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

• engineering strategies in the light of the newly emerging structural information on megasynthases, and argue that fatty acid synthases (FAS) are and will be valuable objects for further developing this field. Keywords: fatty acid synthases; megasynthases; metabolic enzyme engineering; polyketide synthases

• a single module repeatedly condensing precursor units until the specific length/size is attained (iterative systems) [4]. In either case, the enzymatic functions of each module deterministically encode the chemical nature of the final product [5]. Fatty acid synthases (FAS) are a type of PKS

• recent years, a wealth of structural data on FAS multienzyme complexes (type I) has further deepened the insight into the principles of fatty acid (FA) synthesis [13][14][15][16][17][18][19]. Molecular mechanisms of FAS/PKS mode of action Compartmentalization Compartmentalization is a phenomenon seen

Lipids: fatty acids and derivatives, polyketides and isoprenoids

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2017, 13, 793–794, doi:10.3762/bjoc.13.78

• African reed frog that are likely amphibian signaling compounds [1]. Sensu lato, and this is the definition relevant to this Thematic Series: lipids include all kinds of apolar (or less polar) primary and secondary metabolites, including molecules that are formed via fatty acid biosynthesis, the

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• synthases (PKSs), in a process resembling fatty acid biosynthesis by the mammalian fatty acid synthase (FAS) [8] from which the PKSs likely evolved [9]. In both cases, simple acyl-CoA building blocks are concatenated head-to-tail to construct linear chains. Several features distinguish these two pathways

• labeling at C-2, C-4, and C-10 of the macrolide ring. This result was consistent with incorporation of (2S)-methylmalonyl-CoA during the second, fifth, and sixth chain extension cycles, with inversion of configuration at the C-2 center as found for fatty acid biosynthesis (vide infra) [24]. However

• (2RS)-methylmalonyl-CoA in D2O. These labeling patterns are consistent with inversion of stereochemistry occurring in both modules 1 and 2 as in fatty acid biosynthesis without cleavage of the C-2–H bond (giving directly the D-configuration at C-2 observed in the final product), but show that an

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• ’ replacement of existing, fossil resources based synthesis routes with economic alternatives based on renewable sources. Besides chemical platforms based on sugar, lignin or fatty acid containing feedstocks, terpenes present another plant derived feedstock which is of great interest for a variety of industrial

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• ]. The biosynthesis of AQs has been matter of a long-standing debate that could only recently be resolved. Although HHQ could be produced in vitro by a PqsD catalyzed “head-to-head” decarboxylative Claisen condensation of activated anthranilic acid with β-keto fatty acid derivatives [10][11], isotope

Benzothiadiazole oligoene fatty acids: fluorescent dyes with large Stokes shifts

• Lukas J. Patalag and
• Daniel B. Werz

Beilstein J. Org. Chem. 2016, 12, 2739–2747, doi:10.3762/bjoc.12.270

• isomerization are presented. The absorption properties are modulated by the number of conjugated C=C double bonds of the oligoene chain ranging from one to three. Large Stokes shifts of about 4900–5700 cm−1 and fluorescence quantum yields of up to 0.44 were observed. Keywords: fatty acid; fluorescence; lipid

• as the carbohydrate part of glycolipids [7][8]. A further alternative is to render the lipid and especially the fatty acid part fluorescently active by the introduction of fluorescent moieties (Figure 1). Prominent examples in this area are NBD- (nitrobenzoxadiazole) [9][10], BODIPY- (boron

• isomerization has to take place. To access the benzothiadiazole (BTD) fatty acid 3 with just one conjugated double bond we made use of the Wittig reaction starting with commercially available aldehyde 1. As expected, the (Z)-isomer was the major product; thus, we performed a subsequent cis–trans isomerization

Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

• Markus Menke,
• Pardha Saradhi Peram,
• Iris Starnberger,
• Walter Hödl,
• Gregory F.M. Jongsma,
• David C. Blackburn,
• Mark-Oliver Rödel,
• Miguel Vences and
• Stefan Schulz

