Juvenile hormone acid O-methyltransferase

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Juvenile hormone acid O-methyltransferase
Identifiers
EC no. 2.1.1.325
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Juvenile hormone acid O-methyltransferase (JHAMT) is a ~33 kDa enzyme [1] (the molecular mass is species-dependent) that catalyzes the conversion of inactive precursors of Juvenile hormones (JHs) to active JHs in the final stages of JH biosynthesis in the corpora allata of insects. [2] More specifically, the enzyme catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the carboxylate group of JH precursors. [3]

Contents

Structure

The reaction catalyzed by JHAMT is a canonical SN2-like mechanism in which a methyl group is transferred from S-adenosyl-L-methionine (2) to farnesoate (1), generating methyl farneosate (3) and S-adenosyl-L-homocysteine (4). JHAMT Mechanism.png
The reaction catalyzed by JHAMT is a canonical SN2-like mechanism in which a methyl group is transferred from S-adenosyl-L-methionine (2) to farnesoate (1), generating methyl farneosate (3) and S-adenosyl-L-homocysteine (4).

While the crystal structure of JHAMT enzymes have not been solved, homology modeling and docking simulations with Aedes aegypti JHAMT (AaJHAMT) have revealed that enzyme interactions with SAM are very similar to other known SAM-dependentmethyltransferase (SAM-MT) complexes. [4] Further analysis of the predicted secondary structure of AaJHAMT shows a typical SAM-MT fold, with 6-stranded β-sheet with 9 ⍺-helices. [5] These docking studies show that the Asp-69 residue forms hydrogen bonds with two ribose hydroxyl groups of SAM; Asp-49 also forms a hydrogen bond through water with the NH3+ moiety of SAM. [5] Val-70 and Ile-95 form a hydrophobic pocket, which houses the adenine ring of SAM. [5] Two additional residues, Gln-14 and Trp-120, hydrogen bond with the carboxyl group of either farnesoic acid (FA) or juvenile hormone acid III (JHA III) to structurally orient the molecule for catalysis. [5] Ile-151, Ile-154, Tyr 155, Leu-158, Val-221 and Val-224 create the hydrophobic pocket for the carbon tail of JHA III and FA. [5]

Generated structures of JHMAT derived from D. melanogaster , B. mori , T. castaneum , and A. gambiae identified Asp-41, Asp-69, Gln-14, Trp-120 and Ser-176 as the critical conserved residues for SAM and substrate recognition. [5]

Catalytic role

The biosynthesis of juvenile hormone III is dependent on insect taxonomy. In Lepidoptera, an epoxidation step occurs before the methylation step; in Orthoptera, Dictyoptera, Coleoptera, and Diptera methylation occurs first. Insect Juvenile Hormone III Synthesis Pathways.png
The biosynthesis of juvenile hormone III is dependent on insect taxonomy. In Lepidoptera, an epoxidation step occurs before the methylation step; in Orthoptera, Dictyoptera, Coleoptera, and Diptera methylation occurs first.

The enzyme catalyzes a putative SN2 reaction, coordinating either FA or JHA III for facile backside nucleophilic attack on the methyl group of SAM. [6] This reaction results in the formation of S-Adenosyl homocysteine (SAH) and the corresponding methyl ester. Depending on the insect's taxonomy, JHMAT is either the last or second to last step in JH III synthesis. Insects in Orthoptera, Dictyoptera, Coleoptera, and Diptera first methylate farnesoic acid to methyl farneosate with JHAMT, followed by epoxidation mediated by P450 epoxidase to yield JH III. Insects of order Lepidoptera first perform an epoxidation by P450 epoxidase to convert farnesoic acid to JHA III, followed by JHAMT-dependent methylation to produce juvenile hormone III. [5] The enzyme displays a higher affinity to JHA III compared to FA, [7] although other enzymes do exhibit the opposite substrate affinity pattern. [8]

Interestingly, JHAMT In Drosophila melanogaster (DmJHMAT) has been shown to have broad specificity for medium chain free fatty acids when the enzyme is recombinantly expressed in E. coli, converting them into fatty acid methyl esters (FAMEs). [9] More specifically, DmJHAMT is active on fatty acids ranging in size from C12 to C16, exhibiting highest activity for lauric acid, a C12 fatty acid. [9] As FAMEs are considered a component of biodiesel, this raises the possibility of manipulating DmJHAMT for biofuel synthesis. [10] It is important to note that DmJHAMT shows no catalytic activity with respect to shorter chain C8 and C10 fatty acids. [9]

