The shikimate pathway: gateway to metabolic diversity

Natural Product Reports, Journal Year: 2024, Volume and Issue: 41(4), P. 604 - 648

Published: Jan. 1, 2024

Covering: 1997 to 2023The shikimate pathway is the metabolic process responsible for biosynthesis of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Seven steps convert phosphoenolpyruvate (PEP) erythrose 4-phosphate (E4P) into ultimately chorismate, which serves as branch point dedicated acid biosynthesis. Bacteria, fungi, algae, plants (yet not animals) biosynthesize chorismate exploit its intermediates in their specialized metabolism. This review highlights diversity derived from along seven PEP E4P well additional sections on compounds prephenate, anthranilate synonymous aminoshikimate pathway. We discuss genomic basis biochemical support leading shikimate-derived antibiotics, lipids, pigments, cofactors, other metabolites across tree life.

Language: Английский

---

Stereoselective Chemoenzymatic Cascades for the Synthesis of Densely Functionalized Iminosugars

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

1,4-Dicarbonyls are versatile synthons for the construction of diverse pharmacophores and natural products. However, stereoselective synthesis densely functionalized 1,4-dicarbonyls is challenging. Here, we report a biocatalytic route to access chiral 2,3-dihydroxy-1,4-diketones in high yields up gram scale using d-fructose-6-phosphate aldolase (EcFSA). The utility these compounds as exemplified enzyme cascades with subsequent regio- enzymatic transamination form homochiral 1-pyrrolines followed by chemical or reduction tetrasubstituted pyrrolidines.

Language: Английский

---

Redox Out of the Box: Catalytic Versatility Across NAD(P)H‐Dependent Oxidoreductases

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 63(13)

Published: Nov. 4, 2023

The asymmetric reduction of double bonds using NAD(P)H-dependent oxidoreductases has proven to be an efficient tool for the synthesis important chiral molecules in research and on industrial scale. These enzymes are commercially available screening kits C=O (ketones), C=C (activated alkenes), or C=N (imines). Recent reports, however, indicate that ability accommodate multiple reductase activities distinct C=X occurs different enzyme classes, either natively after mutagenesis. This challenges common perception highly selective one type electrophilic substrate. Consideration this underexplored potential screenings protein engineering campaigns may contribute identification complementary biocatalytic processes compounds. review will a global understanding promiscuous behavior bond inspire future discoveries with respect unconventional routes synthesis.

Language: Английский

---

Stereoselective Synthetic Routes to Iminosugars: A Divergent Approach Utilizing a Common Multifunctional Chiral Scaffold

Synthesis, Journal Year: 2024, Volume and Issue: unknown

Published: June 26, 2024

Abstract Starting from an l-serine-derived multifunctional aminobutenolide as a common chiral building block, stereoselective synthetic routes to representative examples of di-, tri-, and tetrahydroxylated iminosugars have been developed. Key steps in the involved intramolecular aminolysis protocol form azaheterocyclic core, functionalization resident alkene moiety towards installation desired substituents at various positions piperidine ring. The strategy approach described are expected provide flexible iminosugar scaffolds structural medicinal chemical significance.

Language: Английский

---

Stereoselective Synthesis of Iminosugar‐C‐Glycosides through Addition of Organometallic Reagents to N‐tert‐Butanesulfinyl Glycosylamines: A Comprehensive Study

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 26(39)

Published: Aug. 31, 2023

Abstract A comprehensive study of the preparation and reactivity N‐tert ‐butanesulfinyl glycosylamines with simple Grignard organo lithium reagents in batch vs . continuous flow chemistry is reported. As they readily react as latent imine equivalents a variety carbon nucleophiles, these carbohydrate derivatives constitute very useful precursors for diastereoselective synthesis bioactive compounds such iminosugar‐ C ‐glycosides. hybrid protocol, involving addition benzylmagnesium chloride to (S R )‐arabinofuranosylamine substrate flow, at room temperature, combined cyclization protocol also described first time. Of note, this semi‐continuous process shortens imino‐ ‐glycoside scaffolds single workday.

