The biosynthesis of JH is similar to that of cholesterol in animals. There are considerable differences between the biosynthesis of the homo-isoprenoid JHs found almost exclusively in Lepidoptera, as opposed to the isoprenoids JH III, JH III bisepoxide, and methyl farnesoate found in other insects. Cholesterol biosynthesis has been exhaustively studied in animals. All steps occur in the cytosol. The starting material is citrate, which is exported by the mitochondrion when metabolic fuels are high. It is converted into acetyl-CoA, ADP, CO2, and oxaloacetate by ATP-citrate
lyase, together with ATP and CoASH as substrates. Three acetyl-CoAs are converted into HMG-CoA by the cytosolic isoforms of
thiolase and 3-hydroxy-3-methylglutaryl-CoA synthase. The HMG-CoA is then reduced by NADPH to mevalonate by
HMG-CoA reductase, the rate controlling enzyme of cholesterol biosynthesis. This enzyme has 8 helical domains anchoring it in the Golgi membrane of the ER; the catalytic domain is in the cytosol. It is strongly inhibited by the
statins, a class of drugs based on a mold metabolite which, at least at one time, were the largest selling class of drugs in the world. Mevalonate is acted of by a series of 3 kinases to give the highly labile 1,2-diphosphomevalonate-3-phosphate, which is acted on by a lyase to give phosphate, CO2, and
isopentenyl diphosphate. Isopentenyl diphosphate isomerase converts the latter to the less stable
dimethylallyl diphosphate.
Farnesyl diphosphate synthase takes one DMAPP and two IPP to give the C15 metabolite
farnesyl diphosphate. There are a large number of additional steps to generate cholesterol from IPP, the ubiquitous precursor of all isoprenoids. It appears that the biosynthesis of JH III is identical to that of cholesterol, from production of IPP to FPP, although there appear to be no studies on export of
citrate or other metabolites from the
mitochondrion into the
cytosol, or formation of
acetyl-CoA. The enzymes of this pathway were first studied in
Manduca sexta, which produces both homoisoprenoid and isoprenoid (JHIII) JHs. Very early on
propionate was shown to incorporate very highly efficiently into JH II and JH I in cell free extracts of
M. sexta] corpora allata.
Mevalonate and
acetate also incorporate into JH I, II, JH III from
M. sexta, albeit far less efficiently that propionate. Baker identified 3-hydroxy-3-ethylglutarate and 3-hydroxy-3-methylglutarate from the same enzyme source incubated with acetyl and
propionyl-CoA. Lee et al. showed that the same source of enzymes efficiently make both
mevalonate and its 3-ethyl homolog, homomevalonate. Bergot showed that the mevalonate and homomevalonate produced by these enzymes has the same 3S optical isomer configuration as the vertebrate enzymes. Baker showed that isopentenyl diphosphate, and its homolog, 3-ethyl-butenyl diphosphate (homoisopentenyl diphosphate) are metabolized to their corresponding allyic diphosphates, DMAPP and homoDMAPP (3-ethyl-3-methylallyl diphosphate). The latter is required for biosynthesis of JH I, JH II, and 4-methylJH I. 2 units of homoDMAPP are required for JH I and 4methyl JH I biosynthesis, and one for JH II biosynthesis. All parts of the
carbon skeleton comes from IPP. Then an enzyme prenyl transferase/farnesyl diphosphate synthase binds IPP, strips the diphosphate off it to give an allylic carbocation, and adds this to an IPP to give geranyl diphosphate (C10). Then it does the same thing to geranyl diphosphate, giving farnesyl diphosphate (C15). This reaction appears to be the only known enzymatic reaction involving the coupling of two molecules with a carbocation. The free electron pair adds to the double bond of IPP, also isomerizing IPP so that the product is an allylic diphosphate. Thus, this part of the isoprenoid pathway appears nearly identical with that of cholesterol with the exception of the insect specific homoisoprenoid units. NAD+-dependent farnesol dehydrogenase, a corpora allata enzyme involved in juvenile hormone synthesis showed that the same source of enzymes efficiently make both mevalonate and its 3-ethyl homolog, homomevalonate. Absolute configuration of homomevalonate and 3-hydroxy-3-ethylglutaryl and 3-hydroxy-3-methylglutaryl coenzyme a, produced by cell-free extracts of insect corpora allata. A cautionary note on prediction of absolute stereochemistry based on liquid chromatographic elution order of diastereomeric derivatives. showed that the
mevalonate and homomevalonate produced by these enzymes has the same 3S optical isomer configuration as the vertebrate enzymes and to also be present in mosquitoes. The next steps of JH biosynthesis differ between orders. In Lepidoptera and mosquitoes farnesoic acid or its homologs is epoxidized by a P450 dependent farnesoic acid methyl epoxidase, then it is methylated by a JH acid methyl transferase In most orders, farnesoic acid is methylated by farensoic acid methyl transferase, and then is epoxidized by a P450 dependent methyl transferas. == See also ==