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

• using stable isotope labeled precursors [7] suggested a two-chain biosynthesis mechanism for photopyrone biosynthesis (Scheme 1): First, thioester-activated 9-methyldecanoic acid 14 is covalently bound to an active site cysteine. Deprotonation of the α-carbon of 14 results in the formation of a

• covalent binding of the fatty acid precursor, as well as amino acids present at the dimer interface (Figure S3, Supporting Information File 1). Using this model we performed docking studies by covalently docking 14 and 16 (Figure 2) into the active site C129, revealing that the binding cavity of modeled

• , Supporting Information File 1) and docking experiments (Figure S9, Supporting Information File 1) with the proposed substrate 17 and intermediate 19 to the active site C124 also confirmed the glutamic acid inside the binding pocket as catalytically important suggesting a biosynthesis model (Scheme S1

Anion effect controlling the selectivity in the zinc-catalysed copolymerisation of CO₂ and cyclohexene oxide

• Sait Elmas,
• Muhammad Afzal Subhani,
• Walter Leitner and
• Thomas E. Müller

Beilstein J. Org. Chem. 2015, 11, 42–49, doi:10.3762/bjoc.11.7

• ], for which an active site comprising two Lewis acidic zinc centres in vicinity had been proposed [29]. Three catalytic cycles, copolymerisation, homopolymerisation and formation of cyclic carbonate are closely linked (Scheme 4) [28]. The reaction is initiated by coordination of an alcoholate to one of

Reversibly locked thionucleobase pairs in DNA to study base flipping enzymes

• Christine Beuck and
• Elmar Weinhold

Beilstein J. Org. Chem. 2014, 10, 2293–2306, doi:10.3762/bjoc.10.239

• active site. The quick and traceless removal of the linker by addition of DTT enables switching of the target base pair from a locked to an unlocked state during the course of the binding experiment. Discussion Here we presented a new and convenient method to engineer a reversibly locked thionucleobase

• bonds, flipping the target base should be easier, but at the same time, the I6S base is not able to form the hydrogen bonds in the active site of the enzyme that are observed in the complex with the native adenine target [77]. Comparing binding of M.TaqI to its native hemi-methylated target DNA and the

• fully methylated DNA (Figure S1, Supporting Information File 1), it is expected that the methylated target base, which is the product of the DNA MTase reaction, sterically interferes with residues in the active site of the enzyme, resulting in favoring the innerhelical target base conformation which

Pyrrolidine nucleotide analogs with a tunable conformation

• Lenka Poštová Slavětínská,
• Dominik Rejman and
• Radek Pohl

Beilstein J. Org. Chem. 2014, 10, 1967–1980, doi:10.3762/bjoc.10.205

• thereof to an active site of a particular enzyme. The knowledge of the conformation of nucleosides, nucleotides and their analogs is therefore essential for the understanding or even prediction of their biological properties. There are several approaches providing information on the conformation of a five

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• our reports on the activity of DGBP, a beautiful set of crystallographic analyses from the Oldfield group attributed the activity of this compound and a number of others in part to a V-like shape [8]. This shape allows one geranyl group to occupy the enzyme channel where FPP enters the active site of

• GGDPS, while at the same time the second isoprenoid chain can fit nicely in the groove where the product GGPP normally departs from the active site. To continue efforts [9] to increase the potency of GGDPS inhibitors, we sought a new set of isoprenoid bisphosphonates as represented by structure 6

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

• Anna M. Bogazkaya,
• Clemens J. von Bühler,
• Sebastian Kriening,
• Alexandrine Busch,
• Alexander Seifert,
• Jürgen Pleiss,
• Sabine Laschat and
• Vlada B. Urlacher

Beilstein J. Org. Chem. 2014, 10, 1347–1353, doi:10.3762/bjoc.10.137

• YX that enables this type of oxidation. Several acyclic terpenoids were tested as possible substrates for CYP154E1, and the regio- and chemoselectivity of their oxidation was investigated. Using a previously established bioinformatics approach we identified position 286 in the active site of CYP154E1

• have been made in this field. By using an iterative mutagenesis approach “combinatorial active-site saturation test (CAST)” Reetz and colleagues constructed several variants of CYP102A1 which demonstrate high regio- and stereoselectivity for testosterone and progesterone oxidation [42]. The parent F87A

