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EPSP synthase
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<h2 id="nomenclature">Nomenclature</h2> <p>The enzyme belongs to the family of <a href="/facts/Transferase/ut43BDxU">transferases</a>, to be specific those transferring <a href="/facts/Aryl/M3z7QRXd">aryl</a> or <a href="/facts/Alkyl/vmEk8X4v">alkyl</a> groups other than <a href="/facts/Methyl/fkM97EMD">methyl</a> groups. The <a href="/facts/List_of_enzymes/w2RP6EwU">systematic name</a> of this enzyme class is phosphoenolpyruvate:3-phosphoshikimate 5-<i>O</i>-(1-carboxyvinyl)-transferase. Other names in common use include: </p> <ul><li>5-enolpyruvylshikimate-3-phosphate synthase,</li> <li>3-enolpyruvylshikimate 5-phosphate synthase,</li> <li>3-enolpyruvylshikimic acid-5-phosphate synthetase,</li> <li>5′-enolpyruvylshikimate-3-phosphate synthase,</li> <li>5-enolpyruvyl-3-phosphoshikimate synthase,</li> <li>5-enolpyruvylshikimate-3-phosphate synthetase,</li> <li>5-enolpyruvylshikimate-3-phosphoric acid synthase,</li> <li>enolpyruvylshikimate phosphate synthase, and</li> <li>3-phosphoshikimate 1-carboxyvinyl transferase.</li></ul> <h2 id="structure">Structure</h2> <p>EPSP synthase is a monomeric enzyme with a molecular mass of approximately 46,000.<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a><a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a><a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> It consists of two domains connected by protein strands that function as a hinge, allowing the two domains to move closer together. When a substrate binds to the enzyme, the conformational change causes the domains to clamp around the substrate at the active site. </p><p>EPSP synthase is classified into two groups based on sensitivity to glyphosate. Class I enzymes, found in plants and some bacteria, are inhibited by low micromolar concentrations of glyphosate. Class II enzymes, found in other bacteria, are resistant to glyphosate inhibition.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p> <h2 id="shikimate-pathway">Shikimate pathway</h2> <p>EPSP synthase participates in the biosynthesis of the <a href="/facts/Aromatic/wK0DzRY6">aromatic</a> amino acids <a href="/facts/Phenylalanine/eyojfW7t">phenylalanine</a>, <a href="/facts/Tyrosine/RJhEgE4C">tyrosine</a>, and <a href="/facts/Tryptophan/JcUxlxAh">tryptophan</a> via the <a href="/facts/Shikimic_acid/DldwC7tm">shikimate pathway</a> in bacteria, fungi, and plants. EPSP synthase is produced only by plants and micro-organisms; the gene coding for it is not in the mammalian <a href="/facts/Genome/31Sm08JT">genome</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> <a href="/facts/Gut_flora/Xy1IWzSP">Gut flora</a> of some animals contain EPSPS.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p> <h3>Reaction</h3> <p>EPSP synthase catalyzes the reaction which converts shikimate-3-phosphate plus phosphoenolpyruvate to 5-enolpyruvylshikimate-3-phosphate (EPSP) by way of an <a href="/facts/Acetal/DuwXfBMz">acetal</a>-like <a href="/facts/Tetrahedral_intermediate/YUtR429h">tetrahedral intermediate</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> Basic and acidic <a href="/facts/Amino_acid/WDxYwBny">amino acids</a> in the <a href="/facts/Active_site/u9ua7rGu">active site</a> are involved in <a href="/facts/Deprotonation/SmUSh369">deprotonation</a> of the <a href="/facts/Hydroxyl_group/1Hs2QAEv">hydroxyl group</a> of PEP and in the proton-exchange steps related to the tetrahedral intermediate itself, respectively.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <p>Studies of the <a href="/facts/Enzyme_kinetics/LJ0lWoMc">enzyme kinetics</a> for this reaction have determined the specific sequence and energetics of each step of the process.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> A neutrally charged <a href="/facts/Lysine/CEetgA9L">lysine</a> (lys-22) acts as a <a href="/facts/General_base/JkJ7LkT6">general base</a>, deprotonating the <a href="/facts/Hydroxyl_group/1Hs2QAEv">hydroxyl group</a> of S3P such that the resulting <a href="/facts/Oxyanion/0GuWXr6D">oxyanion</a> can attack the most <a href="/facts/Electrophilic/1AHFg1zm">electrophilic</a> carbon atom of PEP. A <a href="/facts/Glutamic_acid/7oXbNcvu">glutamic acid</a> (glu-341) acts as a general acid by donating a <a href="/facts/Hydron_(chemistry)/v5Qkumvm">proton</a>. The deprotonated glu-341 then acts as a base, taking back its proton, and the S3P group is kicked off and protonated by the protonated lysine. </p> <h2 id="herbicide-target">Herbicide target</h2> <p>EPSP synthase is the biological target for the herbicide glyphosate.