Beilstein J. Org. Chem. 2016, 12, 2731–2738, doi:10.3762/bjoc.12.269

• acid precursor is often oxidized near the end of the chain to form a polar hydroxy acid. The following ring-closure reduces the hydrophilicity of the compound and increases its vapor pressure, making the resulting macrocycle well-suited to serve as a signal [1]. Fatty acid derived macrolactones were

• ; pheromones; Introduction The lactone motif is found in many compounds that are used in chemical communication. Among them, macrocyclic lactones are an important class because of their biosynthetic availability and their inherent compound properties. During the biosynthesis of macrocyclic lactones, a fatty

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• length of the fatty acid chain of the phospholipid, the cavity size, and the nature of the substituents at the CD [66]. In the literature, the binding constant between cholesterol and β-CD was estimated around 1.7 × 104 M−1 from a solubility method [67][68]. This value proves the good stability of the

• -CD can also be used to reduce LDL cholesterol and alters plasma fatty acid profile [134][135]. In 2016, a double blind, placebo-controlled clinical trial has been published on the effect of oral α-CD [136]. After 12 to 14 weeks, a daily 6 gram dose of α-CD allowed to reduce fasting plasma glucose

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• a remarkable assembly-line paradigm, in which each cycle of polyketide chain extension is accomplished by a different set or module of vertebrate fatty acid synthase (FAS)-related enzyme domains [1][2][3][4]. The direct connection between the number and type of modules and the chemical structure of

• Stigmatella aurantiaca [20], further examples have been uncovered in the PKSs for aureothin [21][22], borrelidin [23][24], lankacidin [25][26], neoaureothin [27], etnangien [28], crocacin [29], ebelactone [30] and thiolactomycin [31][32]. Given the close mechanistic analogy between fatty acid synthases and an

• ) animal fatty acid synthases and that on bacterial modular polyketide synthases, and it also hints at what could be a major mechanism for the evolution of these processive systems. Nevertheless, the highly repetitive nature of the genes encoding modular PKS makes it easy to misassemble sequence data, and

Ionic liquids as transesterification catalysts: applications for the synthesis of linear and cyclic organic carbonates

• Maurizio Selva,
• Alvise Perosa,
• Sandro Guidi and
• Lisa Cattelan

Beilstein J. Org. Chem. 2016, 12, 1911–1924, doi:10.3762/bjoc.12.181

• such or as mixtures are widely used to convert natural triglycerides into FAMEs or FAEEs (fatty acid methyl or ethyl esters) with methanol or ethanol, respectively [10]. The most commonly used system is CaO, which is obtained by calcination of readily available and cheap resources including waste

• (Scheme 2) [15][16]. The reaction allows obtaining FAMEs and fatty acid glycerol carbonate monoesters (FAGCs), without the concurrent formation of glycerol, a frequently formed highly undesirable byproduct. Enzyme catalysts: A major driving force for the choice of enzymes is their high efficiency, which

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

• gene cluster harbours genes that code for a β-hydroxymethylglutaryl-CoA synthase (HCS) cassette (mupG, mupH, mupJ, mupK and macpC) and an iteratively acting type I fatty acid synthase (FAS) (mmpB). During the biosynthesis of the pseudomonic acids, the initially formed PKS product 52 undergoes a complex

• multistep process (Scheme 9). After elongation by the iterative type I fatty acid synthase MmpB, redox transformations and a dehydration on the MacpE-bound substrate 58 finally lead to pseudomonic acid A (61) with a 3,4-dihydroxy-2,5-disubstituted pyran ring. The reason for the elaborate oxidation–reduction

• synthase (NorS) (Scheme 16) [83][85]. NorS is a complex of a NR-PKS PksA and a pair of yeast-like fatty acid synthases HexA/HexB, which provide an unusual hexanoyl-CoA starter unit [86]. Norsolorinic acid (100) undergoes three oxidative rearrangements towards aflatoxin B1 (94): The first rearrangement sets

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• , Ryhage and Stenhagen presented detailed studies on the EI mass spectra of deuterated and methyl-branched fatty acid methyl esters that revealed their fragmentation mechanisms [7][8]. Based on this work, we have recently identified various volatile fatty acid methyl esters (FAMEs) in headspace extracts of

