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 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.
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
- Reversed-phase liquid chromatographic separation of juvenile hormone and its metabolites, and its application for an in vivo juvenile hormone catabolism study in Manduca sexta. Anal. Biochem. 188, 394-397
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.
- Grieneisen, M.L., Kieckbusch, T.D., Dorman, G., Latli, B., Prestwich, G.D., Schooley, D.A., 1995
- Characterization of the juvenile hormone epoxide hydrolase (JHEH) and juvenile hormone diol phosphotransferase (JHDPT) from Manduca sexta Malpighian tubules. Arch. Insect Biochem. Physiol. 30, 255-270
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
The Malpighian tubule system is a type of excretory and osmoregulatory system found in some insects, myriapods, arachnids and tardigrades. The system consists of branching tubules extending from the alimentary canal that absorbs solutes, water, and wastes from the surrounding hemolymph. The wastes then are released from the organism in the form of solid nitrogenous compounds and calcium oxalate. The system is named after Marcello Malpighi, a seventeenth-century anatomist.
Malpighian tubules are slender tubes normally found in the posterior regions of arthropod alimentary canals. Each tubule consists of a single layer of cells that is closed off at the distal end with the proximal end joining the alimentary canal at the junction between the midgut and hindgut. Most tubules are normally highly convoluted. The number of tubules varies between species although most occur in multiples of two. Tubules are usually bathed in hemolymph and are in proximity to fat body tissue. They contain actin for structural support and microvilli for propulsion of substances along the tubules. Malpighian tubules in most insects also contain accessory musculature associated with the tubules which may function to mix the contents of the tubules or expose the tubules to more hemolymph. The insect orders, Dermaptera and Thysanoptera do not possess these muscles and Collembola and Hemiptera:Aphididae completely lack a Malpighian tubule system.
Pre-urine is formed in the tubules, when nitrogenous waste and electrolytes are transported through the tubule walls. Wastes such as urea and amino acids are thought to diffuse through the walls, while ions such as sodium and potassium are transported by active pump mechanisms. Water follows thereafter. The pre-urine, along with digested food, merge in the hindgut. At this time, uric acid precipitates out, and sodium and potassium ions are actively absorbed by the rectum, along with water via osmosis. Uric acid is left to mix with faeces, which are then excreted.
Complex cycling systems of Malpighian tubules have been described in other insect orders. Hemipteran insects use tubules that permit movement of solutes into the distal portion of the tubules while reabsorption of water and essential ions directly to the hemolymph occurs in the proximal portion and the rectum. Both Coleoptera and Lepidoptera use a cryptonephridial arrangement where the distal end of the tubules are embedded in fat tissue surrounding the rectum. Such an arrangement may serve to increase the efficiency of solute processing in the Malpighian tubules.
Although primarily involved in excretion and osmoregulation, Malpighian tubules have been modified in some insects to serve accessory functions. Larvae of all species in genus Arachnocampa use modified and swollen Malpighian tubules to produce a blue-green light attracting prey towards mucus-coated trap lines. In insects which feed on plant material containing noxious allelochemicals, Malpighian tubules also serve to rapidly excrete such compounds from the hemolymph. See also Cryptonephridium.
- Green, L.B.S. (1979) The fine structure of the light organ of the New Zealand glow-worm Arachnocampa luminosa (Diptera: Mycetophilidae). Tissue and Cell 11: 457–465.
- Gullan, P.J. and Cranston, P.S. (2000) The Insects: An Outline of Entomology. Blackwell Publishing UK ISBN 1-4051-1113-5
- Romoser, W.S. and Stoffolano Jr., J.G. (1998) The Science of Entomology. McGraw-Hill Singapore ISBN 0-697-22848-7
- Bradley, T.J. The excretory system: structure and physiology. In: Kerkut, G.A. and Gilbert, L.I. eds. Comprehensive insect physiology, biochemistry and pharmacology. Vol.4 Pergamon Press New York ISBN 0-08-030807-4 pp. 421–465
In insect anatomy, a cryptonephridium is a structure present in most larval Lepidoptera and in other insects (i.e., Coleoptera) inhabiting relatively arid environments. The Malpighian tubules are not free in the hemocele but are bound to the wall of the rectum by the perinephric membrane. This structure allows efficient resorption of water from diuresis and absorption of atmospheric water that is present in the hindgut as humidity. An adaptation for water conservation.
- Wigglesworth, V.B. 1953. The Principles of Insect Physiology. 5th edition, E.P. Dutton & Co. Ltd., New York. p. 369.
- Klowden, M.J. 2007. Physiological Systems in Insects. 2nd edition, Academic Press. p. 416
JHDK (EC 2.1.7.3) 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.
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
Maxwell et al. showed JHDK to contain 3 potential calcium binding sites, and a single ATP-Mg2+ binding site (p-loop).
Calcium-binding proteins are proteins that participate in calcium cell signaling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to calcium and are known to be heterogeneous. One of the functions of calcium binding proteins is to regulate the amount of free (unbound) Ca2+ in the cytosol of the cell. The cellular regulation of calcium is known as calcium homeostasis.
- Kinjo, Tashi G; Schnetkamp, Paul PM. Ca2+ Chemistry, Storage and Transport in Biologic Systems: An Overview. Madame Curie Bioscience Database [Internet]. Retrieved 2 May 2016.
