Territrems: Naturally occurring specific irreversible inhibitors of acetylcholinesterase

Abstract

Between 1983 and 1994, we studied renal function and neonatal conditions for eight pregnancies and births to six women who had received renal transplants in order to assess the effect of an allograft on pregnancy and its outcome. The gestation period was 34 to 39 weeks (mean 36 weeks and 4 days), and four pregnancies ended before term. All eight babies were delivered by cesarean section. Intrauterine growth retardation (IUGR) was found in both babies of one woman who had been treated with conventional (without cyclosporin) immunosuppression. The serum creatinine level did not change during gestation in any of the women but was elevated after delivery in four. Four mothers suffered from proteinuria (25-364 mg/dl) during gestation, but the proteinuria disappeared after delivery in all but one case. The one exception, persistent proteinuria of 100-200 mg/dl, was assumed to result from the recurrence of the original renal disease (lgA nephropathy). The reduction of creatinine clearance and hydronephrosis of one graft noted during gestation were later reversed. None of the eight babies (four females and four males) was congenitally malformed, and their Apar scores were 6 to 9 (median 8). They are now 3 months to 11 years old, and seven of them are healthy and show good growth. One of the two IUGR babies has not grown well; her weight and height are more than 1 SD below the mean for her age, and she is mentally retarded and suffers from muscle weakness. Compared with dialysis patients, female renal allograft recipient have a better quality of life because they can safely deliver a child if they observe the criteria for pregnancy established for renal allogaft recipients.

Territrem B, a Tremorgenic Mycotoxin That Inhibits Acetylcholinesterase with a Noncovalent yet Irreversible Binding Mechanism

“…DISCUSSION In our previous study of TRB inhibition on AChE extracted from the head of Helicoverpa zea, we observed an irreversiblelike inhibition (13). We also reported that although dialysis or dilution recovers the activity of BW284C51-inhibited eel AChE, the same treatment has no effect on TRB-inhibited eel AChE (14). In the present kinetic investigation, we reaffirmed these earlier observations of irreversible AChE inhibition by using very diluted TRB during the preincubation period (Fig.…”

“…In the experiment with NaCl or Triton X-100, the working enzyme solution contained 1 M NaCl or 1% Triton X-100. Enzyme activity was determined as described previously (14) and according to the colorimetric method of Ellman et al (25). The concentration of the catalytic subunit of AChE in the working enzyme solution was calculated using a molar catalytic efficiency of 6.0 ϫ 10 5 M acetylthiocholine hydrolyzed/ min at 25°C (26).…”

“…1A) display very similar AChE-inhibiting potency (14 -16), modifications at the other end (tail) of the molecule often result in greatly reduced or even completely abolished inhibition (14). 3 For example, like TRB, TRC-benzyl (Fig.…”

“…2). The use of nM concentrations TRB instead of M concentrations of an earlier study (14) eliminated the possibility that TRB inhibits AChE via a noncompetitive inhibitory effect due to high inhibitor concentrations.…”

“…This suggestion was first supported by the observed inhibitory activities of territrems on AChE extracted from the head of an insect (13). More recently, TRB and other members of the territrem family were shown to bind tightly and inhibit irreversibly eel AChE with an IC 50 value in the order of 10 Ϫ8 M (14). Independently, Omura et al (15) confirmed that territrems are potent AChE inhibitors by reporting the inhibitory activities of TRB and territrem C (TRC) on AChE from human erythrocytes.…”