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> Glyphosate is a <a href="/facts/Competitive_inhibition/AQ3PLzBe">competitive inhibitor</a> of EPSP synthase, acting as a <a href="/facts/Transition_state_analog/Vl9JeN2d">transition state analog</a> that binds more tightly to the EPSPS-S3P complex than PEP and inhibits the <a href="/facts/Shikimate_pathway/Txnk5FBP">shikimate pathway</a>. This binding leads to inhibition of the enzyme's catalysis and shuts down the pathway. Eventually this results in organism death from lack of aromatic amino acids the organism requires to survive.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>A version of the enzyme that both was resistant to glyphosate and that was still efficient enough to drive adequate plant growth was identified by <a href="/facts/Monsanto/6rVAaIXB">Monsanto</a> scientists after much trial and error in an <i><a href="/facts/Agrobacterium/eu45qB2S">Agrobacterium</a></i> strain called CP4 (<a href="https://www.uniprot.org/uniprot/Q9R4E4">Q9R4E4</a>). The strain CP4 was found surviving in a waste-fed column at a glyphosate production facility. The CP4 EPSP synthase enzyme has been engineered into several <a href="/facts/Genetically_modified_crops/vKkn4oVs">genetically modified crops</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> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Morell H, Clark MJ, Knowles PF, Sprinson DB (January 1967). <a href="https://doi.org/10.1016%2FS0021-9258%2818%2996321-0">"The enzymic synthesis of chorismic and prephenic acids from 3-enolpyruvylshikimic acid 5-phosphate"</a>. <i>The Journal of Biological Chemistry</i>. 242 (1): 82–90. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0021-9258%2818%2996321-0">10.1016/S0021-9258(18)96321-0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/4289188">4289188</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Goldsbrough P (1990). "Gene amplification in glyphosate-tolerant tobacco cells". Plant Science. 72 (1): 53–62. Bibcode:1990PlnSc..72...53G. doi:10.1016/0168-9452(90)90186-r. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Abdel-Meguid SS, Smith WW, Bild GS (December 1985). "Crystallization of 5-enolpyruvylshikimate 3-phosphate synthase from Escherichia coli". Journal of Molecular Biology. 186 (3): 673. doi:10.1016/0022-2836(85)90140-8. PMID 3912512. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Ream JE, Steinrücken HC, Porter CA, Sikorski JA (May 1988). "Purification and Properties of 5-Enolpyruvylshikimate-3-Phosphate Synthase from Dark-Grown Seedlings of Sorghum bicolor". Plant Physiology. 87 (1): 232–238. doi:10.1104/pp.87.1.232. PMC 1054731. PMID 16666109. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1054731" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1054731</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Pollegioni L, Schonbrunn E, Siehl D (August 2011). "Molecular basis of glyphosate resistance-different approaches through protein". The FEBS Journal. 278 (16): 2753–2766. doi:10.1111/j.1742-4658.2011.08214.x. PMC 3145815. PMID 21668647. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Funke T, Han H, Healy-Fried ML, Fischer M, Schönbrunn E (August 2006). "Molecular basis for the herbicide resistance of Roundup Ready crops". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13010–13015. Bibcode:2006PNAS..10313010F. doi:10.1073/pnas.0603638103. JSTOR 30050705. PMC 1559744. PMID 16916934. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1559744" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1559744</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Maeda H, Dudareva N (2012). "The shikimate pathway and aromatic amino Acid biosynthesis in plants". Annual Review of Plant Biology. 