Many different calcium-binding proteins exist, with different cellular and tissue distribution and involvement in specific functions. Calcium binding proteins also serve an important physiological role for cells. The most ubiquitous Ca2+-sensing protein, found in all eukaryotic organisms including yeasts, is calmodulin. Intracellular storage and release of Ca2+ from the sarcoplasmic reticulum is associated with the high-capacity, low-affinity calcium-binding protein calsequestrin. Calretinin is another type of Calcium binding protein weighing 29kD. It is involved in cell signaling and shown to exist in neurons. This type of protein is also found in large quantities in malignant mesothelial cells, which can be easily differentiated from carcinomas. This differentiation is later applied for a diagnosis on ovarian stromal tumors. Also, another member of the EF-hand superfamily is the S100B protein, which regulates p53. P53 is known as a tumor suppressor protein and in this case acts as a transcriptional activator or repressor of numerous genes. S100B proteins are abundantly found in cancerous tumor cells causing them to be overexpressed, therefore making these proteins useful for classifying tumors. In addition, this explains why this protein can easily interact with p53 when transcriptional regulation takes place.
- Yáñez M, Gil-Longo J, Campos-Toimil M (2012). “Calcium binding proteins”. Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 740: 461–82. doi:10.1007/978-94-007-2888-2_19. ISBN 978-94-007-2887-5. PMID 22453954.
- Siegel, George (Ed.). Basic neurochemistry: molecular, cellular and medical aspects. Lippincott Williams and Wilkins / 1999 ISBN 0-397-51820-X
- “NordiQC”. Archived from the original on 2016-06-20. Retrieved 2016-05-04.
- Ikura, Mitsuhiko; Osawa, Masanori; Ames, James B. (July 2002). “The role of calcium-binding proteins in the control of transcription: structure to function” (PDF). BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 24 (7): 625–636. doi:10.1002/bies.10105. PMID 12111723. Retrieved 5 November 2022.
Calcium-binding proteins can be either intracellular and extracellular. Those that are intracellular can contain or lack a structural EF-hand domain. Extracellular calcium-binding proteins are classified into six groups. Since Ca (2+) is an important second messenger, it can act as an activator or inhibitor in gene transcription. Those that belong to the EF-hand superfamily such as Calmodulin and Calcineurin have been linked to transcription regulation. When levels of Ca(2+) increase in the cell, these members of the EF-hand superfamily regulate transcription indirectly by phosphorylating/dephosphorylating transcription factors.
- Yáñez M, Gil-Longo J, Campos-Toimil M (2012). “Calcium binding proteins”. Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 740: 461–82. doi:10.1007/978-94-007-2888-2_19. ISBN 978-94-007-2887-5. PMID 22453954.
- Ikura, Mitsuhiko; Osawa, Masanori; Ames, James B. (July 2002). “The role of calcium-binding proteins in the control of transcription: structure to function” (PDF). BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 24 (7): 625–636. doi:10.1002/bies.10105. PMID 12111723. Retrieved 5 November 2022.
Secretory calcium-binding phosphoprotein
The secretory calcium-binding phosphoprotein (SCPP) gene family consists of an ancient group of genes emerging around the same time as bony fish. SCPP genes are roughly divided into acidic and P/Q-rich types: the former mostly participates in bone and dentin formation, while the latter usually participate in enamel/enameloid formation. In mammals, P/Q-rich SCPP is also found in saliva and milk and includes unorthodox members such as MUC7 (a mucin) and casein. SCPP genes are recognized by exon structure rather than protein sequence.
- Kawasaki, Kazuhiko (2018). “The Origin and Early Evolution of SCPP Genes and Tissue Mineralization in Vertebrates”. Biomineralization. pp. 157–164. doi:10.1007/978-981-13-1002-7_17. ISBN 978-981-13-1001-0. S2CID 91544812.
With their role in signal transduction, calcium-binding proteins contribute to all aspects of the cell’s functioning, from homeostasis to learning and memory. For example, the neuron-specific calexcitin has been found to have an excitatory effect on neurons, and interacts with proteins that control the firing state of neurons, such as the voltage-dependent potassium channel.
- Nelson T, Cavallaro S, Yi C, McPhie D, Schreurs B, Gusev P, Favit A, Zohar O, Kim J, Beushausen S, Ascoli G, Olds J, Neve R, Alkon D (1996). “Calexcitin: a signaling protein that binds calcium and GTP, inhibits potassium channels, and enhances membrane excitability”. PNAS. 93 (24): 13808–13. Bibcode:1996PNAS…9313808N. doi:10.1073/pnas.93.24.13808. PMC 19433. PMID 8943017.
Compartmentalization of calcium binding proteins such as calretinin and calbindin-28 kDa has been noted within cells, suggesting that these proteins perform distinct functions in localized calcium signaling. It also indicates that in addition to freely diffusing through the cytoplasm to attain a homogeneous distribution, calcium binding proteins can bind to cellular structures through interactions that are likely important for their functions.
- Mojumder DK, Wensel TG, Frishman LJ (Aug 2008). “Subcellular compartmentalization of two calcium binding proteins, calretinin and calbindin-28 kDa, in ganglion and amacrine cells of the rat retina”. Molecular Vision. 14: 1600–1613. PMC 2528027. PMID 18769561.
See also
- Calbindin
- Calmodulin
- Calsequestrin
- Troponin
- Calcium-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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.
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
JHDK from M. sexta Malpighian tubules is a cytosolic protein composed of two identical subunits of 20 kDa, as determined by MS.
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
Gel filtration studies indicate it has a molecular mass of approximately 43 kDa. JHDK displays a Km in the nanomolar range for JH I diol, which is appropriate for an enzyme responsible for clearance of a hormone whose titers rarely exceeds 10 nM. Most significantly, the catalytic activity of JHDK parallels developmentally that of JHEH, a requisite if JH diol phosphate is a legitimate terminal metabolite. Analysis of the kcat/Km ratio for the diols of JH I, II, and III indicates that JH I diol is the preferred substrate, suggesting a preference for an ethyl group at the C7 position. JHDK requires both Mg2+ and ATP for activity.
