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User:AutumnSands/L-tryptophan Decarboxylase

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L-tryptophan Decarboxylase (EC 4.1.1.105) is an enzyme distinguished by the substrate L-tryptophan, which is important for the synthesis of serotonin in the brain.[1][2]

This enzyme catalyzes the reaction of L-tryptophan to tryptamine and carbon dioxide.[1][3] The enzymatic reaction namely takes place in the species Psilocybe cubensis, where a decarboxylase, kinase, and methyltransferase work together to synthesize psilocybin.[4][5]

Crystal structure prediction for L-tryptophan decarboxylase courtesy of Alphafold Data and DeepMind Technologies 2022.[6][7][8]

Classification

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The enzyme commission number for L-tryptophan decarboxylase is EC 4.1.1.105.[1] Other common names include psilocybin biosynthesis decarboxylase and psiD.[3] The first digit in the enzyme number is representative of the class of enzymes known as lyases, which catalyze elimination reactions.[1][3] The second and third digits are representative of the subclass of lyases known as decarboxylases that cleave carbon-carbon bonds.[1][3] The last digit is representative of the enzyme’s specific substrate L-tryptophan.[1]

This enzyme is a part of the PLP-independent phosphatidylserine decarboxylase family and most compared to hypothetical proteins of other basidiomycetes fungi.[4] These include Fibulorhizoctonia sp with 60% identical amino acids and Moniliophthora roreri with 52% identical amino acids.[4] A similar enzyme that is not related to L-tryptophan decarboxylase is called aromatic-L-amino-acid decarboxylase with an enzyme number of EC 4.1.1.28.[1]

Reaction pathway

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The first step in the reaction is the substrate binding of L-tryptophan which reacts with a coenzyme hydrogen.[9] The decarboxylase enzyme is able to transform L-tryptophan to tryptamine in the second step by cleaving off two oxygens and a carbon to form tryptamine and CO2 as the products.[1] Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, which makes the molecule polar, while tryptamines have an indole ring structure, a fused double ring consisting of a pyrrole ring, and a benzene ring, which is joined to an amino group by two carbon side chains.[10]

This is the chemical reaction that takes place:

H+ + C11H12N2O2 = CO2 + C10H13N2

Organisms in which L-tryptophan Decarboxylase is found

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L-tryptophan decarboxylase has been characterized in bacteria, plants, and fungi.[1] Fungi that produce psilocybin and psilocin express incredible diversity as they are a part of at least eight genera with hundreds of species belonging to them.[11] The specific reaction pathway for L-tryptophan decarboxylase has been described in twelve species, including Psilocybe cubensis, commonly known as magic mushrooms.[1] All fungi in the genus Psilocybe have a well-defined, umbrella-like cap with gills underneath and a stipe.[11] Other main characteristics of Psilocybe species include purple-brown reproductive spores, the presence of an annulus, and blue bruising with contact.[11] All Psilocybe species are described to feed on microscopic detritus and are found on a variety of surfaces, such as herbivore dung, grasses, roots, wood, and soil.[11] Humans have a documented history of ingesting this psilocybin producing fungi.[11] There are 57 species that are found in Mexico and out of these there have been reports of 35 species and nine varieties being used by ethnic groups.[11]

Function

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In Psilocybe cubensis, L-tryptophan decarboxylase has been described with two other enzymes to biosynthesize psilocybin in a one pot reaction.[4][5] These other two enzymes in this process are psiK, an enzyme that catalyzes the phosphotransfer step, and psiM, an enzyme that catalyzes the iterative N-methyl transfer step.[4] The biosynthesis of psilocybin takes place as follows:

L-tryptophan is decarboxylated to 4-hydroxytryptamine by psiD → psiK phosphorylates 4-hydroxytryptamine to create norbaeocystin → psiM then processively N,N-dimethylates the compound to yield psilocybin.[4]

