Trimethyllysine dioxygenase (TMLHE)

Trimethyllysine dioxygenase (TMLHE) is a mitochondrial enzyme that catalyzes the initial and rate-limiting step in the endogenous biosynthesis of carnitine [UniProt Q9NVH6]. It functions as an iron-dependent and alpha-ketoglutarate-dependent dioxygenase, converting N(6),N(6),N(6)-trimethyl-L-lysine into 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine [IUBMB Life, 2010]. Carnitine produced via this pathway is vital for the transport of long-chain fatty acids into the mitochondrial matrix for energy production through beta-oxidation [NCBI Gene, TMLHE]. Genetic deficiency of TMLHE is recognized as a risk factor for autism spectrum disorder, particularly in males, suggesting a role for carnitine in neurodevelopment [PNAS, 2012]. In the context of cardiovascular health, TMLHE is a target for inhibition to lower the production of trimethylamine N-oxide (TMAO), a metabolite linked to atherosclerosis and heart failure [JAHA, 2017]. Drugs like meldonium (mildronate) interact with the carnitine biosynthetic pathway, although they may show higher affinity for downstream enzymes like gamma-butyrobetaine dioxygenase [PubMed, 2017]. Therapeutic strategies targeting TMLHE aim to modulate metabolic flux to treat conditions ranging from metabolic syndrome to chronic heart disease [PubMed, 2021].

Other names

Trimethyllysine hydroxylaseTML hydroxylaseTMLHTMLDN(6),N(6),N(6)-trimethyl-L-lysine hydroxylaseEpsilon-trimethyllysine hydroxylase

Competitive inhibition of the enzyme to reduce the conversion of trimethyllysine to 3-hydroxy-trimethyllysine, thereby lowering carnitine levels and reducing the production of the pro-atherogenic metabolite trimethylamine N-oxide (TMAO) [PubMed, 28106303].