- Grieneisen, M.L., Kieckbusch, T.D., Dorman, G., Latli, B., Prestwich, G.D., Schooley, D.A., 1995
JHEH is a membrane associated protein, and by photoaffinity labeling has been shown to be a 50 kDA protein in Manduca sexta.
- Touhara K, Soroker V, Prestwich GD (June 1994). “Photoaffinity labeling of juvenile hormone epoxide hydrolase and JH-binding proteins during ovarian and egg development in Manduca sexta”. Insect Biochemistry and Molecular Biology. 24 (6): 633–640. doi:10.1016/0965-1748(94)90100-7.
It has been noted by several that properties of JHEH are similar to those of animal microsomal epoxide hydrolase. Sequence alignments showed that the exact catalytic triad of the animal enzyme (Asp-226, Glu-403 and His-430) is present in JHEH. In addition, the X-ray structure of Bombyx mori JHEH was recently determined.
- Harris SV, Thompson DM, Linderman RJ, Tomalski MD, Roe RM (1999). “Cloning and expression of a novel juvenile hormone-metabolizing epoxide hydrolase during larval-pupal metamorphosis of the cabbage looper, Trichoplusia ni”. Insect Mol. Biol. 8 (1): 85–96. doi:10.1046/j.1365-2583.1999.810085.x. PMID 9927177.
- PDB: 4QLA; Zhou K, Jia N, Hu C, Jiang YL, Yang JP, Chen Y, Li S, Li WF, Zhou CZ (2014). “Crystal structure of juvenile hormone epoxide hydrolase from the silkworm Bombyx mori”. Proteins. 82 (11): 3224–9. doi:10.1002/prot.24676. PMID25143157.
- In enzymology, a microsomal epoxide hydrolase (mEH) (EC 3.3.2.9) is an enzyme that catalyzes the hydrolysis reaction between an epoxide and water to form a diol. This enzyme plays a role in the uptake of bile salts within the large intestine. It functions as a Na+ dependent transporter. This enzyme participates in metabolism of xenobiotics by cytochrome p450. mEH has been identified as playing a large role in the detoxification and bioactivation of a wide variety of substrates, such as polycyclic aromatic hydrocarbons (PAHs), which are known for their carcinogenic properties.
- Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y (January 2006). “EPHX1 polymorphisms and the risk of lung cancer: a HuGE review”. Epidemiology. 17 (1): 89–99. doi:10.1097/01.ede.0000187627.70026.23. PMID 16357600.
- The human homolog of microsomal epoxide hydrolase is EPHX1 and is located on chromosome 1.
- Jackson MR, Craft JA, Burchell B (September 1987). “Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase”. Nucleic Acids Research. 15 (17): 7188. doi:10.1093/nar/15.17.7188. PMC 306212. PMID 3502697.
- Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.
- EPHX1 protein can be found predominantly in the membrane fraction of the endoplasmic reticulum of eucaryotic cells. Its expression in mammals is generally the highest in the liver, followed by adrenal gland, lung, kidney, and intestine. It was found also in bronchial epithelial cells and upper gastrointestinal tract. EPHX1 expression is individually variable among humans and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.
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- Conversion of epoxides to trans-dihydrodiols presents prototypical EPHX1 reaction. EPHX1 has broad substrate specificity. EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc., but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.
- Oesch F, Kaubisch N, Jerina DM, Daly JW (1971). “Hepatic epoxide hydrase. Structure-activity relationships for substrates and inhibitors”. Biochemistry. 10 (26): 4858–66. doi:10.1021/bi00802a005. PMID 5134533.
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- EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes. Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates. EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid and may play an important role in the endocannabinoid signaling pathway.
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- Mutations in EPHX1 have been linked with preeclampsia, elevated blood levels of bile salts (i.e. hypercholanemia), Fetal hydantoin syndrome, and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied. Two SNPs – Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro and their combination was used for deduction of EPHX1 activity. However, their functional effect was not confirmed in human liver microsomes.
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- Due to the EPHX1 role in metabolism of procarcinogens and existence of gene variations with functional effect a number of association studies has been conducted. Significant associations between EPHX1 SNPs and risk of lung, upper aerodigestive tract, breast, and ovarian cancers have been observed in various populations.
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- Tan X, He WW, Wang YY, Shi LJ, Chen MW (2014). “EPHX1 Tyr113His and His139Arg polymorphisms in esophageal cancer risk: a meta-analysis”. Genet. Mol. Res. 13 (1): 649–59. doi:10.4238/2014.January.28.10. PMID 24615030.
- Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer. Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well.
- Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y (2006). “EPHX1 polymorphisms and the risk of lung cancer: a HuGE review”. Epidemiology. 17 (1): 89–99. doi:10.1097/01.ede.0000187627.70026.23. PMID 16357600. S2CID 26035006.
- Liu H, Li HY, Chen HJ, Huang YJ, Zhang S, Wang J (2013). “EPHX1 A139G polymorphism and lung cancer risk: a meta-analysis”. Tumour Biol. 34 (1): 155–63. doi:10.1007/s13277-012-0523-z. PMID 23055191. S2CID 16057113.
- Wang S, Zhu J, Zhang R, Wang S, Gu Z (2013). “Association between microsomal epoxide hydrolase 1 T113C polymorphism and susceptibility to lung cancer”. Tumour Biol. 34 (2): 1045–52. doi:10.1007/s13277-012-0644-4. PMID 23378225. S2CID 18639774.
- Hu JJ, Wang ZT, Li B (2013). “Meta-analysis demonstrates lack of an association of microsomal epoxide hydrolase 1 polymorphisms with esophageal cancer risk”. Genet. Mol. Res. 12 (4): 4540–8. doi:10.4238/2013.October.15.2. PMID 24222229.
