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  Allosteric regulation of substrate channeling in tryptophan synthase: modulation of the L-serine reaction in stage I of the beta-reaction by alpha-site ligands

Ngo, H., Kimmich, N., Harris, R., Niks, D., Blumenstein, L., Kulik, V., et al. (2007). Allosteric regulation of substrate channeling in tryptophan synthase: modulation of the L-serine reaction in stage I of the beta-reaction by alpha-site ligands. Biochemistry, 46(26), 7740-7753. doi:10.1021/bi7003872.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-496B-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-4971-8
Genre: Journal Article
Alternative Title : Allosteric regulation of substrate channeling in tryptophan synthase:  modulation of the l-serine reaction in stage I of the β-reaction by α-Site ligands

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 Creators:
Ngo, Huu, Author
Kimmich, Novelle, Author
Harris, Rodney, Author
Niks, Dimitri, Author
Blumenstein, Lars1, Author              
Kulik, Victor1, Author              
Barends, Thomas1, Author              
Schlichting, Ilme1, Author              
Dunn, Michael F., Author
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1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: In the tryptophan synthase bienzyme complex, indole produced by substrate cleavage at the alpha-site is channeled to the beta-site via a 25 A long tunnel. Within the beta-site, indole and l-Ser react with pyridoxal 5'-phosphate in a two-stage reaction to give l-Trp. In stage I, l-Ser forms an external aldimine, E(Aex1), which converts to the alpha-aminoacrylate aldimine, E(A-A). Formation of E(A-A) at the beta-site activates the alpha-site >30-fold. In stage II, indole reacts with E(A-A) to give l-Trp. The binding of alpha-site ligands (ASLs) exerts strong allosteric effects on the reaction of substrates at the beta-site: the distribution of intermediates formed in stage I is shifted in favor of E(A-A), and the binding of ASLs triggers a conformational change in the beta-site to a state with an increased affinity for l-Ser. Here, we compare the behavior of new ASLs as allosteric effectors of stage I with the behavior of the natural product, d-glyceraldehyde 3-phosphate. Rapid kinetics and kinetic isotope effects show these ASLs bind with affinities ranging from micro- to millimolar, and the rate-determining step for conversion of E(Aex1) to E(A-A) is increased by 8-10-fold. To derive a structure-based mechanism for stage I, X-ray structures of both the E(Aex1) and E(A-A) states complexed with the different ASLs were determined and compared with structures of the ASL complexes with the internal aldimine.

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Language(s): eng - English
 Dates: 2007-04-172007-02-252007-06-092007-06-092007-07-03
 Publication Status: Published in print
 Pages: 14
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 Rev. Type: Peer
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Title: Biochemistry
Source Genre: Journal
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Publ. Info: Columbus, Ohio : American Chemical Society
Pages: - Volume / Issue: 46 (26) Sequence Number: - Start / End Page: 7740 - 7753 Identifier: ISSN: 0006-2960
CoNE: https://pure.mpg.de/cone/journals/resource/954925384103