Chemistry Reference
In-Depth Information
synapses of both the central and peripheral nervous systems. It is the site of action of
OP and carbamate insecticides, and will be described in more detail in Section 2.4.
Butyrylcholinesterase (BuChE) occurs in many vertebrate tissues, including blood
and smooth muscle. Unlike AChE, it does not appear to represent a site of action
for OP or carbamate insecticides. However, the inhibition of BuChE in blood has
been used as a biomarker assay for exposure to OPs (see Thompson and Walker
1994). Neuropathy target esterase (NTE) is another B-esterase located in the nervous
system. Inhibition of NTE can cause delayed neuropathy (see Section 2.4). Finally,
other hydrolases of the nervous system that are sensitive to OP inhibition have been
identified (Chapter 10, Section 10.2.).
The distinction between A- and B-esterases is based on the difference in their
interaction with OPs. Cholinesterases have been more closely studied than other
B-esterases and are taken as models for the whole group. They contain serine at the
active center, and organophosphates phosphorylate this as the first stage in hydroly-
sis (Figure. 2.11). This is a rapid reaction that involves the splitting of the ester bond
and the acylation of serine hydroxyl. The leaving group XO- combines with a proton
from the serine hydroxyl group to form an alcohol, XOH. The next stage in the pro-
cess, the release of the phosphoryl moiety, the restoration of the serine hydroxyl, and
the reactivation of the enzyme, is usually very slow. The OP has acted as a suicide
substrate, inhibiting the enzyme during the course of hydrolytic attack. A further
complication may be the “aging” of the bound phosphoryl moiety. The “R” group is
lost, leaving behind a charged PO- group. If this happens, the inhibition becomes
irreversible, and the enzyme will not spontaneously reactivate.
This process of aging is believed to be critical in the development of delayed
neuropathy, after NTE has been phosphorylated by an OP (see Chapter 10, Section
10.2.4). It is believed that most, if not all, of the B-esterases are sensitive to inhibition
by OPs because they, too, have reactive serine at their active sites. It is important to
emphasize that the interaction shown in Figure 2.11 occurs with OPs that contain an
oxon group. Phosphorothionates, which contain instead a thion group, do not readily
interact in this way. Many OP insecticides are phosphorothionates, but these need to
be converted to phosphate (oxon) forms by oxidative desulfuration before inhibition
of acetylcholinesterase can proceed to any significant extent (see Section 2.3.2.2).
The reason for the contrasting behavior of A-esterases is not yet clearly estab-
lished. It has been suggested that the critical difference from B-esterases is the
k
1
O
O
POX
RO
RO
POX.EH
k
-1
RO
RO
k
2
+EH
XOH
k
3
O
POH
O
POE
RO
RO
RO
RO
fIgure 2.11
Interaction between organophosphates and B-esterases. R, alkyl group; E,
enzyme.
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