- Duan CY, Liu MY, Li SB, Ma KS, Bie P (2014). “Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis”. Tumour Biol. 35 (1): 659–66. doi:10.1007/s13277-013-1090-7. PMID 23955801. S2CID 14846609.
- Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals. Recent meta-analysis comprising 8,259 patients with chronic obstructive pulmonary disease (COPD) and 42,883 controls reported that the predicted slow activity EPHX1 phenotype is a significant risk factor for COPD in Caucasian, but not in Asian population.
- Lee J, Dahl M, Nordestgaard BG (2011). “Genetically lowered microsomal epoxide hydrolase activity and tobacco-related cancer in 47,000 individuals”. Cancer Epidemiol. Biomarkers Prev. 20 (8): 1673–82. doi:10.1158/1055-9965.EPI-10-1165. PMID 21653646.
- Li H, Fu WP, Hong ZH (2013). “Microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease: A comprehensive meta-analysis”. Oncol Lett. 5 (3): 1022–1030. doi:10.3892/ol.2012.1099. PMC 3576314. PMID 23426996.
- Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease, methamphetamine-induced drug dependence, and cerebral metabolism of epoxyeicosatrienoic acids was suggested. Modulation of metabolism of epoxyeicosatrienoic acids by EPHX1 may interfere with, e.g., signal transmission of neurons, vasodilation, cardiovascular homeostasis, and inflammation. Transformation of the current knowledge about EPHX1 into clinical applications is, however, limited by the lack of crystal structure of the enzyme and by the complex relations between its genotype and phenotype.
- Liu, M; Sun, A; Shin, EJ; Liu, X; Kim, SG; Runyons, CR; Markesbery, W; Kim, HC; Bing, G (2006). “Expression of microsomal epoxide hydrolase is elevated in Alzheimer’s hippocampus and induced by exogenous beta-amyloid and trimethyl-tin”. Eur J Neurosci. 23 (8): 2027–2034. doi:10.1111/j.1460-9568.2006.04724.x. PMID 16630050. S2CID 5969583.
- Shin, EJ; Bing, G; Chae, JS; Kim, TW; Bach, JH; Park, DH; Yamada, K; Nabeshima, T; Kim, HC (2009). “Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice”. J Neurosci Res. 87 (16): 3679–3686. doi:10.1002/jnr.22166. PMID 19598248. S2CID 13400323.
- Marowsky, A; Burgener, J; Falck, JR; Fritschy, JM; Arand, M (2009). “Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism”. Neuroscience. 163 (2): 646–661. doi:10.1016/j.neuroscience.2009.06.033. PMID 19540314. S2CID 25808698.
- Jackson MR, Craft JA, Burchell B (September 1987). “Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase”. Nucleic Acids Research. 15 (17): 7188. doi:10.1093/nar/15.17.7188. PMC 306212. PMID 3502697.
- α/β-hydrolase fold enzymes use a catalytic triad in their active site. The catalytic triad present in microsomal epoxide hydrolase is composed of glutamine, histidine and aspartic acid. The substrate is positioned in an orientation poised for nucleophilic attack through hydrogen bonding stabilization from two nearby tyrosine residues The proposed mechanism for the mEH-catalyzed reaction first involves a nucleophilic attack on the oxirane ring of the substrate from the aspartic acid residue near the active site, which forms an esterintermediate. The second step in this mechanism is hydrolysis of the ester that occurs by an activated water molecule. The activation of water is facilitated by proton abstraction via the catalytic triad between a water molecule, glutamine, and histidine. After hydrolysis, the substrate is then released from its bond to the aspartic acid residue, liberating the diol product from the enzyme active site.
- Arand M, Müller F, Mecky A, Hinz W, Urban P, Pompon D, Kellner R, Oesch F (January 1999). “Catalytic triad of microsomal epoxide hydrolase: replacement of Glu404 with Asp leads to a strongly increased turnover rate”. The Biochemical Journal. 337 (1): 37–43. doi:10.1042/0264-6021:3370037. PMC 1219933. PMID 9854022.
- Lewis DF, Lake BG, Bird MG (June 2005). “Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 A resolution: structure-activity relationships in epoxides inhibiting EH activity”. Toxicology in Vitro. 19 (4): 517–22. doi:10.1016/j.tiv.2004.07.001. PMID 15826809.
- Saenz-Méndez P, Katz A, Pérez-Kempner ML, Ventura ON, Vázquez M (April 2017). “Structural insights into human microsomal epoxide hydrolase by combined homology modeling, molecular dynamics simulations, and molecular docking calculations”. Proteins. 85 (4): 720–730. doi:10.1002/prot.25251. PMID 28120429. S2CID 9772104.
- Lacourciere GM, Armstrong RN (November 1993). “The catalytic mechanism of microsomal epoxide hydrolase involves an ester intermediate”. Journal of the American Chemical Society. 115 (22): 10466–10467. doi:10.1021/ja00075a115.
- McCall PM, Srivastava S, Perry SL, Kovar DR, Gardel ML, Tirrell MV (April 2018). “Partitioning and Enhanced Self-Assembly of Actin in Polypeptide Coacervates”. Biophysical Journal. 114 (7): 1636–1645. Bibcode:2018BpJ…114.1636M. doi:10.1016/j.bpj.2018.02.020. PMC 5954293. PMID 29642033.
- Oesch F, Herrero ME, Hengstler JG, Lohmann M, Arand M (May 2000). “Metabolic detoxification: implications for thresholds”. Toxicologic Pathology. 28 (3): 382–7. doi:10.1177/019262330002800305. PMID 10862554.
