Pyridoxal 5 -phosphate hydrazone

Hydrazines may be nucleophiles such as when they interact with aldehyde and keto groups to form hydrazones. This is the basis for the inhibition of enzymes such as transaminases, which rely on pyridoxal phosphate as a coenzyme. Mono-substituted hydrazines can be formed as metabolites when azo groups are reduced, dialkylated hydrazines are dealkylated or hydrazides are hydrolysed. 

Figure 7.42 Reaction of isoniazid with pyridoxal phosphate to form a hydrazone.

Isoniazid reacts with pyridoxal phosphate to form a hydrazone (Fig. 7.42), which is a very potent inhibitor of pyridoxal phosphate kinase. The hydrazone has a much greater affinity for the enzyme (100—lOOOx) than the normal substratepyridoxal. The result of this is a depletion of tissue pyridoxal phosphate. This cofactor is of importance particularly in nervous tissue for reactions involving decarboxylation and transamination. The decarboxylation reactions are principally affected however, with the result that transamination reactions assume a greater importance. 

This drug may cause degeneration of peripheral nerves after repeated exposure as a result of the depletion of vitamin B6. This is because isoniazid reacts with pyridoxal to form a hydrazone that inhibits pyridoxal phosphate kinase, so blocking formation of pyridoxal phosphate. As this effect is due to the parent drug, slow acetylators are more at risk, but the adverse effect can be prevented by supplying vitamin B6 to the patient. 

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). 

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