B117 R CHF 8118 R CHFj

fluoride ion to give the enimine (8.120) (see Equations [8.40] and [8.41]). The electrophilic centres developed in the conjugated systems by the normal or abnormal electron flow react with a nucleophile at the active site of the enzyme. More recent work with other pyridoxal phosphate-dependend enzymes has suggested an alternative mechanism, which is llustrated in Equation [8.42] for the fluoromethyl derivatives. Here the enimines dissociate from the pyridoxal phosphate to give an enamine which then recombines with the lysine of the active site. The co-factor is then attacked by the electrophilic centre of the enamine to yield a stable complex at the active site which leads to irreversible inhbition of the enzyme.

FCH2

(8.41)
(8.42)

Another potent irreversible inhibitor of GABA transaminase is gabaculine (8.121), which is a naturally occurring neurotoxin isolated from Streptomyces toxacaenis. Although not of clinical application, this inhibitor is interesting since it is considered to inhibit the enzyme by a different mechanism to that previously described for suicide inactivators. Gabaculine acts as a substrate and is converted in the normal manner to the ketimine (8.122) (Equation [8.43]). This then aromatizes under the influence of a basic group to form a stable enzyme-bound pyridoxamine derivative and the enzyme is inactivated.

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