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Tetrahydrocannabinolic acid synthase

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of THC is difficult due to high costs and low yields. Therefore, the use of THCA synthase for the production of THC has been explored, as CBGA is easy to synthesize and THCA readily decarboxylates to form THC. Biosynthesis of THCA by expressing THCA synthase in organisms has been attempted in
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Shoyama Y, Tamada T, Kurihara K, Takeuchi A, Taura F, Arai S, Blaber M, Shoyama Y, Morimoto S, Kuroki R (October 2012). "Structure and function of ∆1-tetrahydrocannabinolic acid (THCA) synthase, the enzyme controlling the psychoactivity of Cannabis sativa".
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Zirpel B, Stehle F, Kayser O (September 2015). "Production of Δ9-tetrahydrocannabinolic acid from cannabigerolic acid by whole cells of Pichia (Komagataella) pastoris expressing Δ9-tetrahydrocannabinolic acid synthase from Cannabis sativa L".
339: 269:. Therefore, THCA synthase is considered to be a key enzyme controlling cannabis psychoactivity. Polymorphisms of THCA synthase result in varying levels of THC in Cannabis plants, resulting in 659:
Staginnus C, Zörntlein S, de Meijer E (July 2014). "A PCR marker linked to a THCA synthase polymorphism is a reliable tool to discriminate potentially THC-rich plants of Cannabis sativa L".
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Kojoma M, Seki H, Yoshida S, Muranaka T (June 2006). "DNA polymorphisms in the tetrahydrocannabinolic acid (THCA) synthase gene in "drug-type" and "fiber-type" Cannabis sativa L".
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Lange K, Schmid A, Julsing MK (October 2015). "Δ(9)-Tetrahydrocannabinolic acid synthase production in Pichia pastoris enables chemical synthesis of cannabinoids".
774:"The gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of Delta1-tetrahydrocannabinolic acid synthase from Cannabis sativa L" 319:
and is covalently bound to FAD. Domain II comprises five alpha helices surrounded by eight beta sheets. Enzymes that share similar amino acid sequences include the
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with neighboring amino acid main chains and side chains. The co-crystallization of THCA synthase with substrate or product has not been accomplished yet.
864:"Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes" 1384: 745:
Taura F, Morimoto S, Shoyama Y, Mechoulam R (1995). "First direct evidence for the mechanism of Δ-tetrahydrocannabinolic acid biosynthesis".
545:, the principal psychoactive component of cannabis. Further degradation by temperature, auto-oxidation, and light forms cannabinol. THC and other 905:"Identification and characterization of cannabinoids that induce cell death through mitochondrial permeability transition in Cannabis leaf cells" 472:
group by a tyrosine residue. The monoterpene moiety in CBGA is then positioned to complete cyclization into THCA. Oxidation of reduced FAD by O
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FAD cofactor (in green) is located between domain I and domain II of THCA synthase. Alpha helices are cyan and beta sheets are magenta.
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bacteria, insects, and tobacco plants with limited success. Production of THCA on a milligram scale has been demonstrated in
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is a flavoprotein that catalyzes a similar oxidative cyclization of CPGA into CBDA, the dominant cannabinoid constituent of
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The FAD moiety is the location of enzymatic activity and is covalently bound to His114 and Cys176. FAD is also bound by
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group compared to CBGA, suggesting that the carboxyl group of CBGA is necessary for the reaction to occur.
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are well-known to reduce nausea and vomiting and stimulate hunger, particularly in patients undergoing
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of cannabigerolic acid (CBGA). Similar cyclization reactions occur in monoterpene biosynthesis from
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Shoyama Y, Takeuchi A, Taura F, Tamada T, Adachi M, Kuroki R, Shoyama Y, Morimoto S (August 2005).
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Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa Y, Wada Y, Shoyama Y, Taura F (September 2004).
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Morimoto S, Tanaka Y, Sasaki K, Tanaka H, Fukamizu T, Shoyama Y, Shoyama Y, Taura F (July 2007).
