Vitamin B6-dependent enzymes (PLP-dependent enzymes)

Vitamin B6-dependent enzymes, primarily utilizing pyridoxal 5'-phosphate (PLP) as a cofactor, constitute a vast superfamily of over 140 distinct enzymes essential for human metabolism [3, 11, 22]. They play critical roles in amino acid biosynthesis and degradation, the production of key neurotransmitters like GABA, serotonin, and dopamine, and the synthesis of heme and sphingolipids [3, 6, 11, 17]. Many individual enzymes within this group are established therapeutic targets; for instance, DOPA decarboxylase is targeted in Parkinson's disease, and GABA transaminase is targeted in epilepsy [2, 4, 6]. However, these enzymes are also susceptible to interference by various drugs, such as isoniazid and penicillamine, which can lead to secondary vitamin B6 deficiency and associated neurological complications [1, 7, 15]. Understanding the structural and functional diversity of these enzymes is vital for drug design, particularly in developing selective inhibitors for bacterial or parasitic enzymes while minimizing off-target effects on human metabolism [2, 4, 19, 20]. The versatility of PLP arises from its ability to covalently bind substrates and stabilize carbanionic intermediates, facilitating reactions like transamination, decarboxylation, and racemization [3, 5, 6]. Clinical management of drugs affecting these enzymes often requires monitoring of B6 status and potential supplementation to prevent neurotoxicity [13, 21, 23].

Other names

Pyridoxal 5'-phosphate-dependent enzymesPLP-dependent enzymesB6-dependent enzymesVitamin B6-dependent proteinsPLP-dependent superfamily

Drugs targeting these enzymes typically act through cofactor depletion by forming Schiff bases with PLP, competitive inhibition for the active site, or suicide inhibition of specific enzymes [1, 2, 5]. Some drugs also inhibit B6 salvage enzymes like pyridoxal kinase, reducing the overall availability of the active cofactor [15, 24].