[{"@context":"http:\/\/schema.org\/","@type":"BlogPosting","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/tryptophan-synthase-wikipedia\/#BlogPosting","mainEntityOfPage":"https:\/\/wiki.edu.vn\/en\/wiki24\/tryptophan-synthase-wikipedia\/","headline":"Tryptophan synthase – Wikipedia","name":"Tryptophan synthase – Wikipedia","description":"before-content-x4 From Wikipedia, the free encyclopedia after-content-x4 Tryptophan synthase or tryptophan synthetase is an enzyme (EC 4.2.1.20) that catalyses the","datePublished":"2019-09-24","dateModified":"2019-09-24","author":{"@type":"Person","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/#Person","name":"lordneo","url":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/","image":{"@type":"ImageObject","@id":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","height":96,"width":96}},"publisher":{"@type":"Organization","name":"Enzyklop\u00e4die","logo":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":600,"height":60}},"image":{"@type":"ImageObject","@id":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/6\/63\/Tryptophan_Synthase_Mechanism_5.gif\/220px-Tryptophan_Synthase_Mechanism_5.gif","url":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/6\/63\/Tryptophan_Synthase_Mechanism_5.gif\/220px-Tryptophan_Synthase_Mechanism_5.gif","height":"361","width":"220"},"url":"https:\/\/wiki.edu.vn\/en\/wiki24\/tryptophan-synthase-wikipedia\/","about":["Wiki"],"wordCount":6371,"articleBody":"     (adsbygoogle = window.adsbygoogle || []).push({});before-content-x4From Wikipedia, the free encyclopedia       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Tryptophan synthase or tryptophan synthetase is an enzyme (EC 4.2.1.20) that catalyses the final two steps in the biosynthesis of tryptophan.[1][2] It is commonly found in Eubacteria,[3]Archaebacteria,[4]Protista,[5]Fungi,[6] and Plantae.[7] However, it is absent from Animalia.[8] It is typically found as an \u03b12\u03b22 tetramer.[9][10] The \u03b1 subunits catalyze the reversible formation of indole and glyceraldehyde-3-phosphate (G3P) from indole-3-glycerol phosphate (IGP). The \u03b2 subunits catalyze the irreversible condensation of indole and serine to form tryptophan in a pyridoxal phosphate (PLP) dependent reaction. Each \u03b1 active site is connected to a \u03b2 active site by a 25 angstrom long hydrophobic channel contained within the enzyme. This facilitates the diffusion of indole formed at \u03b1 active sites directly to \u03b2 active sites in a process known as substrate channeling.[11] The active sites of tryptophan synthase are allosterically coupled.[12]       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Table of ContentsEnzyme structure[edit]Enzyme mechanism[edit]Biological function[edit]Substrate scope[edit]Disease relevance[edit]Evolution[edit]Historical significance[edit]See also[edit]References[edit]Enzyme structure[edit]Subunits: Tryptophan synthase typically exists as an \u03b1-\u03b2\u03b2-\u03b1 complex. The \u03b1 and \u03b2 subunits have molecular masses of 27 and 43 kDa respectively. The \u03b1 subunit has a TIM barrel conformation. The \u03b2 subunit has a fold type II conformation and a binding site adjacent to the active site for monovalent cations.[13] Their assembly into a complex leads to structural changes in both subunits resulting in reciprocal activation. There are two main mechanisms for intersubunit communication. First, the COMM domain of the \u03b2-subunit and the \u03b1-loop2 of the \u03b1-subunit interact. Additionally, there are interactions between the \u03b1Gly181 and \u03b2Ser178 residues.[14] The active sites are regulated allosterically and undergo transitions between open, inactive, and closed, active, states.[12]Indole-3-glycerol binding site: See image 1.Indole and serine binding site: See image 1.       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Hydrophobic channel: The \u03b1 and \u03b2 active sites are separated by a 25 angstrom long hydrophobic channel contained within the enzyme allowing for the diffusion of indole. If the channel did not exist, the indole formed at an \u03b1 active site would quickly diffuse away and be lost to the cell as it is hydrophobic and can easily cross membranes. As such, the channel is essential for enzyme complex function.