Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• macrocyclizations (Scheme 1c). NAC thioester and other related mimics (such as coenzyme A (CoA), phosphopantetheine, and thiophenol) span the gap between the chemical synthesis and biosynthesis languages and expand the substrate promiscuity of TE domains. This bridge makes the in vitro TE-catalyzed macrocyclization

• , coenzyme A (CoA), phosphopantetheine, and thiophenol. The thiophenol thioesters exhibited the highest cyclization rates, suggesting that chemical reactivity precedes cofactor recognition [54]. Moreover, CDA3 TE had a broad substrate spectrum, even indicating activity to cyclize daptomycin and its analogs

• methylmalonyl-coenzyme A to its mimic MM-NAC (38) [68], and the substrate from NAC thioester to thiophenol-activated 37, the PKS-mediated conversion proceeded with modest yield to 10-deoxymethynolide (60% yield) and acetylnarbonolide (49% yield) at preparative scale (>1 mmol), generating about 250 mg of both

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• region on chromosome 6 [172]. Chemically, pyripyropene (PP) analogs are meroterpenoids containing a fused pyridyl α-pyrone moiety and eight contiguous stereocenters [170]. Metabolically, PPPA non-covalently binds within the fifth transmembrane domain of acyl-coenzyme A (CoA):cholesterol acyltransferase

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• ]. Compound 17 can be transformed into the coenzyme A thioester 18 by the CoA ligase DmdB, followed by FAD-dependent oxidation to the α,β-unsaturated compound 19 by DmdC. The attack of water to the Michael acceptor catalyzed by the enoyl-CoA hydratase DmdD yields the hemithioacetal 20 that spontaneously

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• -hydroxyoctadecanoic and stearic acids as well as (E)-2-octadecenoic acids are obtained similarly directly from palmitic acid. The proposed biosynthesis likely takes place in form of the conjugated acids, e.g., coenzyme A esters or acyl carrier proteins. Finally, the acids are converted into the isoprenyl esters and

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• kynurenine pathway starting from tryptophan or by anthranilate synthases from the PqsR-controlled phnAB operon starting using chorismic acid as a source [24]. Either way, the ligase PqsA starts PQS synthesis by condensing anthranilic acid with coenzyme A [25]. The resulting activated thioester (anthraniloyl

• of related metabolites and PqsE in virulence. Effector molecules are highlighted in blue. Enzymes are given in bold. Abbreviations: CoA, coenzyme A; 2-ABA-CoA, 2’-aminobenzoylacetyl-CoA; 2-ABA, 2’-aminobenzoylacetate; DHQ, dihydroxyquinoline; 2-AA, 2’-aminoacetophenone; 2-HABA, 2

Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria

• Lisa Ziesche,
• Jan Rinkel,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 1309–1316, doi:10.3762/bjoc.14.112

• DFL-12 as well as PgaI2 from P. inhibens DSM 17395 were heterologously expressed in E. coli and the enzymes isolated for in vitro incubation experiments. The enzymes readily accepted shortened acyl coenzyme A analogs, N-pantothenoylcysteamine thioesters of fatty acids (PCEs). Fifteen PCEs were

• by substitution of the good leaving group 5’-deoxy-5’-thiomethyladenosine (5) of the thioester group, leading to homoserine lactone 4 formation (Scheme 1). Recently a LuxI-homolog, BjaI [20] preferring acyl-coenzyme A (CoA) substrates instead of the common ACP precursors, was characterized [21]. The

• biosynthesis into an AHL, or are stored in a form not cleavable by the TMSH method used. These precursor acids may also originate from fatty acid degradation, a pathway that proceeds via free coenzyme A intermediates and not via acyl carrier protein-bound substrates like in the fatty acid biosynthesis. These

Strategies in megasynthase engineering – fatty acid synthases (FAS) as model proteins

• Manuel Fischer and
• Martin Grininger

Beilstein J. Org. Chem. 2017, 13, 1204–1211, doi:10.3762/bjoc.13.119

• antineoplastic doxorubicin and by the antiparasitic avermectin (Figure 1a) [1]. PK are assembled from acyl-coenzyme A (acyl-CoA) units via a series of Claisen-type condensation reactions catalyzed by polyketide synthases (PKS) (Figure 1b). PKS occur as large multifunctional enzymes, termed megasynthases, which

Synthesis and enzymatic ketonization of the 5-(halo)-2-hydroxymuconates and 5-(halo)-2-hydroxy-2,4-pentadienoates

• Tyler M. M. Stack,
• William H. Johnson Jr. and
• Christian P. Whitman

Beilstein J. Org. Chem. 2017, 13, 1022–1031, doi:10.3762/bjoc.13.101

• + and coenzyme A to produce acetyl-CoA (8a) [12]. Pyruvate and acetyl-CoA can then be funneled into the Krebs cycle. Over the years, variations of this pathway have been reported that process halogenated catechols. One such pathway is found in Comamonas sp. strain CNB-1, which grows on 4

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• serine residue of the PCP-domain using the R4-4 mutant of the promiscuous phosphopantetheinyl transferase Sfp. The substrate peptide is attached to the PCP-domain via a coenzyme A-derived phosphopantetheine moiety. Excess of substrate is removed via centrifugation using centrifugal filter units with an

