Amino acid decarboxylases, irreversible inhibition

Neuroamines are biosynthesized in the central nervous system by decarboxylation of the corresponding amino acids by the amino acid decarboxylases (AADCs), which are present in nerve endings. In consequence, inhibition of the AADCs could be a means to regulate concentration in neuroamines. Research has been based on the hypothesis that a S-fluoromethylene amino acid could be used as a precursor of the inhibitor. If this fluorinated amino acid was a substrate for the AADC, it would then be transformed in situ into a S-fluoromethylene amine, which is an irreversible inhibitor of MAOs (Figure 7.54). ° ... 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

Benserazide (BZ), 2-amino-3-hydroxy-A, -[(2,3,4-trihydroxyphenyl) methyl] propane hydrazide is an irreversible inhibitor of peripheral L-aromatic amino acid decarboxylase (AADC). The decarboxylase inhibitor drugs, e.g., carbidopa and benserazide, inhibit dopamine production outside the brain and permit direct deliveiy of dopamine (LD metabolite) to the brain. This synergistic therapy also minimizes the side effects such as nausea and vomiting induced by levodopa.1 2 Benserazide at the recommended therapeutic dose does not cross the blood-brain barrier to any significant degree. Synergistic effect of levodopa and benserazide reduces the required dose of levodopa for the optimal and earlier therapeutic response.3... 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Allenic amino acids belong to the classical suicide substrates for the irreversible mechanism-based inhibition of enzymes [5], Among the different types of allenic substrates used for enzyme inhibition [128, 129], the deactivation of vitamin B6 (pyr-idoxal phosphate)-dependent decarboxylases by a-allenic a-amino acids plays an important role (Scheme 18.45). In analogy with the corresponding activity of other /3,y-unsaturated amino acids [102,130], it is assumed that the allenic amino acid 139 reacts with the decarboxylase 138 to furnish the imine 140, which is transformed into a Michael acceptor of type 141 by decarboxylation or deprotonation. Subsequent attack of a suitable nucleophilic group of the active site then leads to inhibition of the decarboxylase by irreversible formation of the adduct 142 [131,132]. 

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