Juvenile hormones (JHs) are a group of acyclic

sesquiterpenoid Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificatio ...

s that regulate many aspects of

insect physiology Insect physiology includes the physiology and biochemistry of insect organ systems. Although diverse, insects are quite similar in overall design, internally and externally. The insect is made up of three main body regions (tagmata), the head, thor ...

. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction,

diapause In animal dormancy, diapause is the delay in development in response to regular and recurring periods of adverse environmental conditions.Tauber, M.J., Tauber, C.A., Masaki, S. (1986) ''Seasonal Adaptations of Insects''. Oxford University Press I ...

, and

polyphenism A polyphenic trait is a trait for which multiple, discrete phenotypes can arise from a single genotype as a result of differing environmental conditions. It is therefore a special case of phenotypic plasticity. There are several types of polyphe ...

s.The chemical formula for juvenile hormone is C_18H_30O_3. In

insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three ...

s, JH (formerly called neotenin) refers to a group of

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...

s, which ensure growth of the

larva A larva (; plural larvae ) is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle. ...

, while preventing metamorphosis. Because of their rigid exoskeleton, insects grow in their development by successively shedding their exoskeleton (a process known as

molting In biology, moulting (British English), or molting (American English), also known as sloughing, shedding, or in many invertebrates, ecdysis, is the manner in which an animal routinely casts off a part of its body (often, but not always, an outer ...

). Juvenile hormones are

secreted 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

by a pair of

endocrine gland Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, ...

s behind the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

called the corpora allata. JHs are also important for the production of eggs in female insects. JH was isolated in 1965 by Karel Sláma and Carroll Williams and the first

molecular structure Molecular geometry is the three-dimensional arrangement of the atoms that constitute a molecule. It includes the general shape of the molecule as well as bond lengths, bond angles, torsional angles and any other geometrical parameters that deter ...

of a JH was solved in 1967. Most insect species contain only juvenile growth hormone (JH) III. To date JH 0, JH I, and JH II have been identified only in the Lepidoptera (butterflies and moths). The form JHB₃ (JH III bisepoxide) appears to be the most important JH in the Diptera, or flies. Certain species of

crustaceans Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean gro ...

have been shown to produce and secrete methyl farnesoate, which is juvenile hormone III lacking the epoxide group. Methyl farnesoate is believed to play a role similar to that of JH in crustaceans. Being a sesquiterpenoid, JH chemical structure differs significantly from the structure of other animal hormones. Some JH analogs have been found in conifers.

Control of development

The primary control of juvenile hormone is by 1) the stimulation of the corpora allata by allatotropins short peptides which bind to

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s, which signal the glands to produce JH, and 2), the inhibition of JH production by

allatostatin Allatostatins are neuropeptide hormones in insects and crustacea. They have a twofold function: they both inhibit the generation of juvenile hormone and reduce their food intake. They are therefore putative targets for insecticide research.{{cite ...

s. These fall into three classes: allatostatin A, allatostatin B, and allatostatin C (for a review of these control mechanisms see: Stay and Woodhead 1993). Secondary control of the JH titre found in the

haemolymph Hemolymph, or haemolymph, is a fluid, analogous to the blood in vertebrates, that circulates in the interior of the arthropod (invertebrate) body, remaining in direct contact with the animal's tissues. It is composed of a fluid plasma in which ...

of the developing insect is metabolic inactivation of JH by JH-specific esterase and

juvenile hormone epoxide hydrolase Juvenile hormone epoxide hydrolase (JHEH) is an enzyme that inactivates insect juvenile hormones. This inactivation is accomplished through hydrolysis of the epoxide functional group contained within these hormones into diols. JHEH is one of two ...

. During ecdysis the form of the old cuticle laid down before the next moult is controlled by the JH level in the insect. JH maintains a juvenile state. The level gradually decreases during the development of the insect, allowing it to proceed to successive

instar An instar (, from the Latin '' īnstar'', "form", "likeness") is a developmental stage of arthropods, such as insects, between each moult (''ecdysis''), until sexual maturity is reached. Arthropods must shed the exoskeleton in order to grow or ...

s with each molt. This has been demonstrated in various studies, most prominently that by V. B. Wigglesworth in 1960s. In this study, two adult ''

Rhodnius ''Rhodnius'' is a genus of assassin bugs in the subfamily Triatominae (the kissing bugs), and is an important vector in the spread of Chagas disease. The ''Rhodnius'' species were important models for Sir Vincent Wigglesworth's studies of insec ...

'' had their blood systems linked, ensuring that the JH titre in both would be equal. One was a third instar ''Rhodnius'', the other was a fourth instar. When the corpora allata of the third instar insect were removed, the level of JH was equal in both insects to that in the fourth instar animal, and hence both proceeded to the fifth instar at the next moult. When the fourth instar ''Rhodnius'' had its corpora allata removed, both contained a third instar level of JH and hence one proceeded to instar four, and the other remained at this instar. Generally, the removal of the corpora allata from juveniles will result in a diminutive adult at the next moult. Implantation of corpora allata into last larval instars will boost JH levels and hence produce a supernumerary (extra) juvenile instar etc.

