Carnitine biosynthesis enzymes

The carnitine biosynthesis enzymes are a group of four enzymes—6-N-trimethyllysine dioxygenase (TMLHE), 3-hydroxy-6-N-trimethyllysine aldolase, 4-trimethylammoniobutyraldehyde dehydrogenase (ALDH9A1), and gamma-butyrobetaine dioxygenase (BBOX1)—that facilitate the endogenous production of L-carnitine from lysine (Vaz & Wanders, 2002). L-carnitine is a critical cofactor for the carnitine palmitoyltransferase system, which transports long-chain fatty acids into the mitochondria for energy production via beta-oxidation (Flanagan et al., 2010). While carnitine is also obtained through diet, the biosynthetic pathway is essential for maintaining homeostasis in tissues like the heart and skeletal muscle (Strijbis et al., 2010). The final enzyme in the pathway, BBOX1, is a significant therapeutic target; its inhibition leads to a reduction in carnitine levels and a subsequent metabolic shift from fatty acid oxidation to glucose oxidation (Dambrova et al., 2016). This shift is particularly beneficial in treating myocardial ischemia and peripheral artery disease, as glucose oxidation requires less oxygen per mole of ATP produced (Liepinsh et al., 2011). Additionally, alterations in these enzymes are associated with primary carnitine deficiency and certain metabolic syndromes (Zhu et al., 2021). Pharmacological modulation of this pathway, primarily through the drug meldonium, has been utilized to enhance exercise tolerance and protect against ischemic damage (Jaudzems et al., 2009).

Other names

L-carnitine biosynthetic pathway enzymesTrimethyllysine to carnitine pathwayCarnitine synthesis enzymes

Competitive inhibition of gamma-butyrobetaine dioxygenase (BBOX1), the final enzyme in the carnitine biosynthesis pathway, which leads to decreased carnitine levels and a metabolic shift from fatty acid oxidation to glucose oxidation.