Pyridoxal 5'-phosphate enzymes as targets for therapeutic agents.
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.
Amadasi
Alessio
A
Dipartimento di Biochimica e Biologia Molecolare, Università di Parma, Italy.
Bertoldi
Mariarita
M
Contestabile
Roberto
R
Bettati
Stefano
S
Cellini
Barbara
B
di Salvo
Martino Luigi
ML
Borri-Voltattorni
Carla
C
Bossa
Francesco
F
Mozzarelli
Andrea
A
D000411:Alanine Racemase / Q000037:antagonists & inhibitors; D001710:Biotin / Q000096:biosynthesis; D019757:Carbon-Oxygen Lyases / Q000037:antagonists & inhibitors; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015195:Drug Design; D004798:Enzymes / Q000187:drug effects*; D012696:Glycine Hydroxymethyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors; D008190:Lyases / Q000037:antagonists & inhibitors / Q000235:genetics; D011732:Pyridoxal Phosphate / Q000502:physiology*; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000235:genetics
D004798:Enzymes; D011732:Pyridoxal Phosphate; D001710:Biotin; D012696:Glycine Hydroxymethyltransferase; C022696:O-succinylhomoserine (thiol)-lyase; D000637:Transaminases; D006867:Hydrolases; C021480:kynureninase; D008190:Lyases; D002262:Carboxy-Lyases; D019757:Carbon-Oxygen Lyases; D000411:Alanine Racemase; D019751:Intramolecular Transferases; C061049:glutamate-1-semialdehyde 2,1-aminomutase