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Demand is high for pharmaceutical grade THC and other cannabinoids due to interest in their
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Similar enzymes to THCA synthase catalyze the formation of other cannabinoids. For example,
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Sirikantaramas S, Taura F, Tanaka Y, Ishikawa Y, Morimoto S, Shoyama Y (September 2005).
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Taura F, Sirikantaramas S, Shoyama Y, Yoshikai K, Shoyama Y, Morimoto S (June 2007).
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Reaction mechanism of THCA synthase. Modified from Shoyama et al. J. Mol. Bio. 2012.
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Chemical structure of cannabigerolic acid (CBGA), the substrate for THCA synthase.
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FAD (in green) is covalently bound to histidine 114 and cysteine 176 (in pink).
1444: 1421: 1296: 1138: 830: 637: 408:, but are not oxidative. THCA synthase exhibits no catalytic activity against 316: 1802: 1776: 672: 387: 323: 236: 1238: 1203: 1146: 1107: 1058: 1023: 930: 921: 904: 889: 848: 799: 790: 773: 723: 680: 645: 1005: 971: 946:"Tetrahydrocannabinolic acid, a genuine substance of tetrahydrocannabinol" 880: 863: 505: 962: 945: 758: 112: 1448: 131: 1185: 1037:
Guzmán M (October 2003). "Cannabinoids: potential anticancer agents".
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Yamauchi T, Shoyama Y, Aramaki H, Azuma T, Nishioka I (July 1967).
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A hydride is transferred from CBGA to reduce FAD, concerted by
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positioned between the two domains. Domain I comprises eight
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is divided into two domains (domains I and II), with a
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increases the total mass to approximately 74 kDa. The
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CBDA undergoes a similar decarboxylation to form 206: 194: 182: 177: 154: 142: 130: 118: 106: 94: 82: 77: 65: 60: 38: 1380:4-Hydroxy-3-methylbut-2-enyl diphosphate reductase 434: 1119: 1117: 618: 616: 614: 612: 610: 1570: 1263: 292:(~500 amino acids) monomeric enzyme with the 8: 504:THCA synthase is expressed in the glandular 263:, which is produced from various strains of 1492:: Acting on X-H and Y-H to form an X-Y bond 532:mitochondrial permeability transition pores 225:Tetrahydrocannabinolic acid (THCA) synthase 1577: 1563: 1555: 1270: 1256: 1248: 419:The overall chemical reaction is: CBGA + O 174: 44: 1193: 1097: 1013: 961: 920: 879: 838: 789: 583:, but is stymied by legal regulations of 427: 598:yeast cells in two independent studies. 