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

• pathways such as the acyl carrier protein activation required for fatty acid biosynthesis [13][14][15][16]. In S. aureus, however, recent studies suggest that the antimicrobial activity correlates better with an inhibition of PanK, the regulatory enzyme in CoA biosynthesis in several organisms [17

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• ]. They contain a uridine moiety, two O-glycosidically linked sugars, the so-called tunicamine and a fatty acid moiety, which typically is terminally branched and unsaturated. Two closely related nucleoside antibiotics were isolated later on and named streptoviridins (isolated in 1975 from Streptomyces

• , which is also glycosylated in 5'-position with an aminoribose unit, and they contain a fatty acid moiety as well. Caprazamycins also display noteworthy antimicrobial activity against M. tuberculosis as well as most Gram-positive bacteria (Table 1) [46][48]. All aforementioned nucleoside antibiotics

• = 0.027 μg/mL), which represented activities comparable to those of liposidomycin C (0.05 μg/mL) and mureidomycin A (0.03 μg/mL). As a general trend, higher antimicrobial activities were found for acylated compounds, in particular with longer and functionalised fatty acid side chains. Lin et al. employed

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

• the guest must adopt a J- or U-shape within the cavity; a motif that is sometimes seen when fatty acids bind to fatty-acid transport proteins. Finally, the third and highest energy guest motif within the capsule can be observed with guests such as C26H54. This guest packs with each methyl terminus in

Elucidation of a masked repeating structure of the O-specific polysaccharide of the halotolerant soil bacteria Azospirillum halopraeferens Au4

• Elena N. Sigida,
• Yuliya P. Fedonenko,
• Alexander S. Shashkov,
• Nikolay P. Arbatsky,
• Evelina L. Zdorovenko,
• Svetlana A. Konnova,
• Vladimir V. Ignatov and
• Yuriy A. Knirel

Beilstein J. Org. Chem. 2016, 12, 636–642, doi:10.3762/bjoc.12.62

• , including survival of bacteria under salinity [10][11][12][13]. Preliminary chemical data on the LPS of A. halopraeferens type strain Au4, including fatty acid and monosaccharide composition, have been reported [14]. As biological functions of the LPS are expected to depend on their structures, this study

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• C (57, Figure 14), which have been isolated from different Pseudomonas strains [62][63]. Compounds 55 and 56 had been initially tested positive for antimycobacterial and antiparasitic activities and both inhibited fatty acid biosynthesis [62]. The new derivative 57, possessing a longer eastern acyl

• ellagitannin biosynthesis [73]. The ellagitannins can then be hydrolyzed to ellagic acid (22), and subsequently converted to urolithins (23–27). In microorganisms the PKS-derived origin was independently postulated for numerous compounds. The polyketide biosynthesis has much in common with fatty acid

• reduced by further enzymes involved. In fatty acid biosynthesis usually a complete reductive cycle takes place, i.e., a ketoreductase (KR) generates a hydroxy group, a dehydratase (DH) reduces to an alkene double bond, and an enoyl reductase (ER) yields a completely saturated acyl-backbone. These

Art, auto-mechanics, and supramolecular chemistry. A merging of hobbies and career

• Eric V. Anslyn

Beilstein J. Org. Chem. 2016, 12, 362–376, doi:10.3762/bjoc.12.40

• trielaidin over trielroselaidin (differing only by double bond position in each fatty acid chain, Figure 11) and a second synthetic receptor that did the opposite. Thus, if successful, the demonstration of a differential sensing approach that could classify glycerides, determine their structural features

Thermal and oxidative stability of Atlantic salmon oil (Salmo salar L.) and complexation with β-cyclodextrin

• Daniel I. Hădărugă,
• Mustafa Ünlüsayin,
• Alexandra T. Gruia,
• Cristina Birău (Mitroi),
• Gerlinde Rusu and
• Nicoleta G. Hădărugă

Beilstein J. Org. Chem. 2016, 12, 179–191, doi:10.3762/bjoc.12.20

• well with the KFT kinetic data for β-CD/ASO complexes. Keywords: Atlantic salmon oil (ASO); β-cyclodextrin; differential scanning calorimetry; Karl Fischer titration; omega-3 fatty acid; thermogravimetry; Introduction Functional food products containing omega-3 supplementation are becoming more and

