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Isopentenyl-diphosphate delta isomerase
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<h2 id="enzyme-mechanism">Enzyme mechanism</h2> <p>IPP isomerase catalyzes the isomerization of IPP to DMAPP by an <a href="/facts/Antarafacial_and_suprafacial/4CGzyIwl">antarafacial</a> transposition of <a href="/facts/Hydrogen/BoYHjl0J">hydrogen</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> The empirical evidence suggests that this reaction proceeds by a <a href="/facts/Protonation/q5Gf9z0M">protonation</a>/<a href="/facts/Deprotonation/SmUSh369">deprotonation</a> mechanism, with the addition of a <a href="/facts/Proton/clCjepXP">proton</a> to the <a href="/facts/Cahn%E2%80%93Ingold%E2%80%93Prelog_priority_rules/nkVS9xAq"><i>re</i>-face</a> of the inactivated C3-C4 <a href="/facts/Double_bond/qDemMn0c">double bond</a> resulting in a transient <a href="/facts/Carbocation/vIggUxTh">carbocation</a> <a href="/facts/Reaction_intermediate/BjD9HAHt">intermediate</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP. </p> <h2 id="enzyme-structure">Enzyme structure</h2> <p><a href="/facts/Crystallography/9B5toeqG">Crystallographic</a> studies have observed that the active form of IPP isomerase is a <a href="/facts/Monomer/Gw3CltMb">monomer</a> with alternating <a href="/facts/Alpha_helix/7CESPIYJ">α-helices</a> and <a href="/facts/Beta_sheet/B6mwwR6H">β-sheets</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> The <a href="/facts/Active_site/u9ua7rGu">active site</a> of IPP isomerase is deeply buried within the <a href="/facts/Enzyme/DSI1Fh7y">enzyme</a> and consists of a <a href="/facts/Glutamic_acid/7oXbNcvu">glutamic acid</a> residue and a <a href="/facts/Cysteine/kbqvUm6d">cysteine</a> residue that interact with opposite sides of the IPP <a href="/facts/Substrate_(biochemistry)/6MnaV19h">substrate</a>, consistent with the antarafacial <a href="/facts/Stereochemistry/XkcRVNwd">stereochemistry</a> of isomerization.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> The origin of the initial protonation step has not been conclusively established. Recent evidence suggests that the glutamic acid residue is involved in the protonating step despite the observation that its <a href="/facts/Carboxylic_acid/U4xuMosy">carboxylic acid</a> <a href="/facts/Side_chain/Lw8KPAXn">side-chain</a> is stabilized in its <a href="/facts/Carboxylate/vEDekXRr">carboxylate</a> form.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> This discrepancy has been addressed by the discovery of a <a href="/facts/Water/0lkXnJPK">water</a> molecule in the active site of human IPP isomerase, suggesting a mechanism where the glutamine residue <a href="/facts/Intermolecular_force/xIcFMvL7">polarizes</a> the double bond of IPP and makes it more susceptible to protonation by water.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>IPP isomerase also requires a <a href="/facts/Divalent/ck7cHByj">divalent</a> <a href="/facts/Cation/wrbwhF3z">cation</a> to fold into its active conformation. The enzyme contains several <a href="/facts/Amino_acid/WDxYwBny">amino acids</a>, including the catalytic glutamate, that are involved in <a href="/facts/Dipolar_bond/t7NPflnQ">coordinating</a> with <a href="/facts/Magnesium/XyIhd2FG">Mg2+</a> or <a href="/facts/Manganese/j9ELd1TL">Mn2+</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> The coordination of the metal cation to the glutamate residue stabilizes the carbiocation intermediate after protonation. </p> <h3>Structural studies</h3> <p>As of late 2007, 25 <a href="/facts/Tertiary_structure/VaN6MEYh">structures</a> have been solved for this class of enzymes, with <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> accession codes <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1HX3">1HX3</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1HZT">1HZT</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1I9A">1I9A</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1NFS">1NFS</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1NFZ">1NFZ</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1OW2">1OW2</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1P0K">1P0K</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1P0N">1P0N</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1PPV">1PPV</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1PPW">1PPW</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1PVF">1PVF</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1Q54">1Q54