Insect Developmental Biology:
Juvenile hormone (JH) is a
key lipophilic hormone that
regulates metamorphosis, behavior, reproduction, and other key
biological events in all insects. JH is a sesquiterpenoid
with a methyl ester moity at one end and epoxide moity at the other
(Figure below). Our laboratory has advanced the hypothesis
that JH titer is regulated not only by its biosynthesis, but also by
its metabolism and possibly sequestration. JH is primarily
metabolized by two hydrolytic enzymes in the /-hydrolase fold family
known as JH esterase (JHE) and JH epoxide hydrolase (JHEH).
JHE and JHEH may also function as synthetic enzymes in terms of the
production of JH acid, JH diol, and/or JH acid-diol (Figure below).
We have recently determined the 2.7 Å crystal structure of JHE of the tobacco hornworm Manduca sexta (Figure below).
We are currently using this structural information to gain mechanistic insights into the catalytic activity, degradation, and inhibition of JHE. Highly potent transition state esterase inhibitors such as OTFP (3-octylthio-1,1,1-trifluoropropan-2-one) have been synthesized in our laboratory that allow us to specifically study the biological efficacy of JHE. This has been most clearly shown in lepidopterous larvae where inhibition of JHE reduces the rate of JH degradation and leads to massive larvae and delayed pupation (Figure below). We are currently attempting to design similarly active inhibitors against JHEH. The availability of these and other tools will allow us to test the relative and combined importance of JHE and JHEH in insect development.
