Gosset Creatine biosynthesis pathway Overview
The creatine biosynthesis pathway consists of a series of enzymatic reactions leading to the production of creatine from amino acids, mainly in the kidney and liver. The two main synthetic steps involve AGAT (L-arginine:glycine amidinotransferase) converting arginine and glycine to guanidinoacetate, followed by GAMT (guanidinoacetate methyltransferase) methylating guanidinoacetate to form creatine. The generated creatine is then transported, mainly to muscle and brain, where it is phosphorylated by creatine kinases to create phosphocreatine—a rapid reserve for ATP regeneration in tissues with high, fluctuating energy demands. Impairment of this pathway underlies rare genetic creatine deficiency syndromes characterized by neurological and muscular symptoms. Interventions such as creatine supplementation target the metabolic consequences (not the pathway directly), and the pathway's enzymes are occasionally considered therapeutic targets in specific contexts, rather than the pathway as a whole.
Mechanism of Action
Creatine supplementation increases intracellular creatine/phosphocreatine pools, buffering ATP supply in high-demand tissues. Modulators of the pathway can act by inhibiting or enhancing enzyme activity (e.g., AGAT or GAMT inhibition/deficiency causes disease).
Biological Functions
Disease Associations
Safety Considerations
- Disruption (genetic or acquired) causes severe neurological and muscle dysfunction
- Oral creatine supplements generally safe, but excessive intake or pre-existing kidney disease may pose risks
Interacting Drugs
Associated Biomarkers
| Biomarker |
|---|
| Creatine and phosphocreatine levels in plasma/urine |
| Guanidinoacetate (precursor, accumulates in GAMT deficiency) |
| Genetic testing for AGAT, GAMT, and SLC6A8 mutations |