Biological Function

Insect metamorphosis is a tightly regulated process that involves JHs and JHAMT. The function of JH in immature insects is to maintain the insect's nymph or larval state by preventing the expression of certain genes that activate insect maturation pathways. [11] Once insects have reached their species-specific size, the corpora allata atrophies [11] and JH production halts due to decreased JHAMT activity, lowering JH concentrations to allow metamorphosis to proceed. [12] In the pupal stage of D. melanogaster and B. mori , a decrease in JH concentration correlates with decreased levels of JHAMT mRNA. [13] [14] Furthermore, JHAMT gene suppression is thought to be critical in larval-pupal metamorphosis in Tribolium castaneum . [15]

In D. melanogaster , DmJHMAT is encoded by the CG17330/DmJHAMT gene, and is very specifically expressed in the corpus allatum. [13] Experiments have shown that an overexpression of CG17330/DmJHAMT leads to pupal lethality and a misorientation of male genitalia in D. melanogaster, suggesting that proper temporal regulation of this gene is critical for Drosophila development. [13]

Apis mellifera are also known to encode a similar JHAMT protein (AmJHAMT). [16] The cDNA was found to be 1253bp long, and encodes a 278-aa protein that shares 32-36% identity with other known JHAMTs. During periods of caste development, queen larvae contained significantly higher levels of AmJHAMT mRNA and protein than worker larvae, suggesting that the protein has a significant role in honey bee caste differentiation. [16]

Related Research Articles

Metamorphosis Profound change in body structure during the postembryonic development of an organism

Metamorphosis is a biological process by which an animal physically develops including birth or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and differentiation. Some insects, fish, amphibians, mollusks, crustaceans, cnidarians, echinoderms, and tunicates undergo metamorphosis, which is often accompanied by a change of nutrition source or behavior. Animals can be divided into species that undergo complete metamorphosis ("holometaboly"), incomplete metamorphosis ("hemimetaboly"), or no metamorphosis ("ametaboly").

Methionine Sulfur-containing amino acid

Methionine is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical role in the metabolism and health of many species, including humans. It is encoded by the codon AUG.

DNA methyltransferase Class of enzymes

In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

Histone methyltransferase Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms.

<i>S</i>-Adenosyl methionine Chemical compound found in all domains of life with largely unexplored effects

S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, when marketed as controversial dietary supplement, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.

In animal dormancy, diapause is the delay in development in response to regular and recurring periods of adverse environmental conditions. It is a physiological state with very specific initiating and inhibiting conditions. The mechanism is a means of surviving predictable, unfavorable environmental conditions, such as temperature extremes, drought, or reduced food availability. Diapause is observed in all the life stages of arthropods, especially insects. Embryonic diapause, a somewhat similar phenomenon, occurs in over 130 species of mammals, possibly even in humans, and in the embryos of many of the oviparous species of fish in the order Cyprinodontiformes.

Methionine synthase Mammalian protein found in Homo sapiens

Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes only express the cobalamin-dependent form, whereas the form found in plants is exclusively the cobalamin-independent. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

Jasmonic acid Chemical compound

Jasmonic acid (JA) is an organic compound found in several plants including jasmine. The molecule is a member of the jasmonate class of plant hormones. It is biosynthesized from linolenic acid by the octadecanoid pathway. It was first isolated in 1957 as the methyl ester of jasmonic acid by the Swiss chemist Edouard Demole and his colleagues.

Methyltransferase Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

Hormone-sensitive lipase Enzyme

Hormone-sensitive lipase, also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene.

Phenylethanolamine N-methyltransferase Mammalian protein found in Homo sapiens

Phenylethanolamine N-methyltransferase (PNMT) is an enzyme found primarily in the adrenal medulla that converts norepinephrine (noradrenaline) to epinephrine (adrenaline). It is also expressed in small groups of neurons in the human brain and in selected populations of cardiomyocytes.