</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1R67">1R67</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1VCF">1VCF</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1VCG">1VCG</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1X83">1X83</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1X84">1X84</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2B2K">2B2K</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2DHO">2DHO</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2G73">2G73</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2G74">2G74</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2I6K">2I6K</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2ICJ">2ICJ</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2ICK">2ICK</a>, and <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2PNY">2PNY</a>. </p> <h2 id="biological-function">Biological function</h2> <p>The protonation of an inactivated double bond is rarely seen in nature, highlighting the unique catalytic mechanism of IPP isomerase. The isomerization of IPP to DMAPP is a crucial step in the synthesis of isoprenoids and isoprenoid-derivatives, compounds that play vital roles in the biosynthetic pathways of all living organisms.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Because of the importance of the melavonate pathway in isoprenoid biosynthesis, IPP isomerase is found in a variety of different cellular compartments, including <a href="/facts/Plastid/INesmXK7">plastids</a> and <a href="/facts/Mammal/phSwTzBo">mammalian</a> <a href="/facts/Mitochondria/ErHqrdJ1">mitochondria</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h2 id="disease-relevance">Disease relevance</h2> <p><a href="/facts/Mutation/Ee4NnWbY">Mutations</a> in <i>IDI1</i>, the <a href="/facts/Gene/e1swwPY6">gene</a> that codes for IPP isomerase 1, have been implicated in decreased viability in a number of organisms, including the yeast <i><a href="/facts/Saccharomyces_cerevisiae/sX9MGFrz">Saccharomyces cerevisiae</a></i>, the nematode <i><a href="/facts/Caenorhabditis_elegans/XJVJzPn2">Caenorhabditis elegans</a></i> and the plant <i><a href="/facts/Arabidopsis_thaliana/wt2IMJsC">Arabidopsis thaliana</a></i>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> While there have been no evidence directly implicating <i>IDI1</i> mutations in human disease, <a href="/facts/Full_genome_sequencing/WNuHaU2K">genomic analysis</a> has identified a <a href="/facts/Copy-number_variation/g7GPKrsx">copy-number gain</a> near two IPP isomerase genes in a substantial proportion of patients with sporadic <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">amyotrophic lateral sclerosis</a>, suggesting that the isomerase may play a role in this disease.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=isopentenyldiphosphate+delta-isomerase">isopentenyldiphosphate+delta-isomerase</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"IDI1 - Isopentenyl-diphosphate Delta-isomerase - Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) - IDI1 gene & protein". UniProt. Retrieved 6 June 2016. <a href="https://www.uniprot.org/uniprot/P15496" target="_blank">https://www.uniprot.org/uniprot/P15496</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Kaneda K, Kuzuyama T, Takagi M, Hayakawa Y, Seto H (2001). "An unusual isopentenyl diphosphate isomerase found in the mevalonate pathway gene cluster from Streptomyces sp. strain CL190". Proc. Natl. Acad. Sci. U.S.A. 98 (3): 932–7. doi:10.1073/pnas.020472198. PMC 14687. PMID 11158573. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC14687" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC14687</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Bishop JM (1983). "Cellular oncogenes and retroviruses". Annu. Rev. Biochem. 52: 301–54. doi:10.1146/annurev.bi.52.070183.001505. PMID 6351725. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Agranoff BW, Eggerer H, Henning U, Lynen F (1960). "Biosynthesis of terpenes. VII. Isopentenyl pyrophosphate isomerase". J. Biol. Chem. 235 (2): 326–32. doi:10.1016/S0021-9258(18)69523-7. PMID 13792054. <a href="https://doi.org/10.1016%2FS0021-9258%2818%2969523-7" target="_blank">https://doi.org/10.1016%2FS0021-9258%2818%2969523-7</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Cornforth JW, Cornforth RH, Popják G, Yengoyan L (Sep 1966). "Studies on the biosynthesis of cholesterol. XX. Steric course of decarboxylation of 5-pyrophosphomevalonate and of the carbon to carbon bond formation in the biosynthesis of farnesyl pyrophosphate". The Journal of Biological Chemistry. 