Language: Английский

---

Enzyme‐Triggered Reactions for the Synthesis of Organic Molecules

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 26(47)

Published: Oct. 19, 2023

Abstract The application of enzymes for the synthesis valuable bioactive molecules, synthetic building blocks, fine chemicals and natural products is now well‐established. Biocatalysis has been embraced by industry preparation both bulk active pharmaceutical ingredients, where high activity selectivity can be achieved with low environmental impact. In most cases, biocatalytic transformations involve functional group interconversions , such as redox amination reactions, but do not lead to significant complexity generation in molecule. This review explores less prevalent enzyme‐triggered reactions enzymatic transformation triggers a subsequent spontaneous reaction inter/intramolecularly. examples highlighted this showcase power designing smart substrates their structurally complex three‐dimensional small molecules.

Language: Английский

---

Organic Synthesis and Catalysis Enable Facile Access to Bioactive Compounds and Drugs

ACS Central Science, Journal Year: 2024, Volume and Issue: 11(1), P. 1 - 5

Published: Dec. 16, 2024

InfoMetricsFiguresRef. ACS Central ScienceASAPArticle This publication is Open Access under the license indicated. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialDecember 16, 2024Organic Synthesis Catalysis Enable Facile to Bioactive Compounds DrugsClick copy article linkArticle link copied!Svetlana B. TsogoevaSvetlana TsogoevaMore by Svetlana Tsogoevahttps://orcid.org/0000-0003-4845-0951Kirk S. Schanze*Kirk Schanze*Email: [email protected]More Kirk Schanzehttps://orcid.org/0000-0003-3342-4080Open PDFACS ScienceCite this: Cent. Sci. 2024, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acscentsci.4c02041https://doi.org/10.1021/acscentsci.4c02041Published December 2024 Publication History Published online 16 2024editorial© American Chemical Society. licensed CC-BY 4.0 . License Summary*You are free share (copy redistribute) this in any medium or format adapt (remix, transform, build upon) material for purpose, even commercially within parameters below:Creative Commons (CC): a Creative license.Attribution (BY): Credit must be given creator.View full license*DisclaimerThis summary highlights only some of key features terms actual license. It not has no legal value. Carefully review before using these materials. underCC-BY share(copy adapt(remix, below: Attribution *DisclaimerThis creator. View Publications© SocietyThe process drug discovery development inherently complex, resource-intensive, multidisciplinary. Organic synthesis catalysis play roles transforming enabling efficient construction bioactive compounds pharmaceuticals.Total organic remains fundamental aspect chemistry, allowing generation complex natural molecules while driving development. Recent advancements field have demonstrated innovative new strategies synthesizing novel therapeutics, e.g., anti-inflammatory compounds, treatments osteoporosis, antiviral agents with enhanced efficacy. (1−6) Cutting-edge approaches include enzyme-, transition metal-, photo-, organocatalysis, which instrumental accelerating candidates. advances enzyme enabled substrate-selective chemoenzymatic methods, facilitating products pharmaceuticals regio- stereoselectivity. These recent developments demonstrate growing importance enzyme-catalyzed transformations medicinal providing green, scalable routes therapeutic compounds. (7−12) Catalytic techniques, such as significantly broadened further scope bond forming reactions. Key stereoselective metal-catalyzed additions C–H functionalizations, organo- photocatalyzed transformations, boron-centered radical reactions, all advanced synthetic applications. functional group transfer late-stage diversification, creating valuable demonstrating high impact on chemistry. (13−20)Figure 1Figure 1. Collective efforts toward facile access drugs.High Resolution ImageDownload MS PowerPoint SlideThis Collection latest that been published recently Science, selective pharmaceutically relevant products, drugs. Emphasizing impactful work total synthesis, biocatalysis, catalytic methodologies─including organocatalyzed reactions─this reflects cutting-edge research chemistry related chemistry.Total SynthesisClick section linkSection copied!The cornerstone means but also opportunity explore chemical scaffolds potential role optimization targeting variety diseases. In context, Wang, Gao, co-workers reported two phthalides, falcarinphthalides A B, from Angelica sinensis, falcarinphthalide showing potent antiosteoporotic activity inhibiting NF-κB c-Fos signaling. (1) They successfully achieved bioinspired gram-scale A, offering promising scaffold osteoporosis treatment. structural modification cannabinoid receptor type 2 (CB2R) ligands inverse agonists our understanding their managing inflammatory conditions. Frank, Grether, Carreira, teams presented structure-based design agonists, derived agonist HU-308 modifying side chain introduce phenyl group. (2) The lead compound exhibits affinity CB2R serves versatile platform fluorescent probes retain activity, stabilizing its inactive state without activating signaling pathways. Furthermore, innovations methodology, concise route salvinorin