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Enzymatic Hydrolysis and Group Transfer Reactions 87
Organophosphorus inhibition
His 57
His 57
Ser 195
Ser 195
+
HN N O
HN N
O − O
O
HN N H
+
O
HN NH
O
O
O P
O
O P F
O
O
Chloromethyl ketone inhibition
His 57
His 57
Ser 195
Ser 195
HN N
+
H
O
HN NH
O
O −
O
Cl
Cl
RNH Ph
RNH Ph
His 57
His 57
Ser 195
Ser 195
N
H
H
N
RNH
Ph
Figure 5.6 Inhibitors of serine proteases.
RNH
Ph
His-57, rather than the apparently more reactive serine residue. A stereochemical
analysis of this inactivation reaction has revealed that it proceeds with
retention of conWguration at the chlorine-bearing carbon, suggesting that a
double inversion is taking place. This can be rationalised by attack of the
active site serine on the carbonyl group and displacement of chloride by
the resulting oxyanion, generating an enzyme-bound epoxide. Opening of
the epoxide by the neighbouring histidine leads to covalent modiWcation
of the histidine residue.