Serotonin 2A receptors (5-HT2ARs) stimulation by the active metabolite, psilocin, disrupts serotonergic neurotransmission and produces the characteristic psychedelic effects of this species of fungus.[12] The product formed by L-tryptophan decarboxylase, tryptamine, is relevant to humans because the mammalian brain contains very low concentrations of tryptamine; and serotonin is a tryptamine natural derivative involved in regulating central nervous system processes like sleep, cognition, memory, temperature regulation and behavior.[10] In contrast, the naturally occurring derivatives of tryptamine are found in magic mushrooms (Psilocybe cubensis).[10]

Structure

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L-tryptophan Decarboxylase is 439 amino acid residues long in its native form and a calculated pI 5.3.[4] The crystal structure of L-tryptophan decarboxylase has been modeled and predicted by Alphafold with an average confidence of 91.17% and SWISS-model with an average confidence of 25.37% as an oligo-state monomer, but the crystal structure remains to be described.[6][13]

Active sites

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4-Hydroxy-L-tryptophan is accepted as a substrate by the enzyme in addition to L-tryptophan.[4][5] This subsequent pathway is suggested to yield 4-Hydroxytryptamine instead of tryptamine.[4] Both of these compounds can be used in the biosynthesis of psilocybin.[4] The enzyme is distinct from other fungal and plant aromatic amino acid decarboxylases because it belongs to a class that L-tryptophan has not previously been described as a substrate for.[4] Currently the active sites for L-tryptophan decarboxylase remain to be described.

Evolution

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Due to the multi-step process of psilocybin biosynthesis and its restricted phylogenetic distribution, the pathway involving L-tryptophan Decarboxylase has been suggested to evolve via horizontal gene cluster transfer.[14][15] The phylogenies of the genes involved in psilocybin biosynthesis (including L-tryptophan Decarboxylase) suggests that the process first evolved in wood-decaying fungi, and then evolved in dung-decaying fungi through vertical and horizontal gene transfer due to shared environmental pressures.[14][15] Neurological effects from psilocybin in wood and dung decaying fungi posit that psilocybin could be an ecological modulator acting on insect behavior.[14] This would advantage the fungi by disrupting and inhibiting the behavior of competitors, such as termites and fruit fly larvae, for wood and dung resources.[14][16] Invertebrate competitors that would be especially impacted by this are social insects, where neurotransmitter mimics would disrupt coordination.[17]