analogs kappa-opioid (KOR), were reported. Bohn, Shenvi, an elegant short asymmetric analogs, leveraging sterically confined organocatalyst cobalt-catalyzed cycloaddition focused library (3) resulting potency, selectivity, bias at surpassing properties next-generation analgesics other field, candidates scalability environmental considerations crucial large-scale generation. Along line, Kawajiri outlined scalable, manufacturing SARS-CoV-2 candidate Ensitrelvir, focusing convergent indazole, 1,2,4-triazole, 1,3,5-triazinone fragments. (4) optimized improved yield 7-fold, intermediate stability meta-cresolyl moiety, minimized direct crystallization isolation, reducing solvent reagent waste. Additionally, biomimetic approaches, macrocyclization strategies, employed products. Hong first chejuenolides A–C, based hypothetical Mannich macrocyclization, lactone-based precursor constructed via aldol–Julia–aldol (5) revealed stereochemical insights, β-oxo-δ-lactone unit easily converts C2/C18 diastereoisomers, information about stereoselectivity proposed enzymatic biosynthetic pathway. Finally, Li, Patil, structure–activity relationship exploration laterocidine, cyclic lipodepsipeptide against multidrug-resistant Gram-negative pathogens. (6) identified responsible antimicrobial action led engineered peptide efficacy, including complete inhibition polymyxin-resistant Pseudomonas aeruginosa. Together, remarkable examples illustrate continued power advancing development.Biocatalyzed ReactionsClick copied!Biocatalysis emerged highly useful approach diverse interest technology. Enzyme can serve step enhance efficiency minimizing use harsh reagents. lines, Narayan final cyclization intermediates, azaphilone linear angular tricyclic cores. (7) By utilizing flavin-dependent monooxygenase (FDMO) acyl transferase (AT) sequence, method five several unnatural derivatives single reaction vessel. Recently, Li tumor-associated glycolipid disialosyl globopentaosylceramide (DSGb5) approach. (8) Through sialylation, challenging α2,6-linked sialoside was installed, binding studies DSGb5 higher Siglec-7 than oligosaccharide highlighting ceramide enhancing multivalent interactions recognition. encapsulation metal frameworks directed evolution variants biocatalysis constructing intricate chiral cancer therapeutics. Yuan, Zhang, Cheng, green strategy encapsulating enzymes azolate (MAFs) micelles, like BCL larger molecules. (9) optimizing pore sizes surfactants, BCL@MAF-6-SDS catalyst showed 420 times ZIF-8, achieving 94–99% enantioselectivity near-quantitative yields synthesis. Biocatalytic platforms N-heterocycles underscore study, Arnold biocatalytic N-heterocycles, specifically pyrrolidines indolines, intramolecular C(sp3)–H amination azides. (10) applying cytochrome P411 variants, they developed capable selectively inserting alkyl nitrenes into bonds, enantioselective important building blocks new-to-nature molecule construction.Enzymes leveraged cascades produce scaffolds. Flitsch protecting-group-free cascade iminosugars, steps over 70% product yield. (11) galactose oxidase promiscuous bacterial shikimate dehydrogenases, offers one-pot producing polar iminosugar scaffolds, pharmaceutical targets. Another synthesize cepafungin I analogues, aiming better understand proteasome inhibitors treatment potential, Adibekian, Renata, co-workers. (12) 13 analogues chemoproteomic studies, found more product, one analogue exhibiting 7-fold greater β5 subunit, multiple myeloma mantle cell lymphoma compared clinical bortezomib. enzyme-based methods biologically active applications.Transition Metal-, Photo-, Organocatalyzed copied!Catalytic plays pivotal modern efficient, selective, sustainable molecular architectures. catalysis, opened avenues formation, previously inert groups expanding Zhang 1,4-syn-addition 1,3-dienes hybrid palladium broad substrate tolerance mild (13) enables molecules, TRPV6 inhibitor CFTR modulator, radical-polar crossover mechanism (dr > 20:1). Lu introduced Cu/Cr system functionalization bonds converting them nucleophilic alkyl–Cr(III) species room temperature. (14) facilitates carbonyl addition reactions 1,1-difunctionalization aldehydes conditions, aryl alcohols notable radicals. Wang unveiled generating radicals tetraarylborate salts simple activation reagent. (15) formation C–B, C–C, C–X visible light, broadening applications boron transformations. Similarly, advent Pd-catalyzed glycosylation provided pathways C-glycosides. Yu, Lei, C-glycosides coupling native carboxylic acids glycals, external directing groups. (16) approach, applied different substrates, SGLT-2 antidiabetic manifesting utility diversification. breakthrough involves transformation methyl Hartwig terpenoids functionalization, substitution, elimination, integration skeleton through C–C cleavage. (17) expands groups, architectures relevance Hu nickel-catalyzed enantio- diastereoselective fluorinated vicinal stereogenic centers, need (18) enantioenriched organofluorine difluorides. Dai skeletal recasting editing pyrroles, pyrroles fully substituted phosphoric acid-promoted reaction. (19) tetrasubstituted N–N axial chirality, anticancer Sutent, heterocycles. Qi, three-component synergistic photoredox Brønsted acid α-amino (20) reaction, involving addition, ring-opening, radical–radical coupling, supported