Pyridoxal 5-phosphate-dependent amino acid metabolism enzymes (PLP-dependent enzymes)

Pyridoxal 5-phosphate (PLP)-dependent enzymes are a vast and functionally diverse group of enzymes that utilize the active form of vitamin B6 as an essential cofactor to catalyze a wide range of chemical transformations, primarily involving amino acids (Wikipedia). These enzymes account for approximately 4% of all classified enzymatic activities and are categorized into several distinct structural fold types (Percudani & Peracchi, 2003). They facilitate critical reactions such as transamination, decarboxylation, racemization, and side-chain modifications, which are vital for the biosynthesis of neurotransmitters like dopamine, serotonin, and GABA, as well as heme and various metabolic intermediates (NIH). Due to their central role in human physiology and the metabolism of pathogenic organisms, many specific PLP-dependent enzymes are established or potential therapeutic targets for conditions including Parkinson disease, epilepsy, cancer, and infectious diseases (Amadasi et al., 2007). Pharmacological intervention often involves suicide inhibitors that covalently bind to the PLP cofactor or the enzyme active site, effectively halting catalytic activity. However, the ubiquity of the PLP cofactor across many different enzymes presents a significant challenge for drug selectivity, which can lead to side effects such as peripheral neuropathy or systemic vitamin B6 deficiency (PubMed).

Other names

Vitamin B6-dependent enzymesB6-dependent enzymesPLP-dependent enzymesPyridoxal phosphate-dependent enzymes

Drugs targeting PLP-dependent enzymes primarily utilize mechanism-based (suicide) inhibition, where the drug acts as a substrate analog that, upon partial catalysis, forms a stable covalent bond with the PLP cofactor or an active-site residue, irreversibly inactivating the enzyme (Amadasi et al., 2007). Other mechanisms include competitive inhibition at the substrate binding site and the sequestration or depletion of the essential PLP cofactor itself (NIH).