References

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  1. ^ a b c d e f g h i j "Information on EC 4.1.1.105 - L-tryptophan decarboxylase - BRENDA Enzyme Database". www.brenda-enzymes.org. Retrieved 2022-10-20.
  2. ^ Richard, Dawn M; Dawes, Michael A; Mathias, Charles W; Acheson, Ashley; Hill-Kapturczak, Nathalie; Dougherty, Donald M (2009-03-23). "L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications". International Journal of Tryptophan Research : IJTR. 2: 45–60. ISSN 1178-6469. PMC 2908021. PMID 20651948.
  3. ^ a b c d "UniProt". www.uniprot.org. Retrieved 2022-10-21.
  4. ^ a b c d e f g h i j k Fricke, Janis; Blei, Felix; Hoffmeister, Dirk (2017-09-25). "Enzymatic Synthesis of Psilocybin". Angewandte Chemie International Edition. 56 (40): 12352–12355. doi:10.1002/anie.201705489.
  5. ^ a b c Blei, Felix; Baldeweg, Florian; Fricke, Janis; Hoffmeister, Dirk (2018-07-17). "Biocatalytic Production of Psilocybin and Derivatives in Tryptophan Synthase‐Enhanced Reactions". Chemistry – A European Journal. 24 (40): 10028–10031. doi:10.1002/chem.201801047. ISSN 0947-6539.
  6. ^ a b "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2022-10-21.
  7. ^ Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Žídek, Augustin; Potapenko, Anna; Bridgland, Alex; Meyer, Clemens; Kohl, Simon A. A.; Ballard, Andrew J.; Cowie, Andrew (July 15, 2021). "Highly accurate protein structure prediction with AlphaFold". Nature. 596 (7873): 583–589. doi:10.1038/s41586-021-03819-2. ISSN 1476-4687.
  8. ^ "AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models". academic.oup.com. doi:10.1093/nar/gkab1061. PMC 8728224. PMID 34791371. Retrieved 2022-10-21.{{cite web}}: CS1 maint: PMC format (link)
  9. ^ "Rhea- Annotated reactions database". www.rhea-db.org. Retrieved 2022-10-22.
  10. ^ a b c Tittarelli, Roberta; Mannocchi, Giulio; Pantano, Flaminia; Romolo, Francesco Saverio (January 2015). "Recreational Use, Analysis and Toxicity of Tryptamines". Current Neuropharmacology. 13 (1): 26–46. doi:10.2174/1570159X13666141210222409. ISSN 1570-159X. PMC 4462041. PMID 26074742.
  11. ^ a b c d e f Van Court, R. C.; Wiseman, M. S.; Meyer, K. W.; Ballhorn, D. J.; Amses, K. R.; Slot, J. C.; Dentinger, B. T. M.; Garibay-Orijel, R.; Uehling, J. K. (2022-04-01). "Diversity, biology, and history of psilocybin-containing fungi: Suggestions for research and technological development". Fungal Biology. 126 (4): 308–319. doi:10.1016/j.funbio.2022.01.003. ISSN 1878-6146.
  12. ^ Madsen, Martin K.; Fisher, Patrick M.; Burmester, Daniel; Dyssegaard, Agnete; Stenbæk, Dea S.; Kristiansen, Sara; Johansen, Sys S.; Lehel, Sczabolz; Linnet, Kristian; Svarer, Claus; Erritzoe, David; Ozenne, Brice; Knudsen, Gitte M. (June 2019). "Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels". Neuropsychopharmacology. 44 (7): 1328–1334. doi:10.1038/s41386-019-0324-9. ISSN 1740-634X.
  13. ^ "P0DPA6 | SWISS-MODEL Repository". swissmodel.expasy.org. Retrieved 2022-10-21.
  14. ^ a b c d Reynolds, Hannah T.; Vijayakumar, Vinod; Gluck-Thaler, Emile; Korotkin, Hailee Brynn; Matheny, Patrick Brandon; Slot, Jason C. (April 2018). "Horizontal gene cluster transfer increased hallucinogenic mushroom diversity". Evolution Letters. 2 (2): 88–101. doi:10.1002/evl3.42. PMC 6121855. PMID 30283667.{{cite journal}}: CS1 maint: PMC format (link)
  15. ^ a b Awan, Ali R.; Winter, Jaclyn M.; Turner, Daniel; Shaw, William M.; Suz, Laura M.; Bradshaw, Alexander J.; Ellis, Tom; Dentinger, Bryn T. M. (2018-07-27). "Convergent evolution of psilocybin biosynthesis by psychedelic mushrooms": 374199. doi:10.1101/374199v2.full. {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ Hunt, Toby; Bergsten, Johannes; Levkanicova, Zuzana; Papadopoulou, Anna; John, Oliver St.; Wild, Ruth; Hammond, Peter M.; Ahrens, Dirk; Balke, Michael; Caterino, Michael S.; Gómez-Zurita, Jesús; Ribera, Ignacio; Barraclough, Timothy G.; Bocakova, Milada; Bocak, Ladislav (2007-12-21). "A Comprehensive Phylogeny of Beetles Reveals the Evolutionary Origins of a Superradiation". Science. 318 (5858): 1913–1916. doi:10.1126/science.1146954. ISSN 0036-8075.
  17. ^ Genise, Jorge Fernando (2017), Genise, Jorge Fernando (ed.), "The Trace Fossil Record of Eusociality in Ants and Termites", Ichnoentomology: Insect Traces in Soils and Paleosols, Cham: Springer International Publishing, pp. 285–312, doi:10.1007/978-3-319-28210-7_12, ISBN 978-3-319-28210-7, retrieved 2022-10-21
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