mechanistic quantum calculations.Overall, transformative smoothly aligns overarching covers range topics across sciences, focus high-impact, multidisciplinary connects various fields. set articles provides outstanding leading biology Science past three years. between progress bio- evident, making papers excellent fit Science. editors journal enthusiastic represent interdisciplinary sciences allied fields, authors working areas encouraged submit manuscripts journal.In closing, we hope you enjoy reading special covering exemplify dynamic tools structures precision contributing discovery, broader chemistry.Author InformationClick copied!Corresponding AuthorKirk Schanze, Department Chemistry, University Texas San Antonio, https://orcid.org/0000-0003-3342-4080, Email: protected]AuthorSvetlana Tsogoeva, Chemistry Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, https://orcid.org/0000-0003-4845-0951NotesViews expressed editorial those necessarily views ACS.ReferencesClick copied! references 20 publications. 1Zou, J.; Qiu, Z. C.; Q. Q.; Wu, J. M.; Y. H.; Shi, K. D.; F.; He, R. R.; Qin, L.; Yao, X. Discovery Potent Antiosteoporotic Drug Molecular Scaffold Derived sinensis Its Bioinspired Total Synthesis. 10 (3), 628– 636, DOI: 10.1021/acscentsci.3c01414 Google ScholarThere corresponding record reference.2Kosar, Sarott, Sykes, D. A.; Viray, A. E. G.; Vitale, Tomasevic, N.; X.; Ganzoni, L. Z.; Kicin, B.; Reichert, Flipping GPCR Switch: Structure-Based Development Selective Cannabinoid Receptor Inverse Agonists. (5), 956– 968, 10.1021/acscentsci.3c01461 reference.3Hill, Dao, Dang, V. Stahl, Route Potent, Selective, Biased Salvinorin Space. 2023, 9 (8), 1567– 1574, 10.1021/acscentsci.3c00616 reference.4Kawajiri, T.; Kijima, Iimuro, Ohashi, E.; Yamakawa, K.; Agura, Masuda, Kouki, Kasamatsu, Yanagisawa, Manufacturing Process Convergent COVID-19 Antiviral Ensitrelvir. (4), 836– 843, 10.1021/acscentsci.2c01203 reference.5Zhang, Zheng, Hong, Biomimetic Chejuenolides A-C Cryptic Lactone-Based Macrocyclization: Stereochemical Implications Biosynthesis. (1), 84– 92, 10.1021/acscentsci.2c01096 reference.6Thombare, Swarbrick, Azad, M. Zhu, Y.; Lu, H. Wickremasinghe, Bandiatmakur, Exploring Structure-Activity Relationships Modes Action Laterocidine. (9), 1703– 1717, 10.1021/acscentsci.4c00776 reference.7Wang, Torma, Pyser, Zimmerman, P. Narayan, Substrate-Selective Enabled Azaphilone Natural Products. 708– 716, 10.1021/acscentsci.3c01405 reference.8Liu, Yan, Luo, S.; Xu, Ma, W.; Wen, T. Stereoconvergent Chemoenzymatic Tumor-Associated Glycolipid Disialosyl Globopentaosylceramide Probing Binding Affinity Siglec-7. (2), 417– 425, 10.1021/acscentsci.3c01170 reference.9Ren, W. Guo, Peng, Hu, G. Highly Enantioselective Encapsulated Metal Azolate Frameworks Micelle-Controlled Pore Sizes. 358– 366, 10.1021/acscentsci.3c01432 reference.10Qin, Zou, Liu, Houk, Arnold, F. Construction Chiral Pyrrolidines Indolines Intramolecular C(sp(3))-H Amination. (12), 2333– 2338, 10.1021/acscentsci.3c00516 reference.11Swanson, C. Ford, Mattey, P.; Gourbeyre, Flitsch, Cascades Iminosugar Scaffolds Reveal Promiscuous Activity Shikimate Dehydrogenases. 103– 108, 10.1021/acscentsci.2c01169 reference.12Amatuni, Shuster, Abegg, Comprehensive Structure–Activity Relationship Studies Cepafungin Oxidations. 239– 251, 10.1021/acscentsci.2c01219 reference.13Liang, Bian, Yadav, Zhou, Sun, 1,4-syn-Addition Cyclic 1,3-Dienes Hybrid Palladium Catalysis. (6), 1191– 1200, 10.1021/acscentsci.4c00094 reference.14Peng, Zhong, Tao, Unlocking Nucleophilicity Strong Alkyl C-H Bonds 756– 762, 10.1021/acscentsci.2c01389 reference.15Yue, Ding, Song, Formation C-B, C-C, C-X Nonstabilized Aryl Radicals Generated Diaryl Boryl Radicals. 2268– 2276, 10.1021/acscentsci.3c00993 reference.16Wang, Chen, Dong, J.-Q.; Glycosylation Native Carboxylic Acids: Antidiabetic Inhibitors. 1129– 1139, 10.1021/acscentsci.3c00201 reference.17Kang, Wetterer, Karimov, Kojima, Surke, Martín-Torres, I.; Nicolai, Elkin, Hartwig, Substitution, Elimination, Integration Methyl Groups Terpenes Initiated Bond Functionalization. 10, 2016– 2027, 10.1021/acscentsci.4c01108 reference.18Dhawa, U.; Lavrencic, Nickel-Catalyzed Enantio- Diastereoselective Fluorine-Containing Vicinal Stereogenic Centers. 1657– 1666, 10.1021/acscentsci.4c00819 reference.19Zhou, Huang, Dai, Editing Pyrroles Skeletal Recasting Strategy. 1758– 1767, 10.1021/acscentsci.3c00812 reference.20Che, Y.-N.; Fang, Zhen, G.-J.; C.-J. Asymmetric Three-Component Radical Cascade Reactions Synergistic Photoredox/Brønsted Acid Catalysis: α-Amino Derivatives. 10.1021/acscentsci.4c00970 reference.Cited Click copied!This yet cited publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS copied!https://doi.org/10.1021/acscentsci.4c02041Published 2024© Article Views-Altmetric-Citations-Learn metrics closeArticle Views COUNTER-compliant sum text downloads since November 2008 (both PDF HTML) institutions individuals. regularly updated reflect usage up last few days.Citations number citing article, calculated Crossref daily. Find counts.The Altmetric Attention Score quantitative measure attention received online. Clicking donut icon will load page altmetric.com additional details score social media presence article. how calculated.Recommended Articles FiguresReferencesFigure SlideReferences There reference.

