Pyridoxal phosphate antagonists

Administration of pyridoxal phosphate, a competitive antagonist of 4-methoxypyridoxine, which inhibits the formation of gamma-aminobutyric acid (GABA), prevented further seizures in this case. 

Vitamin deficiency can result from treatment with certain drags. Thus, destruction of intestinal microorganisms by antibiotic therapy can produce symptoms of vitamin K deficiency. Isoniazid, used to treat tuberculosis, is a competitive inhibitor of pyridoxal kinase, which is needed to produce pyridoxal phosphate. Isoniazid can produce symptoms of pyridoxine deficiency. To prevent this, pyridoxine is often incorporated into isoniazid tablets. Methotrexate and related folate antagonists act by competitively inhibiting dihydrofolate reductase (Chapter 27). 

The crucial role played by vitamin Bg in the nervous system and in neuroendocrinology is based on the fact that various putative neurotransmitters as well as taurine, sphingolipids, and polyamines are synthesized by pyridoxal phosphate (PLP)-dependent enzymes. There are numerous biological effects of vitamin Bg unrelated to the role of PLP as a coenzyme. PLP is an antagonist of both the voltage-mediated and the ATP-mediated calcium transport systems. PLP modulates the activities of steroid hormone receptors and transcription factors. The preventive effect of vitamin Bg on tumorigenesis might also derive from the antioxidant functions of this vitamin. 

In many cases, the site of action of a metabolite antagonist is known. Thus pyrithiamine displaces thiamine from the enzyme which phosphoryl-ates it to give the coenzyme. Again, desoxypyridoxine [(p.j), R = - CH3] seems inactive until it is phosphorylated in animals to a derivative which competes with pyridoxal phosphate, which is the coenzyme of the amino-acid decarboxylases (Woolley, 1952). 

Removal of the phosphate group from position 5 of the pyridoxal ring abolished the P2X" purinoceptor antagonist properties of pyridoxal-5-phosphate [54]. Replacement of the aldehyde moiety in pyridoxal-5-phosphate or PPADS with a CH2OH or CH2NH2 group, to... 

These results show that the phosphate and aldehyde moieties of pyridoxal-5-phosphate and its analogues are required for antagonist activity at P2X Punnoceptors in rabbit vas deferens. Among this series of compounds, PPADS was found to be the most interesting P2-antagonist, and it was therefore the subject of a more detailed pharmacological investigation. 

Antagonistic properties of pyridoxal-5-phosphate (PLP) and PPADS at P2X 2Uid P2Y" purinoceptors obtained in functional (pA2 values) and radioligand binding (pKj values) experiments... 

Linatine was originally isolated as an vitamin Bs antagonist from seeds of Linum usitatissimm (flax seeds). The compound is toxic towards both chickens and Azotobacter species. 1-Amino-D-proline has the same toxic effect (158). The toxicity is apparently due to formation of the hydrazone of pyridoxal 5 -phosphate (296, 341). 1-Amino-L-proline and 1-amino-D-proline were found to be equally toxic towards chickens, but the D-isomer was 50 times more toxic than the L-isomer towards Azotobacter vinelandii (158). A review on naturally occurring Be antagonists has been published (157). 

X. Wang, K. Dakshinamurti, S. Musat, and N.S. Dhalla. Pyridoxal 5 -phosphate is an ATP-receptor antagonist in freshly isolated rat cardiomyocytes. J. Mol. Cell Cardiol. 31 1063-1072 (1999). 

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