241 (17): 3970–3987. doi:10.1016/S0021-9258(18)99800-5. PMID 4288360. <a href="https://doi.org/10.1016%2FS0021-9258%2818%2999800-5" target="_blank">https://doi.org/10.1016%2FS0021-9258%2818%2999800-5</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Cornforth RH, Popják G (1969). "Chemical syntheses of substrates of sterol biosynthesis". In Raymond BC (ed.). Methods in Enzymology. Vol. 15. Academic Press. pp. 359–390. <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Reardon JE, Abeles RH (Sep 1986). "Mechanism of action of isopentenyl pyrophosphate isomerase: evidence for a carbonium ion intermediate". Biochemistry. 25 (19): 5609–5616. doi:10.1021/bi00367a040. PMID 3022798. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Street IP, Christensen DJ, Poulter CD (1990). "Hydrogen exchange during the enzyme-catalyzed isomerization of isopentenyl diphosphate and dimethylallyl diphosphate". Journal of the American Chemical Society. 112 (23): 8577–8578. doi:10.1021/ja00179a049. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Hall NR, Fish DE, Hunt N, Goldin RD, Guillou PJ, Monson JR (Jun 1992). "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical Oncology. 1 (3): 223–229. doi:10.1016/0960-7404(92)90068-v. PMID 1285217. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Zheng W, Sun F, Bartlam M, Li X, Li R, Rao Z (Mar 2007). "The crystal structure of human isopentenyl diphosphate isomerase at 1.7 A resolution reveals its catalytic mechanism in isoprenoid biosynthesis". Journal of Molecular Biology. 366 (5): 1447–1458. doi:10.1016/j.jmb.2006.12.055. PMID 17250851. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Hall NR, Fish DE, Hunt N, Goldin RD, Guillou PJ, Monson JR (Jun 1992). "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical Oncology. 1 (3): 223–229. doi:10.1016/0960-7404(92)90068-v. PMID 1285217. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Street IP, Coffman HR, Baker JA, Poulter CD (Apr 1994). "Identification of Cys139 and Glu207 as catalytically important groups in the active site of isopentenyl diphosphate:dimethylallyl diphosphate isomerase". Biochemistry. 33 (14): 4212–4217. doi:10.1021/bi00180a014. PMID 7908830. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Wouters J, Oudjama Y, Barkley SJ, Tricot C, Stalon V, Droogmans L, Poulter CD (Apr 2003). "Catalytic mechanism of Escherichia coli isopentenyl diphosphate isomerase involves Cys-67, Glu-116, and Tyr-104 as suggested by crystal structures of complexes with transition state analogues and irreversible inhibitors". The Journal of Biological Chemistry. 278 (14): 11903–11908. doi:10.1074/jbc.M212823200. PMID 12540835. <a href="https://doi.org/10.1074%2Fjbc.M212823200" target="_blank">https://doi.org/10.1074%2Fjbc.M212823200</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Zhang C, Liu L, Xu H, Wei Z, Wang Y, Lin Y, Gong W (Mar 2007). "Crystal structures of human IPP isomerase: new insights into the catalytic mechanism". Journal of Molecular Biology. 366 (5): 1437–1446. doi:10.1016/j.jmb.2006.10.092. PMID 17137593. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Hall NR, Fish DE, Hunt N, Goldin RD, Guillou PJ, Monson JR (Jun 1992). "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical Oncology. 1 (3): 223–229. doi:10.1016/0960-7404(92)90068-v. PMID 1285217. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Bonanno JB, Edo C, Eswar N, Pieper U, Romanowski MJ, Ilyin V, Gerchman SE, Kycia H, Studier FW, Sali A, Burley SK (Nov 2001). "Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 98 (23): 12896–12901. 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S2CID 1637634. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Okada K, Kasahara H, Yamaguchi S, Kawaide H, Kamiya Y, Nojiri H, Yamane H (Apr 2008). "Genetic evidence for the role of isopentenyl diphosphate isomerases in the mevalonate pathway and plant development in Arabidopsis". Plant & Cell Physiology. 49 (4): 604–616. doi:10.1093/pcp/pcn032. PMID 18303110. <a href="https://doi.org/10.1093%2Fpcp%2Fpcn032" target="_blank">https://doi.org/10.1093%2Fpcp%2Fpcn032</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Kato T, Emi M, Sato H, Arawaka S, Wada M, Kawanami T, Katagiri T, Tsuburaya K, Toyoshima I, Tanaka F, Sobue G, Matsubara K (Nov 2010). "Segmental copy-number gain within the region of isopentenyl diphosphate isomerase genes in sporadic amyotrophic lateral sclerosis". 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