Pyridoxal 5-Phosphate Enzymes as Targets for Therapeutic Agents

Abstract

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.

Comparative Study between the use of Melatonin and A Solution with Melatonin, Tryptophan, and Vitamin B6 as an Inducer of Spontaneous Sleep in Children During an Auditory Response Test: An Alternative to Commonly Used Sedative Drugs

“…Vitamin B6 consists of three related compounds, pyridoxine, pyridoxal, and pyridoxamine, all of which differ in the position 4 substituent. All forms, however, are phosphorylated by a kinase, which represents the basic requirement related to the co-factor activity of vitamin B6 [36,37] . Vitamin B6 is required in the biosynthesis of serotonin [38] as a co-factor in the transformation of L-5-hydroxy tryptophan into serotonin by the enzyme carboxylase of aromatic amino acids [39] .…”

Vitamin B6 metabolism influences the intracellular accumulation of cisplatin

“…19 Nevertheless, our observations cannot explain why pyridoxine and PDXK conjointly affect the adaptive response of A549 cells to several cisplatin-unrelated chemical and physical perturbations, including nutrient deprivation, hyperthermia, hypoxia, chemical inhibition of the respiratory chain, irradiation as well as the exposure to a large collection of cytotoxic agents. 19 As pyridoxal-5-phosphate (the bioactive form of vitamin B6) operates as a prosthetic group for > 4% of the enzymatic activities of the cell, 36 it is tempting to speculate, though remains to be formally demonstrated, that vitamin B6 metabolism is wired to a complex network of signaling pathways that influence adaptive responses in a general fashion.…”

Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase

“…22 Inhibition of β-catenin signaling in HCC cell lines has an antitumor effect; however, no molecules targeting any component of the Wnt/β-catenin pathway are currently being tested in clinical trials for the treatment of HCC. 22 Ornithine aminotransferase 7 is a pyridoxal 5′-phosphate (PLP)-dependent mitochondrial matrix enzyme 9,24 that catalyzes the interconversion of ornithine and α-ketoglutarate to Lglutamate semialdehyde, which cyclizes to Δ 1 -pyrroline-5-carboxylate (P5C), and glutamate (Scheme 1). 7,9,24 The Lglutamate that is formed from OAT is transported away by GLT-1 so that it does not accumulate and become toxic to the cell, and then it is converted by glutamine synthetase to Lglutamine.…”