541:of THCA during storage or smoking forms 1852: 1385:7-Hydroxymethyl chlorophyll a reductase 606: 335: 950:Chemical & Pharmaceutical Bulletin 587:cultivation in many countries. Direct 514:. THCA synthase may contribute to the 229:Δ-tetrahydrocannabinolic acid synthase 35: 7: 1534:Tetrahydrocannabinolic acid synthase 39:Tetrahydrocannibinolic acid synthase 909:The Journal of Biological Chemistry 778:The Journal of Biological Chemistry 435:{\displaystyle \rightleftharpoons } 558:cannabidiolic acid (CBDA) synthase 458:tetrahydrocannabinolic acid (THCA) 25: 994:Cannabis and Cannabinoid Research 990:"9-Tetrahydrocannabinolic Acid A" 381:flavin adenine dinucleotide (FAD) 309:flavin adenine dinucleotide (FAD) 1855: 1544:Dichlorochromopyrrolate synthase 1168:Trost BM, Dogra K (March 2007). 819:Acta Crystallographica Section F 350: 338: 1351:(Methionine synthase) reductase 716:10.1016/j.forsciint.2005.07.005 460:, the product of THCA synthase. 704:Forensic Science International 1: 1522:(-)-bisdechlorogeodin-forming 1517:(+)-bisdechlorogeodin-forming 1231:10.1016/j.jbiotec.2015.06.425 1099:10.1016/j.febslet.2007.05.043 522:plants by producing THCA and 1363:: Acting on CH or CH2 groups 988:Moreno-Sanz G (2016-06-01). 661:Journal of Forensic Sciences 626:Journal of Molecular Biology 1539:Cannabidiolic acid synthase 868:Plant & Cell Physiology 247:(CBGA). THCA is the direct 32:Cannabidiolic acid synthase 1899: 253:tetrahydrocannabinol (THC) 29: 1733:Michaelis–Menten kinetics 1139:10.1007/s10529-015-1853-x 831:10.1107/S1744309105023365 638:10.1016/j.jmb.2012.06.030 581:potential therapeutic use 173: 43: 1625:Diffusion-limited enzyme 1499:Isopenicillin N synthase 1431:Nitrogenase (flavodoxin) 1375:Ribonucleotide reductase 1219:Journal of Biotechnology 673:10.1111/1556-4029.12448 324:berberine bridge enzyme 1039:Nature Reviews. Cancer 922:10.1074/jbc.M700133200 791:10.1074/jbc.M403693200 496: 461: 456:Chemical structure of 436: 372: 301:N-linked glycosylation 288:THCA synthase is a 60 1718:Eadie–Hofstee diagram 1651:Allosteric regulation 1127:Biotechnology Letters 1006:10.1089/can.2016.0008 494: 455: 437: 406:geranyl pyrophosphate 370: 1883:Tetrahydrocannabinol 1728:Lineweaver–Burk plot 1420:: Acting on reduced 1399:iron–sulfur proteins 1306:Superoxide dismutase 478:hydrogen peroxide (H 426: 1529:Aureusidin synthase 1504:Columbamine oxidase 963:10.1248/cpb.15.1075 759:10.1021/ja00143a024 551:cancer chemotherapy 500:Biological function 245:cannabigerolic acid 1687:Enzyme superfamily 1620:Enzyme promiscuity 1513:Sulochrin oxidase 1509:Reticuline oxidase 881:10.1093/pcp/pci166 589:chemical synthesis 497: 462: 432: 373: 363:Reaction mechanism 305:tertiary structure 298:Post-translational 1843: 1842: 1552: 1551: 1186:10.1021/ol063022k 825:(Pt 8): 799–801. 753:(38): 9766–9767. 526:, which are both 524:hydrogen peroxide 375:THCA synthase, a 294:isoelectric point 239:the formation of 222: 221: 218: 217: 137:metabolic pathway 18:THC acid synthase 16:(Redirected from 1890: 1860: 1859: 1851: 1723:Hanes–Woolf plot 1666:Enzyme activator 1661:Enzyme inhibitor 1635:Enzyme catalysis 1579: 1572: 1565: 1556: 1370:Xanthine oxidase 1272: 1265: 1258: 1249: 1243: 1242: 1214: 1208: 1207: 1197: 1165: 1159: 1158: 1121: 1112: 1111: 1101: 1077: 1071: 1070: 1034: 1028: 1027: 1017: 985: 976: 975: 965: 941: 935: 934: 924: 915:(28): 20739–51. 