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• ]. As for most pyranonaphtoquinones, seven rounds of chain extensions followed by controlled cyclisation yield the reactive intermediate 38 after release from the PKS [25][26]. The intermediate is prepared for the action of ActVI-1, which is annotated as a 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• the identification of homologous bacterial flavoproteins (Dfp) that catalyse the decarboxylation of 4’-phospho-N-pantothenoylcysteine to 4’-phosphopantetheine, which is essential for coenzyme A biosynthesis [68] (Figure 5B). This demonstrates how the mechanistic analysis of secondary metabolism can

• biosynthesis of labyrinthopeptin A2. S-[(Z)-2-Aminovinyl]-D-cysteine (AviCys) formation in the epidermin pathway. A) Mechanisms for decarboxylation and 1,4-addition. B) Mechanism for the E. coli Dfp-catalysed conversion of (R)-4'-phospho-N-pantothenoylcysteine into 4'-phosphopantetheine during coenzyme A

A cross-metathesis approach to novel pantothenamide derivatives

• Jinming Guan,
• Matthew Hachey,
• Lekha Puri,
• Vanessa Howieson,
• Kevin J. Saliba and
• Karine Auclair

Beilstein J. Org. Chem. 2016, 12, 963–968, doi:10.3762/bjoc.12.95

• larger groups via cross-metathesis. The method was applied in the synthesis of a new pantothenamide with improved stability in human blood. Keywords: antibiotic; antiplasmodial; coenzyme A; metathesis; pantothenate; Introduction Bacteria, fungi, and parasites are all rapidly acquiring resistance to

• pantothenamides may mimic pantetheine and are extended into a thiol-lacking coenzyme A (CoA) derivative by some of the natural CoA biosynthetic enzymes (pantothenate kinase or PanK, phosphopantetheine adenylyltransferase and dephosphocoenzyme A kinase). The resulting inactive CoA analog affects downstream

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• either ACP (acyl carrier protein) or CoA (coenzyme A) bound thioesters depending whether they originate from fatty acid biosynthesis or degradation, respectively. Due to the variability of the first substrate regarding chain length and starting unit, the different photopyrones A–H (1–8) are produced. We

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

• Patrick Rabe,
• Tim A. Klapschinski,
• Nelson L. Brock,
• Christian A. Citron,
• Paul D’Alvise,
• Lone Gram and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2014, 10, 1796–1801, doi:10.3762/bjoc.10.188

• TDA. The introduction of sulfur proceeds via nucleophilic attack of S-thiocysteine to the Michael acceptor of tropone-2-carboxylic acid coenzyme A ester and oxidative elimination of cysteine. The second sulfur atom is introduced by analogous attack to the vinylogous Michael acceptor. The volatiles

• , and may have other physiological or ecological functions. This result is particularly surprising, because the coenzyme A ester of 13 is an intermediate along the biosynthetic pathway to TDA, so the question arises what may have been the evolutionary advantages of extending the biosynthetic pathway

• from the coenzyme A ester of 13 to TDA by the introduction of two sulfur atoms. A possible answer may be that TDA has more or other targets than 13 which may have the consequence that the development of resistances against TDA is prevented, thus offering an evolutionary advantage. Conclusion We have

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• TBS ethers and methyl esters was performed under mildly acidic conditions followed by pig liver esterase-mediated chemoselective hydrolysis. These conditions are compatible with the presence of a coenzyme A or a SNAc thioester, suggesting that they are generally applicable to the synthesis of complex

• polyketide-derived thioesters suited for biosynthesis studies. Keywords: aldol reaction; coenzyme A; natural products; pig liver esterase; polyketide biosynthesis; protection groups; Introduction Borrelidin (1) is a macrolactone polyketide natural product with promising antibacterial, antimalarial

• be conveniently obtained by loading coenzyme A (CoA) thioesters onto active site serine residues of recombinant ACPs by using 4'-phosphopantetheinyl transferases [12][14]. However, coenzyme A thioesters are synthetically hard to access, especially if the substrate structure is complex. Results and

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates. The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose. Here, the incorporation efficiency into different polyketides of N-acetylcysteamine activated

• methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo. Keywords: biosynthesis; coenzyme A; malonic acid; polyketide; polyketide synthase; Introduction Polyketides are ubiquitous natural products and find

• varying degrees of reduction in each step (Figure 1) [1][2][3]. Additional diversity is introduced by the incorporation of different carboxylic acid starter units and a range of different extender units, usually coenzyme A-activated malonic acid derivatives, with varying substituents at C-2 [4][5

Synthesis and in silico screening of a library of β-carboline-containing compounds

• Kay M. Brummond,
• John R. Goodell,
• Matthew G. LaPorte,
• Lirong Wang and
• Xiang-Qun Xie

Beilstein J. Org. Chem. 2012, 8, 1048–1058, doi:10.3762/bjoc.8.117

• protein, human HDAC4 (PDBID:2vqq); (3) compounds 2{1,5} and 2{1,7} are predicted to be high-affinity ligands for 3-hydroxy-3-methylglutaryl-coenzyme A, reductase (PDBID:2q6b) and HDAC4, respectively, even though they are structurally different from the corresponding cocrystallized ligands HR2 and TGF; and

Identification and isolation of insecticidal oxazoles from Pseudomonas spp.

• Florian Grundmann,
• Veronika Dill,
• Andrea Dowling,
• Aunchalee Thanwisai,
• Edna Bode,
• Narisara Chantratita,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 749–752, doi:10.3762/bjoc.8.85

• 5 and gave initial insights into the biosynthesis. All incorporated biosynthetic precursors of the oxazoles are shown in color. The nitrogen shown in green is derived from transamination as part of the amino acid metabolism. SX = activated ester, which may be coenzyme A or enzyme (acyl carrier