The
vitamin B(6)-derived
pyridoxal 5'-phosphate (PLP) is the cofactor of
enzymes catalyzing a large variety of chemical reactions mainly involved in
amino acid metabolism. These
enzymes have been divided in five families and fold types on the basis of evolutionary relationships and
protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent
enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of
enzyme-catalyzed reactions catalogued by the
Enzyme Commission are PLP-dependent, only a few
enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or
herbicides. PLP-dependent
enzymes for which there are already commercially available drugs are
DOPA decarboxylase (involved in the
Parkinson disease),
GABA aminotransferase (
epilepsy),
serine hydroxymethyltransferase (
tumors and
malaria),
ornithine decarboxylase (
African sleeping sickness and, potentially,
tumors),
alanine racemase (
antibacterial agents), and human cytosolic branched-chain
aminotransferase (pathological states associated to the
GABA/
glutamate equilibrium concentrations). Within each family or metabolic pathway, the
enzymes for which drugs have been already approved for clinical use are discussed first, reporting the
enzyme structure, the catalytic mechanism, the mechanism of
enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent
enzymes that have been recently characterized and proposed as
drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent
enzymes for the selection of
drug targets is discussed.