900: 894: 893: 883: 859: 853: 852: 842: 810: 804: 803: 793: 784:(38): 39767–74. 769: 763: 762: 747:J. Am. Chem. Soc 742: 736: 735: 699: 693: 692: 656: 650: 649: 620: 441: 439: 438: 433: 412:, which lacks a 354: 342: 255:, the principal 235:responsible for 175: 54: 48: 36: 21: 1898: 1897: 1893: 1892: 1891: 1889: 1888: 1887: 1868: 1867: 1866: 1854: 1846: 1844: 1839: 1751:Oxidoreductases 1737: 1713:Enzyme kinetics 1701: 1697:List of enzymes 1670: 1639: 1610:Catalytic triad 1588: 1583: 1553: 1548: 1484: 1435: 1412: 1389: 1355: 1327: 1287: 1280:oxidoreductases 1276: 1246: 1216: 1215: 1211: 1174:Organic Letters 1167: 1166: 1162: 1123: 1122: 1115: 1092:(16): 2929–34. 1079: 1078: 1074: 1051:10.1038/nrc1188 1036: 1035: 1031: 987: 986: 979: 943: 942: 938: 902: 901: 897: 861: 860: 856: 812: 811: 807: 771: 770: 766: 744: 743: 739: 710:(2–3): 132–40. 701: 700: 696: 658: 657: 653: 622: 621: 608: 604: 595:Pichia pastoris 577: 539:decarboxylation 511:Cannabis sativa 502: 485: 481: 475: 449: 445: 424: 423: 422: 365: 358: 355: 346: 343: 286: 266:Cannabis sativa 56: 50: 34: 28: 23: 22: 15: 12: 11: 5: 1896: 1894: 1886: 1885: 1880: 1870: 1869: 1865: 1864: 1841: 1840: 1838: 1837: 1824: 1811: 1798: 1785: 1772: 1759: 1745: 1743: 1739: 1738: 1736: 1735: 1730: 1725: 1720: 1715: 1709: 1707: 1703: 1702: 1700: 1699: 1694: 1689: 1684: 1678: 1676: 1675:Classification 1672: 1671: 1669: 1668: 1663: 1658: 1653: 1647: 1645: 1641: 1640: 1638: 1637: 1632: 1627: 1622: 1617: 1612: 1607: 1602: 1596: 1594: 1590: 1589: 1584: 1582: 1581: 1574: 1567: 1559: 1550: 1549: 1547: 1546: 1541: 1536: 1531: 1526: 1525: 1524: 1519: 1511: 1506: 1501: 1495: 1493: 1486: 1485: 1483: 1482: 1481: 1480: 1475: 1470: 1465: 1454: 1452: 1437: 1436: 1434: 1433: 1427: 1425: 1414: 1413: 1411: 1410: 1404: 1402: 1391: 1390: 1388: 1387: 1382: 1377: 1372: 1366: 1364: 1357: 1356: 1354: 1353: 1348: 1342: 1340: 1329: 1328: 1326: 1325: 1324: 1323: 1318: 1313: 1302: 1300: 1289: 1288: 1277: 1275: 1274: 1267: 1260: 1252: 1245: 1244: 1209: 1160: 1133:(9): 1869–75. 1113: 1072: 1045:(10): 745–55. 1029: 1000:(1): 124–130. 977: 936: 895: 874:(9): 1578–82. 854: 805: 764: 737: 694: 651: 605: 603: 600: 576: 573: 537:Non-enzymatic 501: 498: 483: 479: 473: 447: 443: 431: 420: 364: 361: 360: 359: 356: 349: 347: 344: 337: 331:hydrogen bonds 285: 282: 220: 219: 216: 215: 210: 204: 203: 198: 192: 191: 186: 180: 179: 171: 170: 159: 152: 151: 146: 140: 139: 134: 128: 127: 122: 116: 115: 110: 104: 103: 98: 92: 91: 86: 80: 79: 75: 74: 69: 63: 62: 58: 57: 49: 41: 40: 26: 24: 14: 13: 10: 9: 6: 4: 3: 2: 1895: 1884: 1881: 1879: 1876: 1875: 1873: 1863: 1858: 1853: 1849: 1835: 1831: 1830: 1825: 1822: 1818: 1817: 1812: 1809: 1805: 1804: 1799: 1796: 1792: 1791: 1786: 1783: 1779: 1778: 1773: 1770: 1766: 1765: 