Phosphatidylethanolamine N-methyltransferase

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

Juvenile-hormone esterase

In enzymology, juvenile hormone esterase (JH esterase) is an enzyme that catalyzes the hydrolysis of juvenile hormone. For example, the juvenile hormone II (found in Lepidoptera):

NNMT

Nicotinamide N-methyltransferase (NNMT) is an enzyme that in humans is encoded by the NNMT gene. NNMT catalyzes the methylation of nicotinamide and similar compounds using the methyl donor S-adenosyl methionine (SAM-e) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide.

GNMT

Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.

Halloween genes Set of genes that influence embryonic development

The halloween genes are a set of genes identified in Drosophila melanogaster that influence embryonic development. All of the genes code for cytochrome P450 enzymes in the ecdysteroidogenic pathway (biosynthesis of ecdysone from cholesterol). Ecdysteroids such as 20-hydroxyecdysone and ecdysone influence many of the morphological, physiological, biochemical changes that occur during molting in insects.

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 enzymes involved in the termination of signaling properties of the various juvenile hormones. The other is juvenile-hormone esterase, or JHE.

The conjugate (10S,11S) JH diol phosphate is the product of a two-step enzymatic process: conversion of JH to JH diol and then addition of a phosphate group to C10. The enzyme responsible for the phosphorylation of JH diol is JH diol kinase (JHDK), which was first characterized from the Malpighian tubules of early fifth instars of M. sexta. JHDK was discovered when an analysis of JH I metabolites in vivo yielded, in addition to the expected metabolites, a very polar JH I conjugate that was subsequently identified as JH I diol phosphate. Maxwell et al. showed JHDK to contain 3 potential calcium binding sites, and a single ATP-Mg2+ binding site (p-loop). The modeled structure contains nine helices, one beta sheet, and 10 loops. JHDK is also present in the silkworm, where it also functions as homodimer. It lacks a JH response element; Li et al. (2005). It has a high degree of identity to M. sexta JHDK. Later Uno et al. (2007) characterized the A. mellifera enzyme in a proteomic study. It has 183 amino acid residues. More recently, Zeng et al. (2015) have characterized JHDK from Spodoptera litura. It also has 183 amino acid residues, just as does the B. mori enzyme. These enzymes all have high sequence similarity. The M. sexta enzyme contains 184 residues.

Cytochrome P450, family 6, also known as CYP6, is a cytochrome P450 family found in Insect genome. CYP6 and CYP9, another insect CYP family, belong to the same clan as mammalian CYP3 and CYP5 families.

