6. **Cytoskeleton:** Tubulin dimers bind GTP. GTP-bound β-tubulin favors polymerization at the plus end, and GTP hydrolysis drives dynamic instability. Drugs that target microtubules include: - Taxanes and vinca alkaloids - Mebendazole and albendazole - Griseofulvin - Colchicine 7. **Purine biosynthesis regulation:** GTP is a substrate for AMP synthesis, and ATP is a substrate for GMP synthesis. This reciprocal arrangement balances adenine and guanine nucleotide pools. 8. **Other roles:** Dynamin-mediated vesicle scission in endocytosis, SRP/SRP receptor function in co-translational translocation into the ER, and Ran-GTP in nuclear transport. Also a precursor of cGMP (guanylyl cyclase), which mediates NO/vasodilation (nitrates, PDE-5 inhibitors) and ANP signaling.

**Clinical pearls:** - GTPγS and other non-hydrolyzable GTP analogs lock G proteins in the active state (experimental tools). - Mycophenolate (IMPDH inhibitor) depletes guanine nucleotides and selectively impairs lymphocyte proliferation, because lymphocytes rely on de novo purine synthesis. - Do not confuse GTP with **γ-glutamyl transpeptidase (GGT/γ-GT)**, which is sometimes abbreviated "GTP" or "GGTP" in older or non-standard usage. GGT is a marker of cholestasis and alcohol use and is elevated in biliary disease, while it is normal in bone disease (the way to distinguish an elevated ALP source). Also, "SGPT" (= ALT) is sometimes confused with it.