[15]  Image 2: Proposed mechanism of tryptophan synthaseEnzyme mechanism[edit]\u03b1 subunit reaction: The \u03b1 subunit catalyzes the formation of indole and G3P from a retro-aldol cleavage of IGP. The \u03b1Glu49 and \u03b1Asp60 are thought to be directly involved in the catalysis as shown.[11] The rate limiting step is the isomerization of IGP.[16] See image 2.\u03b2 subunit reaction: The \u03b2 subunit catalyzes the \u03b2-replacement reaction in which indole and serine condense to form tryptophan in a PLP dependent reaction. The \u03b2Lys87, \u03b2Glu109, and \u03b2Ser377 are thought to be directly involved in the catalysis as shown.[11] Again, the exact mechanism has not been conclusively determined. See image 2.Net reaction: See image 3.  Image 3: Reaction catalyzed by tryptophan synthase  Image 1: Active sites for \u03b1 and \u03b2 subunits showing hypothesized catalytic residuesBiological function[edit]Tryptophan synthase is commonly found in Eubacteria, Archaebacteria, Protista, Fungi, and Plantae. It is absent from animals such as humans. Tryptophan is one of the twenty standard amino acids and one of nine essential amino acids for humans. As such, tryptophan is a necessary component of the human diet.Substrate scope[edit]Tryptophan synthetase is also known to accept indole analogues, e.g., fluorinated or methylated indoles, as substrates, generating the corresponding tryptophan analogues.[17]Disease relevance[edit]As humans do not have tryptophan synthase, this enzyme has been explored as a potential drug target.[18] However, it is thought that bacteria have alternate mechanisms to produce amino acids which might make this approach less effective. In either case, even if the drug only weakens bacteria, it might still be useful as the bacteria are already vulnerable in the hostile host environment. As such, the inhibition of tryptophan synthase along with other PLP-enzymes in amino acid metabolism has the potential to help solve medical problems.[19]Inhibition of tryptophan synthase and other PLP-enzymes in amino acid metabolism has been suggested for:Evolution[edit]It is thought that early in evolution the trpB2 gene was duplicated. One copy entered the trp operon as trpB2i allowing for its expression with trpA. TrpB2i formed transient complexes with TrpA and in the process activated TrpA unidirectionally. The other copy remained outside as trpB2o, and fulfilled an existing role or played a new one such as acting as a salvage protein for indole. TrpB2i evolved into TrpB1, which formed permanent complexes with trpA resulting in bidirectional activation. The advantage of the indole salvage protein declined and the TrpB gene was lost. Finally, the TrpB1 and TrpA genes were fused resulting in the formation the bifunctional enzyme.[22]Historical significance[edit]Tryptophan synthase was the first enzyme identified that had two catalytic capabilities that were extensively studied. It was also the first identified to utilize substrate channeling. As such, this enzyme has been studied extensively and is the subject of great interest.[11]See also[edit]References[edit]^ Dunn MF, Niks D, Ngo H, Barends TR, Schlichting I (June 2008). “Tryptophan synthase: the workings of a channeling nanomachine”. Trends in Biochemical Sciences. 33 (6): 254\u201364. doi:10.1016\/j.tibs.2008.04.008. PMID\u00a018486479.^ Miles EW (1991). “Structural basis for catalysis by tryptophan synthase”. Advances in Enzymology and Related Areas of Molecular Biology. Advances in Enzymology and Related Areas of Molecular Biology. Vol.\u00a064. pp.\u00a093\u2013172. doi:10.1002\/9780470123102.ch3. ISBN\u00a09780470123102. PMID\u00a02053470.^ Jablonski P, Jablonski L, Pintado O, Sriranganathan N, Howde C (September 1996). “Tryptophan synthase: Identification of Pasteurella multocida tryptophan synthase B-subunit by antisera against strain PI059”. Microbiology. 142: 115\u201321. doi:10.1099\/13500872-142-1-115. PMID\u00a08581158.^ Lazcano A, Diaz-Villgomez E, Mills T, Oro J (March 1995). “On the levels of enzymatic substrate specificity: Implications for the early evolution of metabolic pathways”. Advances in Space Research. 15 (3): 345\u201356. doi:10.1016\/S0273-1177(99)80106-9. PMID\u00a011539248.^ Anderson I, Watkins R, Samuelson J, Spencer D, Majoros W, Grey M, Loftus B (August 2005). “Gene Discovery in the Acanthamoeba castellanii Genome”. Protist. 156 (2): 203\u201314. doi:10.1016\/j.protis.2005.04.001. PMID\u00a016171187.