- Reetz MT, Bocola M, Wang LW, Sanchis J, Cronin A, Arand M, Zou J, Archelas A, Bottalla AL, Naworyta A, Mowbray SL (June 2009). “Directed evolution of an enantioselective epoxide hydrolase: uncovering the source of enantioselectivity at each evolutionary stage”. Journal of the American Chemical Society. 131 (21): 7334–43. doi:10.1021/ja809673d. PMID 19469578.
- The active site of this enzyme lies within a hydrophobic pocket in the enzyme, which in turn leads to the enzyme’s preferential reactivity with molecules with hydrophobic side-chains. The mEH enzyme typically binds to small organic epoxides, such as styrene epoxide and cis-stillbene-oxide. mEH does not catalyze the hydrolysis of bulkier molecules, as their large side-chains may sterically disrupt the charge relay system responsible for water activation.
- Lewis DF, Lake BG, Bird MG (June 2005). “Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 A resolution: structure-activity relationships in epoxides inhibiting EH activity”. Toxicology in Vitro. 19 (4): 517–22. doi:10.1016/j.tiv.2004.07.001. PMID 15826809.
- Václavíková R, Hughes DJ, Souček P (October 2015). “Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease”. Gene. 571 (1): 1–8. doi:10.1016/j.gene.2015.07.071. PMC 4544754. PMID 26216302.
- In humans, mEH has been found in the ovary, lung, kidney, lymphocytes, epithelial cells, and liver. Microsomal epoxide hydrolase serves as a protective enzyme against potentially harmful small molecules derived from the external environment. This hydrolysis of genotoxic epoxides causes subsequent effects in several signal transduction pathways, rendering this enzyme important to metabolism.
- Bachmann K (2009). “Chapter 8: Drug Metabolism”. Pharmacology. Elsevier. pp. 131–173. doi:10.1016/b978-0-12-369521-5.00008-7. ISBN 978-0-12-369521-5.
- Oesch F (May 1973). “Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds”. Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 3 (5): 305–40. doi:10.3109/00498257309151525. PMID 4584115.
- Samuelsson B, Dahlén SE, Lindgren JA, Rouzer CA, Serhan CN (September 1987). “Leukotrienes and lipoxins: structures, biosynthesis, and biological effects”. Science. 237 (4819): 1171–6. Bibcode:1987Sci…237.1171S. doi:10.1126/science.2820055. PMID 2820055.
- Moghaddam MF, Grant DF, Cheek JM, Greene JF, Williamson KC, Hammock BD (May 1997). “Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase”. Nature Medicine. 3 (5): 562–6. doi:10.1038/nm0597-562. PMC 7095900. PMID 9142128.
- Microsomal epoxide hydrolase plays a large role in its effects on human health. Studies have shown that mutations EPHX1 in humans may be the cause of hypercholanemia, preeclampsia, and may contribute to fetal hydantoin syndrome. Research also suggests that maternal polymorphisms in EPHX1 in pregnant women were related to facial malformations of children born from women taking phenytoin during their first trimester of pregnancy. While mEH participates in the protection of human health via detoxification of various environmental substances, it also has been found to facilitate the activation of carcinogens.
- Zhu QS, Xing W, Qian B, von Dippe P, Shneider BL, Fox VL, Levy D (July 2003). “Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia”. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 1638 (3): 208–16. doi:10.1016/s0925-4439(03)00085-1. PMID 12878321.
- Zusterzeel PL, Rütten H, Roelofs HM, Peters WH, Steegers EA (February 2001). “Protein carbonyls in decidua and placenta of pre-eclamptic women as markers for oxidative stress”. Placenta. 22 (2–3): 213–9. doi:10.1053/plac.2000.0606. PMID 11170826.
- Laasanen J, Romppanen EL, Hiltunen M, Helisalmi S, Mannermaa A, Punnonen K, Heinonen S (September 2002). “Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia”. European Journal of Human Genetics. 10 (9): 569–73. doi:10.1038/sj.ejhg.5200849. PMID 12173035.
- Buehler BA, Delimont D, van Waes M, Finnell RH (May 1990). “Prenatal prediction of risk of the fetal hydantoin syndrome”. The New England Journal of Medicine. 322 (22): 1567–72. doi:10.1056/NEJM199005313222204. PMID 2336087.
- Azzato EM, Chen RA, Wacholder S, Chanock SJ, Klebanoff MA, Caporaso NE (January 2010). “Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations”. Pharmacogenetics and Genomics. 20 (1): 58–63. doi:10.1097/fpc.0b013e328334b6a3. PMID 19952982. S2CID 29336596.
- Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y (January 2006). “EPHX1 polymorphisms and the risk of lung cancer: a HuGE review”. Epidemiology. 17 (1): 89–99. doi:10.1097/01.ede.0000187627.70026.23. PMID 16357600.
- mEH detoxifies reactive epoxides that are commonly caused from cigarette smoke, and as such it is hypothesized that mutations in EPHX1 in humans may have an effect on an individual’s susceptibility to COPD, emphysema and lung cancer. Some sources have demonstrated that individuals affected by COPD have a higher rate of containing an under-active variant of the EPHX1 gene, yet also demonstrated that the overactive variant of the gene was also found in higher frequencies in individuals affected by disease as well. Other research has provided evidence supporting the idea that EPHX1 variants do not contribute to susceptibility of disease, but do contribute to disease severity. The role that mEH plays in lung cancer and COPD is still not fully elucidated, as the data on the topic in the literature is not completely unanimous.
- Smith CA, Harrison DJ (August 1997). “Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema”. Lancet. 350 (9078): 630–3. doi:10.1016/s0140-6736(96)08061-0. PMID 9288046. S2CID 23974600.