In honey bees

There is a complex interaction between JH, the hormone

ecdysone Ecdysone is a prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. It is of steroidal structure. Insect molting hormones (ecdysone and its homologues) are generally called ecdysteroids. ...

and

vitellogenin Vitellogenin (VTG or less popularly known as VG) (from Latin ''vitellus'', yolk, and ''genero'', I produce) is a precursor of egg yolk that transports protein and some lipid from the liver through the blood to the growing oocytes where it becomes ...

. In the development stage, as long as there is enough JH, the ecdysone promotes larva-to-larva molts. With lower amounts of JH, ecdysone promotes pupation. Complete absence of JH results in formation of the adult. In adult

honey bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosm ...

s, JH and

Vitellogenin Vitellogenin (VTG or less popularly known as VG) (from Latin ''vitellus'', yolk, and ''genero'', I produce) is a precursor of egg yolk that transports protein and some lipid from the liver through the blood to the growing oocytes where it becomes ...

titers in general show an inverse pattern. JH titers in worker honey bees progressively increase through the first 15 or so days of the worker's life before the onset of

foraging Foraging is searching for wild food resources. It affects an animal's fitness because it plays an important role in an animal's ability to survive and reproduce. Foraging theory is a branch of behavioral ecology that studies the foraging behavi ...

. During the first 15 days, workers perform tasks inside the

hive A hive may refer to a beehive, an enclosed structure in which some honey bee species live and raise their young. Hive or hives may also refer to: Arts * ''Hive'' (game), an abstract-strategy board game published in 2001 * "Hive" (song), a 201 ...

, such as nursing larvae, constructing comb, and cleaning cells. JH titers peak around day 15; workers this age guard, remove dead bees from the colony, and fan at the colony entrance to cool the nest. Aggressiveness of guard bees is correlated with their blood JH levels. Even though guards have high JH levels, their ovaries are relatively undeveloped. Although, JH does not activate foraging. Rather it is involved in controlling the pace at which bees develop into foragers. Vitellogenin titers are high at the beginning of adult life and slowly decrease. JH has been known to be involved in the queen-worker caste differentiation during the larval stage. The unique negative relationship between JH and Vitellogenin may be important to the understanding of queen longevity.

In Lepidoptera

JH in many butterfly and moth species are necessary for the production and release of the sex

pheromone A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...

by females. Experiments conducted in ''

Mythimna unipuncta ''Mythimna unipuncta'', the true armyworm moth, white-speck moth, common armyworm or rice armyworm, is a nocturnal agricultural pest belonging to the family Noctuidae. This moth is also commonly referred to by the scientific name ''Pseudaletia ...

'' (true armyworm moth) and ''

Agrotis ipsilon ''Agrotis ipsilon'', the dark sword-grass, black cutworm, greasy cutworm, floodplain cutworm or ipsilon dart, is a small noctuid moth found worldwide. The moth gets its scientific name from black markings on its forewings shaped like the letter ...

'' (black cutworm moth) have shown that removing the corpus allata, which secretes JH, stops all release of sex pheromone. Furthermore, JH is important for ovarian development. In the black cutworm, it was shown that JH is also necessary in males for pheromone responsiveness. JH has also been shown to be transferred from the male to the female ''

Heliothis virescens ''Chloridea virescens'', commonly known as the tobacco budworm, is a moth of the family Noctuidae found throughout the eastern and southwestern United States along with parts of Central America and South America. It is a major pest of field cro ...

'' during copulation.

Forms

* Methyl farnesoate ** CAS methyl (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienoate ** Formula: C₁₆H₂₆O₂ * Juvenile hormone 0 (found in Lepidoptera) ** CAS methyl (2E,6E)-10R,11S-(oxiranyl)-3,7-diethyl-11-methyl-2,6-tridecadienoate ** Formula: C₁₉H₃₂O₃ * Juvenile hormone I (found in Lepidoptera) ** CAS methyl (2E,6E)-10R,11S-(oxiranyl)-7-ethyl-3,11-dimethyl-2,6-tridecadienoate ** Formula: C₁₈H₃₀O₃ * Juvenile hormone II (found in Lepidoptera) ** CAS methyl (2E,6E)-10R,11S-(oxiranyl)-3,7,11-trimethyl-2,6-tridecadienoate ** Formula: C₁₇H₂₈O₃ ** CAS methyl (2E,6E)-10R-(oxiranyl)-3,7,11-trimethyl-2,6-dodecadienoate ** Formula: C₁₆H₂₆O₃
Juvenile hormone JHB3
(found in diptera) ** CAS methyl (2E,6E)-6S,7S,10R-(dioxiranyl)-3,7,11-trimethyl-2-dodecaenoate ** Formula: C₁₆H₂₆O₄

Use as an insecticide

Synthetic analogues of the juvenile hormone are used as an insecticide, preventing the larvae from developing into adult insects. JH itself is expensive to synthesize and is unstable in light. At high levels of JH, larvae can still molt, but the result will only be a bigger larva, not an adult. Thus the insect's reproductive cycle is broken. One JH analogue,

methoprene Methoprene is a juvenile hormone (JH) analog which acts as a growth regulator when used as an insecticide. It is an amber-colored liquid with a faint fruity odor. Methoprene does not kill insects. Instead, it interferes with an insect’s life ...

