343-91-9Relevant academic research and scientific papers
METHODS FOR PRODUCING D-TRYPTOPHAN AND SUBSTITUTED D-TRYPTOPHANS
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Page/Page column 17, (2021/04/01)
Single-module nonribosomal peptide synthetases (NRPSs) and NRPS-like enzymes activate and transform carboxylic acids in both primary and secondary metabolism; and are of great interest due to their biocatalytic potentials. The single-module NRPS IvoA is essential for fungal pigment biosynthesis. As disclosed herein, we show that IvoA catalyzes ATP-dependent unidirectional stereoinversion of L-tryptophan to D-tryptophan with complete conversion. While the stereoinversion is catalyzed by the epimerization (E) domain, the terminal condensation (C) domain stereoselectively hydrolyzes D-tryptophanyl-S-phosphopantetheine thioester and thus represents a noncanonical C domain function. Using IvoA, we demonstrate a biocatalytic stereoinversion/deracemization route to access a variety of substituted D-tryptophan analogs in high enantiomeric excess.
Complete Stereoinversion of l -Tryptophan by a Fungal Single-Module Nonribosomal Peptide Synthetase
Hai, Yang,Jenner, Matthew,Tang, Yi
supporting information, p. 16222 - 16226 (2019/10/14)
Single-module nonribosomal peptide synthetases (NRPSs) and NRPS-like enzymes activate and transform carboxylic acids in both primary and secondary metabolism and are of great interest due to their biocatalytic potentials. The single-module NRPS IvoA is essential for fungal pigment biosynthesis. Here, we show that IvoA catalyzes ATP-dependent unidirectional stereoinversion of l-tryptophan to d-tryptophan with complete conversion. While the stereoinversion is catalyzed by the epimerization (E) domain, the terminal condensation (C) domain stereoselectively hydrolyzes d-tryptophanyl-S-phosphopantetheine thioester and thus represents a noncanonical C domain function. Using IvoA, we demonstrate a biocatalytic stereoinversion/deracemization route to access a variety of substituted d-tryptophan analogs in high enantiomeric excess.
One-Pot Biocatalytic Synthesis of Substituted d -Tryptophans from Indoles Enabled by an Engineered Aminotransferase
Parmeggiani, Fabio,Rué Casamajo, Arnau,Walton, Curtis J. W.,Galman, James L.,Turner, Nicholas J.,Chica, Roberto A.
, p. 3482 - 3486 (2019/04/13)
d-Tryptophan and its derivatives are important precursors of a wide range of indole-containing pharmaceuticals and natural products. Here, we developed a one-pot biocatalytic process enabling the synthesis of d-tryptophans from indoles in good yields and high enantiomeric excess (91% to >99%). Our method couples the synthesis of l-tryptophans catalyzed by Salmonella enterica tryptophan synthase with a stereoinversion cascade mediated by Proteus myxofaciens l-amino acid deaminase and an aminotransferase variant that we engineered to display native-like activity toward d-tryptophan. Our process is applicable to preparative-scale synthesis of a broad range of d-tryptophan derivatives containing electron-donating or -withdrawing substituents at all benzene-ring positions on the indole group.
PCSK9 ANTAGONIST COMPOUNDS
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Page/Page column 70-72, (2020/01/12)
Disclosed are compounds of Formula I, or a salt thereof: where A, B, D, X, R1, R2 and R8 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.
Biosynthesis of violacein, structure and function of L-tryptophan oxidase VioA from chromobacterium violaceum
Füller, Janis J.,R?pke, René,Krausze, Joern,Rennhack, Kim E.,Daniel, Nils P.,Blankenfeldt, Wulf,Schulz, Stefan,Jahn, Dieter,Moser, Jürgen
, p. 20068 - 20084 (2016/11/05)
Violacein is a natural purple pigment of Chromobacterium violaceum with potential medical applications as antimicrobial, antiviral, and anticancer drugs. The initial step of violacein biosynthesis is the oxidative conversion of L-tryptophan into the corresponding α-imine catalyzed by the flavoenzyme L-tryptophan oxidase (VioA). A substrate-related (3-(1H-indol-3-yl)-2-methylpropanoic acid) and a product-related (2-(1H-indol-3-ylmethyl)prop-2-enoic acid) competitive VioA inhibitor was synthesized for subsequent kinetic and x-ray crystallographic investigations. Structures of the binary VioA?FADH2 and of the ternary VioA?FADH2 ?2-(1H-indol-3-ylmethyl)prop-2-enoic acid complex were resolved. VioA forms a "loosely associated" homodimer as indicated by small-angle x-ray scattering experiments. VioA belongs to the glutathione reductase family 2 of FAD-dependent oxidoreductases according to the structurally conserved cofactor binding domain. The substrate-binding domain of VioA is mainly responsible for the specific recognition of L-tryptophan. Other canonical amino acids were efficiently discriminated with a minor conversion of L-phenylalanine. Furthermore, 7-aza-tryptophan, 1-methyl-tryptophan, 5-methyl-tryptophan, and 5-fluoro-tryptophan were efficient substrates of VioA. The ternary product-related VioA structure indicated involvement of protein domain movement during enzyme catalysis. Extensive structure-based mutagenesis in combination with enzyme kinetics (using L-tryptophan and substrate analogs) identified Arg64 , Lys269 , and Tyr309 as key catalytic residues of VioA. An increased enzyme activity of protein variant H163A in the presence of L-phenylalanine indicated a functional role of His163 in substrate binding. The combined structural and mutational analyses lead to the detailed understanding of VioA substrate recognition. Related strategies for the in vivo synthesis of novel violacein derivatives are discussed.