Language: Английский

---

Redox mal anders: katalytische Vielseitigkeit bei NAD(P)H‐abhängigen Oxidoreduktasen

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 136(13)

Published: Nov. 4, 2023

Abstract Die asymmetrische Reduktion von Doppelbindungen unter Verwendung NAD(P)H‐abhängigen Oxidoreduktasen hat sich als effizientes Werkzeug für die Synthese wichtiger chiraler Moleküle in der Forschung und im industriellen Maßstab bewährt. Diese Enzyme sind Screening‐Kits zur C=O‐ (Ketone), C=C‐ (aktivierte Alkene) oder C=N‐Bindungen (Imine) kommerziell erhältlich. Aktuelle Berichte zeigen, dass Fähigkeit, mehrere Reduktaseaktivitäten mit verschiedenartigen C=X‐Bindungen zu beherbergen, verschiedenen Enzymklassen auftritt – entweder nativ nach Mutagenese. Dies stellt gängige Vorstellung infrage, hochselektiv eine bestimmte Art des Elektrophils sein. Eine Berücksichtigung dieses wenig erforschten Potentials Screenings Enzymen Protein‐Engineering‐Projekten könnte dazu beitragen, ergänzende biokatalytische Prozesse Verbindungen identifizieren. Dieser Übersichtsartikel soll zum allgemeinen Verständnis promiskuitiven Verhaltens bei beitragen zukünftige Entdeckungen unkonventioneller biokatalytischer Routen asymmetrischen inspirieren.

---