- Brøgger J, Steen VM, Eiken HG, Gulsvik A, Bakke P (April 2006). “Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1”. The European Respiratory Journal. 27 (4): 682–8. doi:10.1183/09031936.06.00057005. PMID 16585076.
- Postma DS, Silverman EK (2009). “Chapter 4 – Genetics of Asthma and COPD”. Genetics of Asthma and COPD. Elsevier. pp. 37–51. doi:10.1016/b978-0-12-374001-4.00004-3. ISBN 9780123740014.
- Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y (January 2006). “EPHX1 polymorphisms and the risk of lung cancer: a HuGE review”. Epidemiology. 17 (1): 89–99. doi:10.1097/01.ede.0000187627.70026.23. PMID 16357600.
- There is some evidence that mEH variants may contribute to the occurrence of childhood asthma in combination with variants on the GSTP1 gene.
- Salam MT, Lin PC, Avol EL, Gauderman WJ, Gilliland FD (December 2007). “Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma”. Thorax. 62 (12): 1050–7. doi:10.1136/thx.2007.080127. PMC 2094290. PMID 17711870.
- Compared to soluble epoxide hydrolase, the contribution of mEH to metabolism of beneficial epoxy fatty acids such as Epoxyeicosatrienoic acid is considered minor since they are relatively poor mEH substrates in vitro. Yet, in vivo, it was found that mEH can play a considerable role in regulation of EET levels and hence inhibition of mEH or dual inhibition of mEH and sEH might have therapeutic potential. Amide, amine and urea based mEH inhibitors have been explored. Based on the most potent inhibitors characterized, an amide with a bulky alpha-substituent and a phenyl ring with lipophilic groups at meta-positions appear to be key pharmacophore units.
- Marowsky A, Burgener J, Falck JR, Fritschy JM, Arand M (June 2009). “Distribution of Soluble and Microsomal Epoxide Hydrolase in the Mouse Brain and Its Contribution to Cerebral Epoxyeicosatrienoic Acid Metabolism”. Neuroscience. 163 (2): 646–661. doi:10.1016/j.neuroscience.2009.06.033. PMID 19540314. S2CID 25808698.
- Edin ML, Hamedani BG, Gruzdev A, Graves JP, Lih FB, Arbes SJ, Singh R, Leon AO, Bradbury JA, DeGraff LM, Hoopes SL, Arand M, Zeldin DC (January 2018). “Epoxide hydrolase 1 (EPHX1) hydrolyzes epoxyeicosanoids and impairs cardiac recovery after ischemia”. The Journal of Biological Chemistry. 293 (9): 3281–3292. doi:10.1074/jbc.RA117.000298. PMC 5836130. PMID 29298899.
- Morisseau C, Newman JW, Dowdy DL, Goodrow MH, Hammock BD (April 2001). “Inhibition of Microsomal Epoxide Hydrolases by Ureas, Amides, and Amines”. Chemical Research in Toxicology. 14 (4): 409–415. doi:10.1021/tx0001732. PMID 11304129.
- Barnych B, Singh N, Negrel S, Zhang Y, Magis D, Roux C, Hua X, Ding Z, Morisseau C, Tantillo DJ, Siegel JB, Hammock BD (March 2020). “Development of potent inhibitors of the human microsomal epoxide hydrolase”. European Journal of Medicinal Chemistry. 193: 112206. doi:10.1016/j.ejmech.2020.112206. PMC 7366823. PMID 32203787
- The overall effect that mEH has on human health is still debated, with some sources finding evidence that the overactive EPHX1 gene is the culprit for some diseases, while other evidence supports that the under active variant is the cause of others.
Characterization of the juvenile hormone epoxide hydrolase (JHEH) and juvenile hormone diol phosphotransferase (JHDPT) from Manduca sexta Malpighian tubules. Arch. Insect Biochem. Physiol. 30, 255-270), although excess Mg2+ and Ca2+ inhibit its activity.
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
The specificity of JHDK for JH I diol is relatively high, considering the multitude of potential phosphate acceptor groups present in a cell. The enzyme does not recognize methyl geranoate diol (one isoprenyl unit shorter than JH) nor methyl geranylgeranoate diol (one isoprenyl group longer than JH), yet it does recognize JH I ethyl ester diol. It also recognizes both JH diol enantiomers, indicating that the absolute stereospecificity of the hydroxy groups is of minor importance. Most surprising is the enzyme’s inability to recognize JH acid diols. Because JH acid diol cannot be phosphorylated by JHDK, the generally accepted pathway for JH catabolism (JH acid is converted to JH acid diol) must be reconsidered. Still, the role of cellular JHE becomes problematic if the pathway catalyzed by JHEH and JHDK is the major pathway for JH catabolism in the cell. The fact that JH diol phosphate is a significant metabolite certainly weakens the long-held dogma that JH esterase is most important in JH catabolism. While JHE has been noted to have phosphatase activity, to our knowledge it has never been tested on JH diol phosphate.
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
The sequence and hypothetical structures of M. sexta, D. melanogaster, and B. mori JHDK have been analyzed. A partial characterization of JHDK from whole-body homogenates of D. melanogaster indicates that it is similar to the enzyme in M. sexta, with the exception of its subunit structure. The active D. melanogaster JHDK is a monomer of ~20 kDa, while the active M. sexta (GenBank accession number: AJ430670) and B. mori JHDKs (GenBank accession number: AY363308) are composed of two identical 20 kDa subunits. Similarities in chromatographic properties, isoelectric point, and enzyme activity led to conclude that sarcoplasmic calcium-binding protein 2 (dSCP2) is the probable D. melanogaster homologue of M. sexta JHDK. The M. sexta gene codes for an enzyme that has 59% sequence identity and >80% similarity to dSCP2 of D. melanogaster (GenBank accession number: AF093240; CG14904).