^ Ireland C, Peekhaus N, Lu P, Sangari R, Zhang A, Masurekar P, An Z (April 2008). “The tryptophan synthetase gene TRP1 of Nodulisporium sp.: molecular characterization and its relation to nodulisporic acid A production”. Appl Microbiol Biotechnol. 79 (3): 451\u20139. doi:10.1007\/s00253-008-1440-3. PMID\u00a018389234. S2CID\u00a07230896.^ Sanjaya, Hsiao PY, Su RC, Ko SS, Tong CG, Yang RY, Chan MT (April 2008). “Overexpression of Arabidopsis thaliana tryptophan synthase beta 1 (AtTSB1) in Arabidopsis and tomato confers tolerance to cadmium stress”. Plant Cell Environ. 31 (8): 1074\u201385. doi:10.1111\/j.1365-3040.2008.01819.x. PMID\u00a018419734.{{cite journal}}:  CS1 maint: multiple names: authors list (link)^ Eckert SC, Kubler E, Hoffmann B, Braus GH (June 2000). “The tryptophan synthase-encoding trpB gene of Aspergillus nidulans is regulated by the cross-pathway control system”. Mol Gen Genet. 263 (5): 867\u201376. doi:10.1007\/s004380000250. PMID\u00a010905354. S2CID\u00a022836208.^ Ahmed SA, Miles EW, Davies DR (March 1985). “Crystallization and preliminary X-ray crystallographic data of the tryptophan synthase alpha 2 beta 2 complex from Salmonella typhimurium”. The Journal of Biological Chemistry. 260 (6): 3716\u20133718. doi:10.1016\/s0021-9258(19)83682-7. PMID\u00a03882715.^ Hyde CC, Ahmed SA, Padlan EA, Miles EW, Davies DR (November 1988). “Three-dimensional structure of the tryptophan synthase alpha 2 beta 2 multienzyme complex from Salmonella typhimurium”. The Journal of Biological Chemistry. 263 (33): 17857\u201317871. doi:10.1016\/s0021-9258(19)77913-7. PMID\u00a03053720.^ a b c d Raboni S, Bettati S, Mozzarelli A (April 2009). “Tryptophan synthase: a mine for enzymologists”. Cell Mol Life Sci. 66 (14): 2391\u2013403. doi:10.1007\/s00018-009-0028-0. hdl:11381\/2293687. PMID\u00a019387555. S2CID\u00a030220030.^ a b Fatmi MQ, Ai R, Chang CA (September 2009). “Synergistic regulation and ligand-induced conformational changes of tryptophan synthase”. Biochemistry. 48 (41): 9921\u201331. doi:10.1021\/bi901358j. PMID\u00a019764814.^ Grishin NV, Phillips MA, Goldsmith EJ (July 1995). “Modeling of the spatial structure of ornithine decarboxylases”. Protein Sci. 4 (7): 1291\u2013304. doi:10.1002\/pro.5560040705. PMC\u00a02143167. PMID\u00a07670372.^ Schneider TR, Gerhardt E, Lee M, Liang PH, Anderson KS, Schlichting I (April 1998). “Loop closure and intersubunit communication in tryptophan synthase”. Biochemistry. 37 (16): 5394\u2013406. doi:10.1021\/bi9728957. PMID\u00a09548921.^ Huang X, Holden HM, Raushel FM (2001). “Channeling of Substrates and Intermediates in Enzyme-Catalyzes Reactions”. Annu Rev Biochem. 70: 149\u201380. doi:10.1146\/annurev.biochem.70.1.149. PMID\u00a011395405.^ Anderson KS, Miles EW, Johnson KA (May 1991). “Serine modulates substrate channeling in tryptophan synthase. A novel intersubunit triggering mechanism”. J Biol Chem. 266 (13): 8020\u201333. doi:10.1016\/S0021-9258(18)92934-0. PMID\u00a01902468.^ Wilcox M (June 1974). “The enzymatic synthesis of L-tryptophan analogues”. Analytical Biochemistry. 59 (2): 436\u2013440. doi:10.1016\/0003-2697(74)90296-6. PMID\u00a04600987.^ a b c Chaudhary K, Roos DS (September 2005). “Protozoan genomics for drug discovery”. Nat Biotechnol. 23 (9): 1089\u201391. doi:10.1038\/nbt0905-1089. PMC\u00a07096809. PMID\u00a016151400.^ Becker D, Selbach M, Rollenhagen C, Ballmaier M, Meyer TF, Mann M, Bumann D (March 2006). “Robust Salmonella metabolism limits possibilities for new antimicrobials”. Nature. 440 (7082): 303\u20137. doi:10.1038\/nature04616. PMID\u00a016541065. S2CID\u00a04426157.^ Caldwell HD, Wood H, Crane D, Baily R (June 2003). “Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates”. J Clin Invest. 111 (11): 1757\u201369. doi:10.1172\/JCI17993. PMC\u00a0156111. PMID\u00a012782678.^ Kulik V, Hartmann E, Weyand M, Frey M, Gierl A, Niks D, Dunn MF, Schlichting I (September 2005). “On the structural basis of the catalytic mechanism and the regulation of the \u03b1-subunit of tryptophan synthase from Salmonella typhimurium and BXI from maize, two evolutionarily related enzymes”. J Mol Biol. 352 (3): 608\u201320. doi:10.1016\/j.jmb.2005.07.014. PMID\u00a016120446.^ Leopoldseder S, Hettwer S, Sterner R (November 2006). “Evolution of Multi-Enzyme Complexes: The Case of Tryptophan Synthase”. Biochemistry. 45 (47): 14111\u20139. doi:10.1021\/bi061684b. PMID\u00a017115706.       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