References

  1. ↑ Jiang M, Lü S, Zhang Y (May 2017). "Characterization of Juvenile Hormone Related Genes Regulating Cantharidin Biosynthesis in Epicauta chinensis". Scientific Reports. 7 (1): 2308. Bibcode:2017NatSR...7.2308J. doi:10.1038/s41598-017-02393-w. PMC   5442126 . PMID   28536442.
  2. ↑ Shinoda T, Itoyama K (October 2003). "Juvenile hormone acid methyltransferase: a key regulatory enzyme for insect metamorphosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (21): 11986–91. Bibcode:2003PNAS..10011986S. doi: 10.1073/pnas.2134232100 . PMC   218700 . PMID   14530389.
  3. ↑ Li W, Huang ZY, Liu F, Li Z, Yan L, Zhang S, et al. (2013-07-09). "Molecular cloning and characterization of juvenile hormone acid methyltransferase in the honey bee, Apis mellifera, and its differential expression during caste differentiation". PLOS ONE. 8 (7): e68544. Bibcode:2013PLoSO...868544L. doi: 10.1371/journal.pone.0068544 . PMC   3706623 . PMID   23874662.
  4. ↑ Mayoral JG, Nouzova M, Yoshiyama M, Shinoda T, Hernandez-Martinez S, Dolghih E, et al. (January 2009). "Molecular and functional characterization of a juvenile hormone acid methyltransferase expressed in the corpora allata of mosquitoes". Insect Biochemistry and Molecular Biology. 39 (1): 31–7. doi:10.1016/j.ibmb.2008.09.010. PMC   2727726 . PMID   18984053.
  5. 1 2 3 4 5 6 7 Defelipe LA, Dolghih E, Roitberg AE, Nouzova M, Mayoral JG, Noriega FG, Turjanski AG (April 2011). "Juvenile hormone synthesis: "esterify then epoxidize" or "epoxidize then esterify"? Insights from the structural characterization of juvenile hormone acid methyltransferase". Insect Biochemistry and Molecular Biology. 41 (4): 228–35. doi:10.1016/j.ibmb.2010.12.008. PMC   3057355 . PMID   21195763.
  6. ↑ O'Hagan D, Schmidberger JW (June 2010). "Enzymes that catalyse SN2 reaction mechanisms". Natural Product Reports. 27 (6): 900–18. doi:10.1039/B919371P. PMID   20372740.
  7. ↑ Van Ekert E, Heylen K, Rougé P, Powell CA, Shatters RG, Smagghe G, Borovsky D (May 2014). "Aedes aegypti juvenile hormone acid methyl transferase, the ultimate enzyme in the biosynthetic pathway of juvenile hormone III, exhibits substrate control". Journal of Insect Physiology. 64: 62–73. doi:10.1016/j.jinsphys.2014.03.001. PMID   24657668.
  8. ↑ Van Ekert E, Shatters RG, Rougé P, Powell CA, Smagghe G, Borovsky D (2015). "Cloning and expressing a highly functional and substrate specific farnesoic acid o-methyltransferase from the Asian citrus psyllid (Diaphorina citri Kuwayama)". FEBS Open Bio. 5 (1): 264–75. doi:10.1016/j.fob.2015.03.012. PMC   4398755 . PMID   25893162.
  9. 1 2 3 Sherkhanov S, Korman TP, Clarke SG, Bowie JU (April 2016). "Production of FAME biodiesel in E. coli by direct methylation with an insect enzyme". Scientific Reports. 6 (1): 24239. Bibcode:2016NatSR...624239S. doi: 10.1038/srep24239 . PMC   4823748 . PMID   27053100.
  10. ↑ Yunus IS, Palma A, Trudeau DL, Tawfik DS, Jones PR (January 2020). "Methanol-free biosynthesis of fatty acid methyl ester (FAME) in Synechocystis sp. PCC 6803". Metabolic Engineering. 57: 217–227. doi:10.1016/j.ymben.2019.12.001. PMID   31821864. S2CID   209317175.
  11. 1 2 Subramanian S, Shankarganesh K (2016-01-01). "Chapter 20 - Insect Hormones (as Pesticides)". In Omkar (ed.). Ecofriendly Pest Management for Food Security. San Diego: Academic Press. pp. 613–650. doi:10.1016/B978-0-12-803265-7.00020-8. ISBN   978-0-12-803265-7.
  12. ↑ Riddiford LM (June 2008). "Juvenile hormone action: a 2007 perspective". Journal of Insect Physiology. 54 (6): 895–901. doi:10.1016/j.jinsphys.2008.01.014. PMID   18355835.
  13. 1 2 3 Niwa R, Niimi T, Honda N, Yoshiyama M, Itoyama K, Kataoka H, Shinoda T (July 2008). "Juvenile hormone acid O-methyltransferase in Drosophila melanogaster" (PDF). Insect Biochemistry and Molecular Biology. 38 (7): 714–20. doi:10.1016/j.ibmb.2008.04.003. hdl: 2241/100120 . PMID   18549957.
  14. ↑ Kinjoh T, Kaneko Y, Itoyama K, Mita K, Hiruma K, Shinoda T (August 2007). "Control of juvenile hormone biosynthesis in Bombyx mori: cloning of the enzymes in the mevalonate pathway and assessment of their developmental expression in the corpora allata". Insect Biochemistry and Molecular Biology. 37 (8): 808–18. doi:10.1016/j.ibmb.2007.03.008. PMID   17628279.
  15. ↑ Minakuchi C, Namiki T, Yoshiyama M, Shinoda T (June 2008). "RNAi-mediated knockdown of juvenile hormone acid O-methyltransferase gene causes precocious metamorphosis in the red flour beetle Tribolium castaneum". The FEBS Journal. 275 (11): 2919–31. doi: 10.1111/j.1742-4658.2008.06428.x . PMID   18435763. S2CID   2614078.
  16. 1 2 Li W, Huang ZY, Liu F, Li Z, Yan L, Zhang S, et al. (2013). "Molecular cloning and characterization of juvenile hormone acid methyltransferase in the honey bee, Apis mellifera, and its differential expression during caste differentiation". PLOS ONE. 8 (7): e68544. Bibcode:2013PLoSO...868544L. doi: 10.1371/journal.pone.0068544 . PMC   3706623 . PMID   23874662.
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