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Li, S., Zhang, Q.R., Xu, W.H., Schooley, D.A., 2005. The Figure shows a model from this paper of the computer generated structure. Juvenile hormone diol kinase, a calcium-binding protein with kinase activity, from the silkworm, Bombyx mori. Insect Biochem Mol. Biol. 35, 1235-1248
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
Li et al reported that the B. mori JHDK is composed of a single exon of 637 bp. The B. mori JHDK is expressed most prevalently in the gut, as determined by Northern blot analyses, and is not under the direct control of JH at the transcriptional level.
- Li, S., Zhang, Q.R., Xu, W.H., Schooley, D.A., 2005. Juvenile hormone diol kinase, a calcium-binding protein with kinase activity, from the silkworm, Bombyx mori. Insect Biochem Mol. Biol. 35, 1235-1248
Maxwell et al. generated a 3D model that they used for in silico docking simulations. They capitalized on the facts that the catalytic site of JHDK must contain a purine (GTP) binding site and hydrophobic pocket for JH diol, and that the scaffolding for dSCP2 is known. Surrounding the putative substrate-binding site, both the M. sexta and D. melanogaster JHDKs contain the three conserved nucleotide-binding elements common to nucleotide binding proteins. The model further demonstrates that the protein contains four domains that form two pairs of a helix-loop-helix motif (EF-hand;.Charge interactions in the hydrophobic binding pocket, as well as its depth (19 Â), are complementary to the extended conformation of the diol. Moreover, the hydrophobic nature of the binding pocket complements the C1 ester of the substrate and supports the observation that JH diol is the only substrate for this enzyme.
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002b. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Branden, C., Tooze, J., 1999. Introduction to Protein Structure, 2nd ed. Garland Publishing, Inc., New York
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
Usually, an enzyme molecule has only one active site, and the active site fits with one specific type of substrate. An active site contains a binding site that binds the substrate and orients it for catalysis. The orientation of the substrate and the close proximity between it and the active site is so important that in some cases the enzyme can still function properly even though all other parts are mutated and lose function.
- Dagmar R, Gregory A (2008). “How Enzymes Work”. Science. 320 (5882): 1428–1429. doi:10.1126/science.1159747. PMID 18556536. S2CID 43617575.
Initially, the interaction between the active site and the substrate is non-covalent and transient. There are four important types of interaction that hold the substrate in a defined orientation and form an enzyme-substrate complex (ES complex): hydrogen bonds, van der Waals interactions, hydrophobic interactions and electrostatic force interactions. The charge distribution on the substrate and active site must be complementary, which means all positive and negative charges must be cancelled out. Otherwise, there will be a repulsive force pushing them apart. The active site usually contains non-polar amino acids, although sometimes polar amino acids may also occur. The binding of substrate to the binding site requires at least three contact points in order to achieve stereo-, regio-, and enantioselectivity. For example, alcohol dehydrogenase which catalyses the transfer of a hydride ion from ethanol to NAD+ interacts with the substrate methyl group, hydroxyl group and the pro-(R) hydrogen that will be abstracted during the reaction.
- Robert A (2000). Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis (PDF) (2nd ed.). Wiley-Blackwell. ISBN 9780471359296.
- Shanmugam S (2009). Enzyme Technology. I K International Publishing House. p. 48. ISBN 9789380026053.
In order to exert their function, enzymes need to assume their correct protein fold (native fold) and tertiary structure. To maintain this defined three-dimensional structure, proteins rely on various types of interactions between their amino acid residues. If these interactions are interfered with, for example by extreme pH values, high temperature or high ion concentrations, this will cause the enzyme to denature and lose its catalytic activity.
A tighter fit between an active site and the substrate molecule is believed to increase the efficiency of a reaction. If the tightness between the active site of DNA polymerase and its substrate is increased, the fidelity, which means the correct rate of DNA replication will also increase. Most enzymes have deeply buried active sites, which can be accessed by a substrate via access channels.
- Pravda L, Berka K, Svobodová Vařeková R, et al. (2014). “Anatomy of Enzyme Channels”. BMC Bioinformatics. 15 (1): 379. doi:10.1186/s12859-014-0379-x. PMC 4245731. PMID 25403510.
- Kool ET (1984). “Active site tightness and substrate fit in DNA replication”. Annual Review of Biochemistry. 71: 191–219. doi:10.1146/annurev.biochem.71.110601.135453. PMID 12045095.
There are three proposed models of how enzymes fit their specific substrate: the lock and key model, the induced fit model, and the conformational selection model. The latter two are not mutually exclusive: conformational selection can be followed by a change in the enzyme’s shape. Additionally, a protein may not wholly follow either model. Amino acids at the binding site of ubiquitin generally follow the induced fit model, whereas the rest of the protein generally adheres to conformational selection. Factors such as temperature likely influences the pathway taken during binding, with higher temperatures predicted to increase the importance of conformational selection and decrease that of induced fit.
- Csermely, Peter; Palotai, Robin; Nussinov, Ruth (2010). “Induced fit, conformational selection and independent dynamic segments: an extended view of binding events”. Trends in Biochemical Sciences. 35 (10): 539–546. arXiv:1005.0348. doi:10.1016/j.tibs.2010.04.009. ISSN 0968-0004. PMC 3018770. PMID 20541943.
- Lock and key hypothesis
- This concept was suggested by the 19th-century chemist Emil Fischer. He proposed that the active site and substrate are two stable structures that fit perfectly without any further modification, just like a key fits into a lock. If one substrate perfectly binds to its active site, the interactions between them will be strongest, resulting in high catalytic efficiency.
