|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
- tryptamine + secologanin 3-alpha(S)-strictosidine + H2O
Thus, the two substrates of this enzyme are tryptamine and secologanin, whereas its two products are 3-alpha(S)-strictosidine and H2O. Since the condensation of tryptamine and secologanin is the first committed step in alkaloid synthesis, strictosidine synthase plays a fundamental role for the great majority of the indole-alkaloid pathways.
This enzyme belongs to the family of lyases, specifically amine lyases, which cleave carbon-nitrogen bonds. It can be isolated from several alkaloid-producing plants from the Apocynaceae family (e.g. Catharanthus roseus, Voacanga africana).  The systematic name of this enzyme class is 3-alpha(S)-strictosidine tryptamine-lyase (secologanin-forming). Other names in common use include strictosidine synthetase, STR, and 3-alpha(S)-strictosidine tryptamine-lyase. Originally isolated from the plant Rauvolfia serpentina, a medicinal plant widely used in Indian folk medicine, this enzyme participates in terpenoid biosynthesis and indole and ipecac alkaloid biosynthesis, both of which produce many compounds with significant physiological and medicinal properties.
Mechanism of catalysis
According to structural studies of strictosidine synthase from Rauvolfia serpentina, tryptamine is located at the bottom of the pocket, where Glu 309 forms a hydrogen bond with the substrate’s primary amine group. The residues Phe 226 and Tyr 151, which lie parallel to the tryptamine’s indole ring, further stabilize its binding by fixing tryptamine in a sandwich structure through pi-bond interactions.
Upon substrate binding, secologanin's position is located at the pocket’s entrance, where the positively-charged residues His 307 and His 277 bind with secologanin's glucose moiety. A Schiff base forms between secologanin's aldehyde-group and tryptamine’s amine group, from which Glu309 deprotonates tryptamine’s carbon 2. This allows for strictosidine’s formation under the subsequent ring closure via electrophilic substitution, as shown in the image to the right. 
Strictosidine synthase facilitates 3-alpha(S)-strictosidine formation by acting as a scaffold to increase local concentrations of tryptamine, secologanin, and acid catalysts. Its binding pocket also properly orients the iminium intermediate during cyclization to disastereoselectively produce its alkaloid products. Unlike the mechanisms behind the formation of several Pictet-Spengler compounds, a spiroindolenine intermediate containing a five-membered ring does not form during strictosidine synthesis. Theoretical calculations indicated that a direct interconversion from the iminium to a six-membered ring is several orders of magnitude faster than the spiroindolenine.
Strictosidine synthase’s overall structure consists of a 6-bladed beta propeller fold arranged in a six-fold pseudo-symmetry axis, with each propeller blade containing four-beta strands that form a twisted, anti-parallel beta-sheet. Three alpha helices are also present within the enzyme structure, with the alpha 3-helix shaping the hydrophobic binding pocket at the top of the propeller and forming a cap for the active site. The main amino acid residues forming the active site are Tyr 105, Trp 149, Val 167, Met 180, Val 208, Phe 226, Ser 269, Met 276, His 277, His 307, Phe 308, Glu 309, Leu 323, and Phe 324.
As stated in the introduction, strictosidine synthase catalyzes the biological Pictet–Spengler reaction of tryptamine and secologanin to stereoselectively form 3-alpha(S)-strictosidine, the universal precursor for monoterpenoid indole alkloid compounds. It also catalyses the formation of 12-aza-strictosidine, an important intermediate for cytotoxic alkaloids, from coupling secologanin with 7-aza-tryptamine.  The enzyme is encoded by a single-copy gene, which is subject to coordinate regulation from plant hormones involved in controlling primary and secondary plant metabolism. The encoding gene is rapidly down-regulated by auxin, an essential promoter in cell division, leading to lower levels of alkaloid accumulation.  Conversely, the gene is upregulated by jasmonate, a plant stress hormone, through the activation of a 42 base-pair region in the str promoter.  Several studies of the Catharanthus roseus strictosidine synthase indicate that the enzyme plays a regulatory role in sustaining high rates of alkaloid biosynthesis. However, high activities of the enzyme are not enough to increase alkaloid production by itself.  No additional cofactors are needed for strictosidine synthase to achieve optimal activity, although early studies of the enzyme derived from Apocynaceae plants identified p-chloromercuribenzoate as a potent inhibitor. 
Many indole alkaloids formed from strictosidine synthase-catalyzed condensation are important precursors to medicinally important compounds such as quinine, the antineoplastic drug camptothecin, and anticancer drugs vincristine and vinblastine.  Because of this, strictosidine synthase is widely known as the enzyme of choice for investigations towards chemoenzymatic alkaloid synthesis. One such investigation found (21S)-12-aza-nacycline, a 12-aza-strictosidine derivative, to exhibit potent cytotoxicity to the A549 cancer cell line.  However, the enzyme possesses a high degree of substrate specificity, with the indole moiety of tryptamine required for substrate recognition.  Recent mutant studies, however, have suggested that strictosidine synthase can be easily manipulated to have a broader range of substrate specificity. For instance, mutation of valine-208 to alanine allows strictosidine synthase to generate 5-methyl and 5-methoxystrictosidines from its tryptamine analogs while retaining chirality. Also, binding with various secologanin analogs with the same stereoselectivity as that of 3-alpha(S)-strictosidine can be achieved through the mutation of aspartate-177 to alanine, permitting the synthesis of a wider range of possible alkaloid compounds for further drug discovery investigations.