63 (1): 73–105. doi:10.1146/annurev-arplant-042811-105439. PMID 22554242. The AAA pathways consist of the shikimate pathway (the prechorismate pathway) and individual postchorismate pathways leading to Trp, Phe, and Tyr.... These pathways are found in bacteria, fungi, plants, and some protists but are absent in animals. Therefore, AAAs and some of their derivatives (vitamins) are essential nutrients in the human diet, although in animals Tyr can be synthesized from Phe by Phe hydroxylase....The absence of the AAA pathways in animals also makes these pathways attractive targets for antimicrobial agents and herbicides. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Cerdeira AL, Duke SO (2006). "The current status and environmental impacts of glyphosate-resistant crops: a review". Journal of Environmental Quality. 35 (5): 1633–1658. Bibcode:2006JEnvQ..35.1633C. doi:10.2134/jeq2005.0378. PMID 16899736. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Furdui CM, Anderson KS (2010). "8.18.4.1.1. EPSP synthase: A tetrahedral ketal phosphate enzyme intermediate". Comprehensive Natural Products II. Chemistry and Biology. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. Vol. 8. pp. 663–688. doi:10.1016/B978-008045382-8.00158-1. <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>Anderson KS, Sammons RD, Leo GC, Sikorski JA, Benesi AJ, Johnson KA (February 1990). "Observation by 13C NMR of the EPSP synthase tetrahedral intermediate bound to the enzyme active site". Biochemistry. 29 (6): 1460–1465. doi:10.1021/bi00458a017. PMID 2334707. <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>Park H, Hilsenbeck JL, Kim HJ, Shuttleworth WA, Park YH, Evans JN, et al. (February 2004). "Structural studies of Streptococcus pneumoniae EPSP synthase in unliganded state, tetrahedral intermediate-bound state and S3P-GLP-bound state". Molecular Microbiology. 51 (4): 963–971. doi:10.1046/j.1365-2958.2003.03885.x. PMID 14763973. S2CID 45549442. <a href="https://doi.org/10.1046%2Fj.1365-2958.2003.03885.x" target="_blank">https://doi.org/10.1046%2Fj.1365-2958.2003.03885.x</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Anderson KS, Sikorski JA, Johnson KA (September 1988). "A tetrahedral intermediate in the EPSP synthase reaction observed by rapid quench kinetics". Biochemistry. 27 (19): 7395–7406. doi:10.1021/bi00419a034. PMID 3061457. <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>Fonseca EC, da Costa KS, Lameira J, Alves CN, Lima AH (December 2020). "Investigation of the target-site resistance of EPSP synthase mutants P106T and T102I/P106S against glyphosate". RSC Advances. 10 (72): 44352–44360. Bibcode:2020RSCAd..1044352F. doi:10.1039/D0RA09061A. PMC 9058485. PMID 35517162. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058485" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058485</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Pollegioni L, Schonbrunn E, Siehl D (August 2011). "Molecular basis of glyphosate resistance-different approaches through protein". The FEBS Journal. 278 (16): 2753–2766. doi:10.1111/j.1742-4658.2011.08214.x. PMC 3145815. PMID 21668647. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Schönbrunn E, Eschenburg S, Shuttleworth WA, Schloss JV, Amrhein N, Evans JN, et al. (February 2001). "Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail". Proceedings of the National Academy of Sciences of the United States of America. 98 (4): 1376–1380. Bibcode:2001PNAS...98.1376S. doi:10.1073/pnas.98.4.1376. PMC 29264. PMID 11171958. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC29264" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC29264</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Pollegioni L, Schonbrunn E, Siehl D (August 2011). "Molecular basis of glyphosate resistance-different approaches through protein". The FEBS Journal. 278 (16): 2753–2766. doi:10.1111/j.1742-4658.2011.08214.x. PMC 3145815. PMID 21668647. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145815</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Green JM, Owen MD (June 2011). "Herbicide-resistant crops: utilities and limitations for herbicide-resistant weed management". Journal of Agricultural and Food Chemistry. 59 (11): 5819–5829. Bibcode:2011JAFC...59.5819G. doi:10.1021/jf101286h. PMC 3105486. PMID 20586458. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105486" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105486</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> </ol>