[Frontiers in Bioscience E4, 897-913, January 1, 2012]

Biomedical aspects of pyridoxal 5'-phosphate availability

Martino L. di Salvo1, Martin K. Safo2, Roberto Contestabile1

1Dipartimento di Scienze Biochimiche, A. Rossi Fanelli and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Universita di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy, 2Department of Medicinal Chemistry, School of Pharmacy, and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Role of PLP-dependent enzymes in brain function
2.2. Supply of PLP to the enzymes that require it as a cofactor.
3. Reasons and consequences of PLP deficiency
3.1. Inherited defects in the salvage pathway enzymes
3.1.1. Pyridoxine (pyridoxamine) 5'-phosphate oxidase deficiency
3.1.2. Hypophosphatasia
3.2. Inherited defects in enzymes involved in other metabolisms
3.2.1. Pyridoxine-dependent epilepsy
3.2.2. Hyperprolinemia type II
3.3. Drugs and natural compounds which affect PLP availability
3.3.1. Drugs and natural compounds that interact with vitamin B6
3.3.2. Drugs and natural compounds that interact with PLK
4. Multifactorial diseases related to PLP availability
4.1. Autism
4.2. Schizophrenia
4.3. Epilepsy
4.4. Alzheimer's disease, cognition, dementia, ageing
4.5. Parkinson's disease
4.6. Malaria
5. Acknowledgements
6. References

1. ABSTRACT

The biologically active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a cofactor in over 160 enzyme activities involved in a number of metabolic pathways, including neurotransmitter synthesis and degradation. In humans, PLP is recycled from food and from degraded PLP-dependent enzymes in a salvage pathway requiring the action of pyridoxal kinase, pyridoxine 5'-phosphate oxidase and phosphatases. Once pyridoxal 5'-phosphate is made, it is targeted to the dozens different apoenzymes that need it as a cofactor. The regulation of the salvage pathway and the mechanism of addition of PLP to the apoenzymes are poorly understood and represent a very challenging research field. Severe neurological disorders, such as convulsions and epileptic encephalopathy, result from a reduced availability of pyridoxal 5'-phosphate in the cell, due to inborn errors in the enzymes of the salvage pathway or other metabolisms and to interactions of drugs with PLP or pyridoxal kinase. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of PLP.