• more popular and are promoted for their beneficial effects on human health, especially in cardiovascular and brain disorders [1][2] as well as for mental health [3][4][5]. The main source of omega-3 fatty acid (FA) containing compounds is fish oil [6]. Many fish species are used as the oil source. They

• strongly reduced after thermal and oxidative degradation. It is obvious that protection against oxidation for these omega-3 fatty acid glycerides is needed. Thus, good yields from preparation of β-CD/ASO complexes by co-crystallization and kneading have been obtained. Furthermore, thermal and KFT analyses

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• . The basic principle of labeling an organic molecule in a way that is incognito for metabolism, but easy to follow for the researcher still remains the same. The first application of this idea probably was the investigation on fatty acid degradation by Knoop in 1904, even long before isotopes were

• may not precisely follow the IUPAC rules. Review Polyketides Polyketide synthases (PKS) are multidomain enzymes that catalyze the formation of natural products via reaction steps similar to fatty acid biosynthesis, in which C2-units are fused in Claisen condensations and modified in an iterative or

• modular fashion [15]. In contrast to fatty acid synthases (FAS), PKSs do not necessarily process the initially formed 3-keto functions through a complete reductive cycle, which leads to structurally diverse products as shown in Figure 1 for lovastatin (1), an inhibitor of 3-hydroxy-3-methylglutaryl CoA

Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

• Davide Bello and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 1902–1909, doi:10.3762/bjoc.11.205

• molecular weight carboxylic acids are found widely in metabolism, often as their co-enzyme A esters, and they then undergo condensation reactions through enols or enolates to generate C–C bonds typified by the processes of long chain fatty acid biosynthesis. α-Fluorovinyl thioethers, illustrated in Figure 2

Cross metathesis of unsaturated epoxides for the synthesis of polyfunctional building blocks

• Meriem K. Abderrezak,
• Kristýna Šichová,
• Nancy Dominguez-Boblett,
• Antoine Dupé,
• Zahia Kabouche,
• Christian Bruneau and
• Cédric Fischmeister

Beilstein J. Org. Chem. 2015, 11, 1876–1880, doi:10.3762/bjoc.11.201

• a concentration of 0.5 M to operate with full conversion. This characteristic was previously observed in cross metathesis of fatty acid methyl esters with methyl acrylate [13]. Finally, neither toluene as solvent nor Hoveyda 2nd generation catalyst have led to improvements of the reaction

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

• Ivan Bassanini,
• Karl Hult and
• Sergio Riva

Beilstein J. Org. Chem. 2015, 11, 1583–1595, doi:10.3762/bjoc.11.174

• lipases and proteases in organic solvents. Moreover, both substrates and acylating agents’ scope could be significantly expanded. Lipases, whose natural substrates are fatty acid triglycerides, and proteases, enzymes acting on peptides and proteins, were found to be able to catalyze, i.e., the

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

• and they all share the thiolase fold [9]. The crystal structure of a mammalian [10] and a fungal [11] fatty acid synthase confirmed the dimeric nature of the KS. Recently KS have been described, whose substrates deviate from the usual ones. Examples are the widespread class of KS catalyzing the

• OleA, which is part of the olefin biosynthesis in Xanthomonas campestris by promoting a head-to-head condensation of two long-chain fatty acid thioesters to form a long-chain β-ketoacid that can be further processed to an olefin [14]. KS with acylating activity have been reported in the cervimycin [15

• 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

Potential of acylated peptides to target the influenza A virus

• Daniel Lauster,
• Damian Pawolski,
• Julian Storm,
• Kai Ludwig,
• Rudolf Volkmer,
• Henry Memczak,
• Andreas Herrmann and
• Sumati Bhatia

Beilstein J. Org. Chem. 2015, 11, 589–595, doi:10.3762/bjoc.11.65

• influenza A/Aichi/2/1968 H3N2 (X31) and avian pathogenic A/FPV/Rostock/34 H7N1. Inspired by the strategy of Matsubara et al. we attached a C18 fatty acid chain to this peptide, called PeBGF, to assemble multivalent structures which enhanced the antiviral potential compared to the monomeric form. In this