1760: 1757: 1753: 1752: 1747: 1746: 1744: 1740: 1734: 1731: 1729: 1726: 1724: 1721: 1719: 1716: 1714: 1711: 1710: 1708: 1704: 1698: 1695: 1693: 1692:Enzyme family 1690: 1688: 1685: 1683: 1680: 1679: 1677: 1673: 1667: 1664: 1662: 1659: 1657: 1656:Cooperativity 1654: 1652: 1649: 1648: 1646: 1642: 1636: 1633: 1631: 1628: 1626: 1623: 1621: 1618: 1616: 1615:Oxyanion hole 1613: 1611: 1608: 1606: 1603: 1601: 1598: 1597: 1595: 1591: 1587: 1580: 1575: 1573: 1568: 1566: 1561: 1560: 1557: 1545: 1542: 1540: 1537: 1535: 1532: 1530: 1527: 1523: 1520: 1518: 1515: 1514: 1512: 1510: 1507: 1505: 1502: 1500: 1497: 1496: 1494: 1491: 1487: 1479: 1476: 1474: 1471: 1469: 1466: 1464: 1461: 1460: 1459: 1456: 1455: 1453: 1450: 1446: 1442: 1438: 1432: 1429: 1428: 1426: 1423: 1419: 1415: 1409: 1406: 1405: 1403: 1400: 1396: 1392: 1386: 1383: 1381: 1378: 1376: 1373: 1371: 1368: 1367: 1365: 1362: 1358: 1352: 1349: 1347: 1346:Ceruloplasmin 1344: 1343: 1341: 1338: 1334: 1330: 1322: 1319: 1317: 1314: 1312: 1309: 1308: 1307: 1304: 1303: 1301: 1298: 1294: 1290: 1285: 1281: 1273: 1268: 1266: 1261: 1259: 1254: 1253: 1250: 1240: 1236: 1232: 1228: 1224: 1220: 1213: 1210: 1205: 1201: 1196: 1191: 1187: 1183: 1179: 1175: 1171: 1164: 1161: 1156: 1152: 1148: 1144: 1140: 1136: 1132: 1128: 1120: 1118: 1114: 1109: 1105: 1100: 1095: 1091: 1087: 1083: 1076: 1073: 1068: 1064: 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272: 268: 267: 262: 259:component of 258: 254: 250: 246: 242: 238: 234: 230: 226: 214: 211: 209: 205: 202: 199: 197: 193: 190: 187: 185: 181: 176: 172: 169: 166: 163: 160: 157: 153: 150: 147: 145: 141: 138: 135: 133: 129: 126: 123: 121: 117: 114: 113:NiceZyme view 111: 109: 105: 102: 99: 97: 93: 90: 87: 85: 81: 76: 73: 70: 68: 64: 59: 53: 47: 42: 37: 33: 19: 1829:Translocases 1826: 1813: 1800: 1787: 1774: 1764:Transferases 1761: 1748: 1605:Binding site 1533: 1458:Glutaredoxin 1443:: Acting on 1397:: Acting on 1335:: Oxidizing 1295:: Acting on 1222: 1218: 1212: 1180:(5): 861–3. 1177: 1173: 1163: 1130: 1126: 1089: 1086:FEBS Letters 1085: 1075: 1042: 1038: 1032: 997: 993: 953: 949: 939: 912: 908: 898: 871: 867: 857: 822: 818: 808: 781: 777: 767: 750: 746: 740: 707: 703: 697: 664: 660: 654: 629: 625: 593: 584: 578: 575:Significance 563: 555: 547:cannabinoids 536: 519: 516:self-defense 509: 503: 463: 418: 410:cannabigerol 377:flavoprotein 374: 328: 287: 277: 275:"fiber-type" 264: 257:psychoactive 228: 224: 223: 101:BRENDA entry 1600:Active site 1408:Nitrogenase 1299:as acceptor 569:cannabidiol 562:fiber-type 399:monoterpene 395:cyclization 280:varieties. 271:"drug-type" 227:(full name 89:IntEnz view 61:Identifiers 1872:Categories 1803:Isomerases 1777:Hydrolases 1644:Regulation 1445:phosphorus 1422:flavodoxin 1297:superoxide 1286:1.15–1.21) 602:References 317:beta sheet 315:and eight 237:catalyzing 158:structures 125:KEGG entry 30:See also: 1878:EC 1.21.3 1682:EC number 1451:in donors 1401:as donors 1225:: 68–76. 