- Stöckigt J, Antonchick AP, Wu F, Waldmann H (September 2011). "The Pictet-Spengler reaction in nature and in organic chemistry". Angew. Chem. Int. Ed. Engl. 50 (37): 8538–64. doi:10.1002/anie.201008071. PMID 21830283.
- Treimer JF, Zenk MH (November 1979). "Purification and properties of strictosidine synthase, the key enzyme in indole alkaloid formation". Eur. J. Biochem. 101 (1): 225–33. doi:10.1111/j.1432-1033.1979.tb04235.x. PMID 510306.
- Stöckigt J, Barleben L, Panjikar S, Loris EA (March 2008). "3D-Structure and function of strictosidine synthase--the key enzyme of monoterpenoid indole alkaloid biosynthesis". Plant Physiol. Biochem. 46 (3): 340–55. doi:10.1016/j.plaphy.2007.12.011. PMID 18280746.
- Maresh JJ, Giddings LA, Friedrich A, Loris EA, Panjikar S, Trout BL, Stöckigt J, Peters B, O'Connor SE (January 2008). "Strictosidine synthase: mechanism of a Pictet-Spengler catalyzing enzyme". J. Am. Chem. Soc. 130 (2): 710–23. doi:10.1021/ja077190z. PMC 3079323. PMID 18081287.
- Zou, H. B.; Zhu, H. J.; Zhang, L.; Yang, L. Q.; Yu, Y. P.; Stöckigt, J. (2010). "A Facile Chemoenzymatic Approach: One-Step Syntheses of Monoterpenoid Indole Alkaloids". Chemistry - an Asian Journal 5 (11): 2400. doi:10.1002/asia.201000520.
- Pasquali, G.; Goddijn, O. J. M.; Waal, A.; Verpoorte, R.; Schilperoort, R. A.; Hoge, J. H. C.; Memelink, J. (1992). "Coordinated regulation of two indole alkaloid biosynthetic genes from Catharanthus roseus by auxin and elicitors". Plant Molecular Biology 18 (6): 1121–1131. doi:10.1007/BF00047715. PMID 1600148.
- Whitmer, S.; Verpoorte, R.; Canel, C. (1998). Plant Cell, Tissue and Organ Culture 53 (2): 135. doi:10.1023/A:1006019620897.
- Menke, F. L. H.; Champion, A.; Kijne, J. W.; Memelink, J. (1999). "A novel jasmonate- and elicitor-responsive element in the periwinkle secondary metabolite biosynthetic gene Str interacts with a jasmonate- and elicitor-inducible AP2-domain transcription factor, ORCA2". The EMBO Journal 18 (16): 4455–4463. doi:10.1093/emboj/18.16.4455. PMC 1171520. PMID 10449411.
- Canel, C.; Lopes-Cardoso, M. I. #X. 0. E. ;S.; Whitmer, S.; Van Der Fits, L.; Pasquali, G.; Van Der Heijden, R.; Hoge, J. H. C.; Verpoorte, R. (1998). "Effects of over-expression of strictosidine synthase and tryptophan decarboxylase on alkaloid production by cell cultures of Catharanthus roseus". Planta 205 (3): 414–419. doi:10.1007/s004250050338. PMID 9640666.
- Kutchan, T. M. (1995). "Alkaloid Biosynthesis-The Basis for Metabolic Engineering of Medicinal Plants". The Plant Cell Online 7 (7): 1059–1070. doi:10.1105/tpc.7.7.1059. PMC 160910. PMID 12242397.
- Loris, E. A.; Panjikar, S.; Ruppert, M.; Barleben, L.; Unger, M.; Schübel, H.; Stöckigt, J. (2007). "Structure-Based Engineering of Strictosidine Synthase: Auxiliary for Alkaloid Libraries". Chemistry & Biology 14 (9): 979. doi:10.1016/j.chembiol.2007.08.009.
- Chen, S.; Galan, M. C.; Coltharp, C.; O'Connor, S. E. (2006). "Redesign of a Central Enzyme in Alkaloid Biosynthesis". Chemistry & Biology 13 (11): 1137. doi:10.1016/j.chembiol.2006.10.009.
- Kutchan TM (1993). "Strictosidine: from alkaloid to enzyme to gene". Phytochemistry. 32 (3): 493–506. doi:10.1016/S0031-9422(00)95128-8. PMID 7763429.
- de Waal A, Meijer AH, Verpoorte R (Pt 2). "Strictosidine synthase from Catharanthus roseus: purification and characterization of multiple forms". Biochem. J. 306: 571–80. PMC 1136556. PMID 7887913.
- Ruppert M, Woll J, Giritch A, Genady E, Ma X, Stockigt J (2005). "Functional expression of an ajmaline pathway-specific esterase from Rauvolfia in a novel plant-virus expression system". Planta. 222 (5): 888–898. doi:10.1007/s00425-005-0031-0. PMID 16133216.
- McCoy E, Galan MC, O'Connor SE (2006). "Substrate specificity of strictosidine synthase". Bioorg. Med. Chem. Lett. 16 (9): 2475–2478. doi:10.1016/j.bmcl.2006.01.098. PMID 16481164.
- Ma X, Panjikar S, Koepke J, Loris E, Stockigt J (2006). "The structure of Rauvolfia serpentina strictosidine synthase is a novel six-bladed beta-propeller fold in plant proteins". Plant. Cell. 18 (4): 907–920. doi:10.1105/tpc.105.038018. PMC 1425862. PMID 16531499.