Directed evolution of the tryptophan synthase β-subunit for stand-alone function recapitulates allosteric activation
Buller, Andrew R.,Brinkmann-Chen, Sabine,Romney, David K.,Herger, Michael,Murciano-Calles, Javier,Arnold, Frances H.
, p. 14599 - 14604 (2015/12/05)
Enzymes in heteromeric, allosterically regulated complexes catalyze a rich array of chemical reactions. Separating the subunits of such complexes, however, often severely attenuates their catalytic activities, because they can no longer be activated by their protein partners. We used directed evolution to explore allosteric regulation as a source of latent catalytic potential using the β-subunit of tryptophan synthase from Pyrococcus furiosus (PfTrpB). As part of its native αββα complex, TrpB efficiently produces tryptophan and tryptophan analogs; activity drops considerably when it is used as a stand-alone catalyst without the α-subunit. Kinetic, spectroscopic, and X-ray crystallographic data show that this lost activity can be recovered by mutations that reproduce the effects of complexation with the α-subunit. The engineered PfTrpB is a powerful platform for production of Trp analogs and for further directed evolution to expand substrate and reaction scope.
Synthesis of tryptophans by alkylation of chiral glycine enolate equivalents with quaternary gramines
Reinfelds, Matiss,Kalinins, Konstantins,Katkevica, Dace,Zemribo, Ronalds,Katkevics, Martins
, p. 5882 - 5885 (2015/11/02)
Quaternary gramines were found to be a suitable source of the 3-methylindole fragment for diastereoselective alkylation. The best yields and stereoselectivity were obtained for the alkylation of a chiral William's morpholinone enolate. Based on this transformation, a general method for the synthesis of enantiopure, indole ring substituted tryptophan derivatives was developed with good overall yields.
Regioselective enzymatic halogenation of substituted tryptophan derivatives using the FAD-dependent halogenase RebH
Frese, Marcel,Guzowska, Paulina H.,Voss, Hauke,Sewald, Norbert
, p. 1270 - 1276 (2014/05/20)
Regioselective methods to establish carbon-halide bonds are still rare, although halogenation is considered as a commonly used methodology for the functionalization of organic compounds. The incorporation of halogen substituents by organic synthesis usually requires hazardous conditions, shows poor regioselectivity and results in the formation of unwanted byproducts. In addition, halogenation by electrophilic aromatic substitution (SEAr) obeys distinct rules depending on electron-withdrawing or -donating groups already present in the aromatic ring. We employed the tryptophan-7-halogenase RebH for regioselective enzymatic halogenation to overcome these limitations. In combination with a tryptophan synthase, an array of C5- and C6-substituted tryptophan derivatives was synthesized and halogenated by RebH. The halogenase is able override these directing effects and halogenates at the electronically unfavored C7-meta-position, even in presence of ortho/para-directing groups. No business as usual: The tryptophan halogenase RebH from Lechevalieria aerocolonigenes is able to halogenate at the electronically unfavored C7-meta-position of C5-substituted tryptophan derivatives, even in presence of deactivating ortho/para-directing groups.
Synthesis of tripeptides containing d-Trp substituted at the indole ring, assessment of opioid receptor binding and in vivo central antinociception
De Marco, Rossella,Bedini, Andrea,Spampinato, Santi,Gentilucci, Luca
, p. 6861 - 6866 (2014/10/15)
The noncationizable tripeptide Ac-d-Trp-Phe-GlyNH2 was recently proposed as a novel minimal recognition motif for μ-opioid receptor. The introduction of different substituents (methyl, halogens, nitro, etc.) at the indole of d-Trp significantly influenced receptor affinities and resulted in serum stability and in a measurable effect on central antinociception in mice after ip administration.
An expression system for the efficient incorporation of an expanded set of tryptophan analogues
Petrovic, Dejan M.,Leenhouts, Kees,Van Roosmalen, Maarten L.,Broos, Jaap
, p. 1329 - 1336 (2013/06/27)
Biosynthetic incorporation of tryptophan (Trp) analogues in recombinant proteins using an E. coli Trp auxotroph expression host is limited to analogues modified with a small substituent like a fluoro atom or a hydroxyl or amine group. We report here the e