585:C. sativa 564:C. sativa 528:cytotoxic 506:trichomes 476:produces 430:⇌ 392:oxidative 379:, uses a 284:Structure 278:C. sativa 249:precursor 78:Databases 1706:Kinetics 1630:Cofactor 1593:Activity 1424:as donor 1239:26197418 1204:17266321 1155:16544089 1147:25994576 1108:17544411 1059:14570037 1024:28861488 931:17513301 890:16024552 849:16511162 800:15190053 732:38866142 724:16143478 689:29683549 681:24579739 646:22766313 520:Cannabis 470:hydroxyl 442:THCA + H 414:carboxyl 388:catalyze 384:cofactor 296:at 6.4. 261:cannabis 231:) is an 213:proteins 201:articles 189:articles 162:RCSB PDB 72:1.21.3.7 1862:Biology 1816:Ligases 1586:Enzymes 1449:arsenic 1195:2597621 1067:7868655 1015:5549534 972:5583149 840:1952348 397:of the 149:profile 132:MetaCyc 55:​ 1848:Portal 1790:Lyases 1278:Other 1237:  1202:  1192:  1153:  1145:  1106:  1065:  1057:  1022:  1012:  970:  929:  888:  847:  837:  798:  730:  722:  687:  679:  644:  402:moiety 233:enzyme 196:PubMed 178:Search 168:PDBsum 108:ExPASy 96:BRENDA 84:IntEnz 67:EC no. 27:Enzyme 1742:Types 1478:GLRX5 1473:GLRX3 1468:GLRX2 1337:metal 1151:S2CID 1063:S2CID 728:S2CID 685:S2CID 468:of a 243:from 144:PRIAM 1834:list 1827:EC7 1821:list 1814:EC6 1808:list 1801:EC5 1795:list 1788:EC4 1782:list 1775:EC3 1769:list 1762:EC2 1756:list 1749:EC1 1490:1.21 1463:GLRX 1441:1.20 1418:1.19 1395:1.18 1361:1.17 1339:ions 1333:1.16 1321:SOD3 1316:SOD2 1311:SOD1 1293:1.15 1235:PMID 1200:PMID 1143:PMID 1104:PMID 1055:PMID 1020:PMID 968:PMID 927:PMID 886:PMID 845:PMID 796:PMID 720:PMID 677:PMID 642:PMID 390:the 273:and 241:THCA 208:NCBI 165:PDBe 120:KEGG 52:3VTE 1447:or 1227:doi 1223:211 1190:PMC 1182:doi 1135:doi 1094:doi 1090:581 1047:doi 1010:PMC 1002:doi 958:doi 917:doi 913:282 876:doi 835:PMC 827:doi 786:doi 782:279 755:doi 751:117 712:doi 708:159 669:doi 634:doi 630:423 543:THC 518:of 508:of 386:to 290:kDa 251:of 184:PMC 156:PDB 1874:: 1284:EC 1233:. 1221:. 1198:. 1188:. 1176:. 1172:. 1149:. 1141:. 1131:37 1129:. 1116:^ 1102:. 1088:. 1084:. 1061:. 1053:. 1041:. 1018:. 1008:. 996:. 992:. 980:^ 966:. 954:15 952:. 948:. 925:. 911:. 907:. 884:. 872:46 870:. 866:. 843:. 833:. 823:61 821:. 817:. 794:. 780:. 776:. 749:. 726:. 718:. 706:. 683:. 675:. 665:59 663:. 640:. 628:. 609:^ 571:. 553:. 488:. 1850:: 1836:) 1832:( 1823:) 1819:( 1810:) 1806:( 1797:) 1793:( 1784:) 1780:( 1771:) 1767:( 1758:) 1754:( 1578:e 1571:t 1564:v 1282:( 1271:e 1264:t 1257:v 1241:. 1229:: 1206:. 1184:: 1178:9 1157:. 1137:: 1110:. 1096:: 1069:. 1049:: 1043:3 1026:. 1004:: 998:1 974:. 960:: 933:. 919:: 892:. 878:: 851:. 829:: 802:. 788:: 761:. 757:: 734:. 714:: 691:. 671:: 648:. 636:: 486:) 484:2 482:O 480:2 474:2 448:2 446:O 444:2 421:2 20:)

Index

THC acid synthase
Cannabidiolic acid synthase

3VTE
EC no.
1.21.3.7
IntEnz
IntEnz view
BRENDA
BRENDA entry
ExPASy
NiceZyme view
KEGG
KEGG entry
MetaCyc
metabolic pathway
PRIAM
profile
PDB
RCSB PDB
PDBe
PDBsum
PMC
articles
PubMed
articles
NCBI
proteins
enzyme
catalyzing

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