- As time went by, limitations of this model started to appear. For example, the competitive enzyme inhibitor methylglucoside can bind tightly to the active site of 4-alpha-glucanotransferase and perfectly fits into it. However, 4-alpha-glucanotransferase is not active on methylglucoside and no glycosyl transfer occurs. The Lock and Key hypothesis cannot explain this, as it would predict a high efficiency of methylglucoside glycosyl transfer due to its tight binding. Apart from competitive inhibition, this theory cannot explain the mechanism of action of non-competitive inhibitors either, as they do not bind to the active site but nevertheless influence catalytic activity.
- Daniel E (1995). “The Key–Lock Theory and the Induced Fit Theory”. Angewandte Chemie International Edition. 33 (2324): 2375–2378. doi:10.1002/anie.199423751.
- Induced fit hypothesis
- Daniel Koshland‘s theory of enzyme-substrate binding is that the active site and the binding portion of the substrate are not exactly complementary. The induced fit model is a development of the lock-and-key model and assumes that an active site is flexible and changes shape until the substrate is completely bound. This model is similar to a person wearing a glove: the glove changes shape to fit the hand. The enzyme initially has a conformation that attracts its substrate. Enzyme surface is flexible and only the correct catalyst can induce interaction leading to catalysis. Conformational changes may then occur as the substrate is bound. After the reaction products will move away from the enzyme and the active site returns to its initial shape. This hypothesis is supported by the observation that the entire protein domain could move several nanometers during catalysis. This movement of protein surface can create microenvironments that favour the catalysis.
- Dagmar R, Gregory A (2008). “How Enzymes Work”. Science. 320 (5882): 1428–1429. doi:10.1126/science.1159747. PMID 18556536. S2CID 43617575.
- Sullivan SM (2008). “Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection”. Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13829–13834. Bibcode:2008PNAS..10513829S. doi:10.1073/pnas.0805364105. PMC 2544539. PMID 18772387.
- Daniel Koshland‘s theory of enzyme-substrate binding is that the active site and the binding portion of the substrate are not exactly complementary. The induced fit model is a development of the lock-and-key model and assumes that an active site is flexible and changes shape until the substrate is completely bound. This model is similar to a person wearing a glove: the glove changes shape to fit the hand. The enzyme initially has a conformation that attracts its substrate. Enzyme surface is flexible and only the correct catalyst can induce interaction leading to catalysis. Conformational changes may then occur as the substrate is bound. After the reaction products will move away from the enzyme and the active site returns to its initial shape. This hypothesis is supported by the observation that the entire protein domain could move several nanometers during catalysis. This movement of protein surface can create microenvironments that favour the catalysis.
- Conformational selection hypothesis
- This model suggests that enzymes exist in a variety of conformations, only some of which are capable of binding to a substrate. When a substrate is bound to the protein, the equilibrium in the conformational ensemble shifts towards those able to bind ligands (as enzymes with bound substrates are removed from the equilibrium between the free conformations).
- Copeland, Robert A. (2013). “Drug–Target Residence Time”. Evaluation of Enzyme Inhibitors in Drug Discovery. John Wiley & Sons, Ltd. pp. 287–344. ISBN 978-1-118-54039-8.
- This model suggests that enzymes exist in a variety of conformations, only some of which are capable of binding to a substrate. When a substrate is bound to the protein, the equilibrium in the conformational ensemble shifts towards those able to bind ligands (as enzymes with bound substrates are removed from the equilibrium between the free conformations).
References
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
- Reversed-phase liquid chromatographic separation of juvenile hormone and its metabolites, and its application for an in vivo juvenile hormone catabolism study in Manduca sexta. Anal. Biochem. 188, 394-397
- Grieneisen, M.L., Kieckbusch, T.D., Dorman, G., Latli, B., Prestwich, G.D., Schooley, D.A., 1995
- Characterization of the juvenile hormone epoxide hydrolase (JHEH) and juvenile hormone diol phosphotransferase (JHDPT) from Manduca sexta Malpighian tubules. Arch. Insect Biochem. Physiol. 30, 255-270
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
- Grieneisen, M.L., Kieckbusch, T.D., Dorman, G., Latli, B., Prestwich, G.D., Schooley, D.A., 1995
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890
- Halarnkar, P.P., Jackson, G.P., Straub, K.M., Schooley, D.A., 1993. Juvenile hormone catabolism in Manduca sexta – homologue selectivity of catabolism and identification of a diol-phosphate conjugate as a major end product. Experientia 49, 988-994
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Li, S., Zhang, Q.R., Xu, W.H., Schooley, D.A., 2005. The Figure shows a model from this paper of the computer generated structure. Juvenile hormone diol kinase, a calcium-binding protein with kinase activity, from the silkworm, Bombyx mori. Insect Biochem Mol. Biol. 35, 1235-1248
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Li, S., Zhang, Q.R., Xu, W.H., Schooley, D.A., 2005. Juvenile hormone diol kinase, a calcium-binding protein with kinase activity, from the silkworm, Bombyx mori. Insect Biochem Mol. Biol. 35, 1235-1248
- Maxwell, R.A., Welch, W.H., Schooley, D.A., 2002b. JH diol kinase: part I-Purification, characterization and substrate specificity of juvenile hormone selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21874–21881
- Branden, C., Tooze, J., 1999. Introduction to Protein Structure, 2nd ed. Garland Publishing, Inc., New York
- Maxwell, R.A., Welch, W.H., Horodyski, F.M., Schegg, K.M., Schooley, D.A., 2002. JH diol kinase: part II- Sequencing, cloning, and molecular modeling of juvenile hormone-selective diol kinase from Manduca sexta. J. Biol. Chem. 277, 21882–21890