, is approved by the

WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...

for use in drinking water cisterns to control

mosquito Mosquitoes (or mosquitos) are members of a group of almost 3,600 species of small flies within the family Culicidae (from the Latin ''culex'' meaning " gnat"). The word "mosquito" (formed by ''mosca'' and diminutive ''-ito'') is Spanish for "li ...

larvae due to its exceptionally low toxicity (LD50 >35,000 mg/kg in the rat).

Regulation

Juvenile hormone is produced in the corpora allata of insects. JH will disperse throughout the haemolymph and act on responsive tissues. JH is principally degraded by the enzymes juvenile-hormone esterase (JHE) or

(JHEH). JHE and JHEH both lead to suppression of JH signaling and response. Tissues responsive to JH may produce one or both of these enzymes. JH stimulates the

accessory glands Male accessory glands (MAG) in humans are the seminal vesicles, prostate gland, and the bulbourethral glands (also called Cowper's glands). In insects, male accessory glands produce products that mix with the sperm to protect and preserve them, in ...

of adult males, promoting gland growth and the production of accessory gland secretion. Yolk production (

vitellogenesis Vitellogenesis is the process of yolk protein formation in the oocytes of non mammalian vertebrates during sexual maturation. The term ''vitellogenesis'' comes from the Latin ''vitellus'' ("egg yolk"). Yolk proteins, such as Lipovitellin and P ...

) in female ovaries is also stimulated by JH action. JH may also regulate reproductive behaviour in both sexes.

Metabolism

Juvenile hormone's activity is destroyed by two enzymes. JH esterase cleaves the methyl ester giving JH acid. JH acid is attached by JH epoxide hydrolase, which converts the epoxide group to a diol. The order of cleavage depends on the order of insect. In the Lepidoptera, the order is as given here; ester cleavage preceding epoxide hydration. Either one terminates the activity of the hormone. JH diol acid, the product of both enzymes, is acted on by JH diol kinase to increase the solubility for excretion.

Biosynthesis

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 Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway. Thiolases are ubiquitous enzymes that have key roles in many vital biochemi ...

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 Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...

or other metabolites from the mitochondrion into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, or formation of acetyl-CoA. The enzymes of this pathway were first studied in ''

Manduca sexta ''Manduca sexta'' is a moth of the family Sphingidae present through much of the Americas. The species was first described by Carl Linnaeus in his 1763 ''Centuria Insectorum''. Commonly known as the Carolina sphinx moth and the tobacco hawk mo ...

'', which produces both homoisoprenoid and isoprenoid (JHIII) JHs. Very early on

propionate Propionic acid (, from the Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula CH3CH2CO2H. It is a liqu ...

was shown to incorporate very highly efficiently into JH II and JH I in cell free extracts of ''M. sexta]'' corpora allata.

Mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...

and acetate also incorporate into JH I, II, JH III from ''M. sexta'', albeit far less efficiently that propionate. Jennings et al. showed that homomevalonate incorporates into JH II in ''M. sexta''. Baker identified 3-hydroxy-3-ethylglutarate and 3-hydroxy-3-methylglutarate from the same enzyme source incubated with acetyl and

propionyl-CoA Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain (without the coenzyme, it is a 3 carbon structure) and its production and metabolic fate depend on which organism it is present in. Several diffe ...

. Lee et al. showed that the same source of enzymes efficiently make both

mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''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.Baker, F.C., Lee, E., Bergot, B.J., Schooley, D.A., 1981. Isomerization of isopentenyl pyrophosphate and homoisopentenyl pyrophosphate by ''Manduca sexta'' corpora cardiaca - corpora allata homogenates., in: Pratt, G.E., Brooks, G.T. (Eds.), Juvenile Hormone Biochemistry. Elsevier, Amsterdam, pp. 67-80 All parts of the

carbon skeleton The skeletal formula, or line-angle formula or shorthand formula, of an organic compound is a type of molecular structural formula that serves as a shorthand representation of a molecule's bonding and some details of its molecular geometry. A ...

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

and homomevalonate produced by these enzymes has the same 3S optical isomer configuration as the vertebrate enzymes 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. However, at this point these pathways diverge. While the vast majority of farnesyl diphosphate is converted into ultimately cholesterol in animals, in insects it is apparently acting on by a diphosphatase to give farnesol, which in turn is acted on by an NAD+ dependent enzyme, farnesol/farnesal dehydrogenase in ''M. sexta'' to give farnesoic acid. Subsequent work has shown that the enzyme is highly specific for trans allylic alcohols with at least three isoprene units, 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. A recent publication by Nouzova et al. (2015) shows that allatostatin C, the peptide which inhibits JH production by the corpora allata, blocks the transport of citrate out of the mitochondrion in ''

Aedes aegypti ''Aedes aegypti'', the yellow fever mosquito, is a mosquito that can spread dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its le ...

''. This is a very logical control mechanism for JH biosynthesis.