• leading to mainly 8-hydroxy derivatives. Moreover, by bioinformatics analysis position 286 was identified and a simple point mutation changed the geometry of the active site of this P450 enzyme to shift the product spectrum for the selective oxidation of geranylacetone (9) and nerylacetone (10) to yield

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• active site located on the cytosolic side of the membrane [10][11][12][13][14]. For previously reported SAR studies on muraymycins and their analogues, the fatty acid side chain was either neglegted or replaced with a structurally distinct lipophilic mimic [15][16][17]. Mansour and co-workers found a

• direct relation of the lipophilicity of semi-synthetic muraymycin C1 analogues and their biological activity [18]. They thus also postulated that the lipid structure might be involved in transporting the molecule to the active site of the target enzyme. The most recent SAR investigation on synthetic

Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates

• Michał Górny vel Górniak,
• Anna Czernicka,
• Piotr Młynarz,
• Waldemar Balcerzak and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 741–745, doi:10.3762/bjoc.10.68

• acids and their short peptides are a class of well-established inhibitors of serine proteases [11][12]. Their mechanism of action involves phosphonylation of the active-site of these enzymes with simultaneous release of the appropriate phenol [13][14]. Therefore, the synthesis of such inhibitors

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

• position 12 in 1 is installed by the dehydratase of polyketide synthase (PKS) module 3 (BorDH3). Characteristic residues in the active site of the preceding ketoreductase point towards a 3D configuration of the BorDH3 precursor 3 [10][11]. Furthermore, we have shown in a previous study that BorDH3

• recognition of this prosthetic group is essential for proper substrate orientation in the active site and catalysis with natural stereoselectivity [13]. To mimic the ACP-bound state of PKS intermediates, their analogues, free SNAc thioesters, are used in enzyme assays. Alternatively, ACP-bound substrates can

• 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

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• ]. Several studies have revealed the bio-similarity of triazoles with amide bonds. For example, X-ray studies towards triazole based-mimics of the HIV-1 protease inhibitor amprenavir showed an equivalent binding mode with the protease active site as compared to the amide-bond inhibitor [81][83][84

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• residues in the active site, the metal coordinating site and the substrate-binding site of these enzymes (Figure 1) [37][38]. After all, the interconversion between D-fructose and D-psicose catalyzed by DTEase enzymes is an equilibrium process, thus large scale and high yield production of D-psicose as

• biocatalysts for industrial-scale applications. The active site in D-psicose 3-epimerase (DPEase) in the presence of D-fructose, showing the metal coordinating site and the substrate-binding site. The purple ball indicates the manganese(II) ion coordinating with key amino acid residues (Glu150, Asp183, His209

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• single crystal X-ray structure of carmegliptin bound in the human DPP-4 active site has been published indicating how the fluoromethylpyrrolidone moiety extends into an adjacent lipophilic pocket [81]. Additional binding is provided by π–π interaction between the aromatic substructure and an adjacent

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• epoxy groups on the support can occur which would result in a lower amount of enzyme retention. The multipoint attachment in case of direct immobilization may block the active site of the enzyme and, as a consequence, this would result in a lower degree of activity retention. In case of the indirect

• method the enzyme was separated from the support by a spacer element. This was formed by the reaction of ethylenediamine and glutaraldehyde. This reaction reduces the probability of blocking the active site of the enzyme which would provide higher activity retention. For the direct method, our results

• [51]. Product inhibition study The product inhibition study was carried out in order to understand whether there is an effect of product formed during the reaction which might block the active site of the enzyme. To achieve this we carried out three reactions for 40 minutes at 70 °C. The amount of

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• kinase inhibitory effects of 26 [18]. Solving the crystal structure of the catalytic subunit Cα of cAMP-dependent protein kinase bound to 26 gave pivotal insights in the binding mode [19]. Staurosporine (26) targets the active site of the adenosine-binding pocket of most protein kinases. This is achieved

A³-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS-functionalized cellulose nanocrystalline films

• Jian-Lin Huang,
• Derek G. Gray and
• Chao-Jun Li

Beilstein J. Org. Chem. 2013, 9, 1388–1396, doi:10.3762/bjoc.9.155

• coupled plasma (ICP) analytical techniques. Both the HS-CNC and the Au sponge were inactive, implying that the Au is the active site and that the controlling of Au nanoparticle size is essential for the present reactions. The catalytic activity first increased with the increase of the Au loading up to 4.4

Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review

• Lucio Melone and
• Carlo Punta

Beilstein J. Org. Chem. 2013, 9, 1296–1310, doi:10.3762/bjoc.9.146

• yields. Enzyme laccase Enzyme laccase is a family of “blue-copper” oxidase proteins, containing four copper ions in the active site, which cooperates in the degradation of the biopolymer lignin in woody tissues. With respect to other powerful oxidant enzymes, laccase has a lower redox potential. For this

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

• Magnus Liljenberg,
• Tore Brinck,
• Tobias Rein and
• Mats Svensson

Beilstein J. Org. Chem. 2013, 9, 791–799, doi:10.3762/bjoc.9.90

• QM methods and other parts with MM methods, for example, in enzymes where the active site can be modeled with QM and the remaining structure with MM methods. Predictive models for the SNAr reaction This paper is a continuation of our work on the predictive computational modeling of the synthetically

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

• -propargylerythromycin A (Scheme 2) [39]. In that experiment, the active site of DEBS AT6 was redesigned to increase acceptance of 5 for incorporation into erythromycin A. A targeted mutation was introduced into the erythromycin producer S. erythraea. The wild-type strain showed no incorporation of 5 over the background

• , CH2Cl2, Ar, 0 °C → rt, 6 h, then aq NaHCO3 (pH 8.0), quant. (by TLC and 1H NMR). Incorporation of a propargylated malonic acid derivative into erythromycin through an active-site mutation in the acyltransferase in DEBS module 6 (DEBS AT6*) [39]. Supporting Information Supporting Information File 64: NMR

Caryolene-forming carbocation rearrangements

• Quynh Nhu N. Nguyen and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2013, 9, 323–331, doi:10.3762/bjoc.9.37

• /reprotonation pathway is rather flat, indicating that once C is formed, transformation to E should be facile, provided that the architecture of the active site supports deprotonation/reprotonation. Conclusion Which pathway to caryolene is more likely? On the basis of our computed energetics (Figure 8), we favor

• a mechanism for caryolene formation that involves a concerted but asynchronous [2 + 2] cycloaddition, deprotonation by an enzyme active-site base (as yet, with identity unknown [55][58][59][60][61][62][63][64]), and concerted but asynchronous reprotonation/cyclization (Scheme 2, right). However

Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions

• Matthias Leven,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2013, 9, 155–165, doi:10.3762/bjoc.9.18

• of a carboxylic amide (Scheme 3). The active site consists of a primary amino group and a sulfonic acid group, which can form chelates with cations. The sulfonic acid derivatives are accessible through efficient transformations of diamines with 2-sulfobenzoic anhydrides 4 (Scheme 3). Typical yields

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• as a zinc binding group within the active site of the HDAC protein. Furthermore, we demonstrated the importance of the oxime unit of psammaplin A and related analogues for high potency and selectivity against recombinant HDAC1 (rHDAC1) in vitro (Scheme 1). More recently, we disclosed highly potent

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• intracellular replication and differentiation of the T. cruzi parasite [17]. A variety of small-molecule cruzain inhibitors have been described, the majority of which act irreversibly by reaction with the catalytic cysteine in the enzyme active site [18][19][20][21][22][23][24][25][26][27]. One of the earliest

• inhibitors 1–4, known TcCYP51 inhibitor 5, dihydro controls 6–8, and truncated analogues 12 and 13. The “P2” and “P3” side chains of 1 are labeled and bind, respectively, in the S2 and S3 sub-sites of the cruzain active site. Computational docking models. (A) Predicted binding modes of 4 and (R)-5 bound to

Synthesis of a derivative of α-D-Glcp(1->2)-D-Galf suitable for further glycosylation and of α-D-Glcp(1->2)-D-Gal, a disaccharide fragment obtained from varianose

• Carla Marino,
• Carlos Lima,
• Karina Mariño and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2012, 8, 2142–2148, doi:10.3762/bjoc.8.241

• )Galf and β-Galf(1→6)Galf [12][13][14]. Synthetic oligosaccharides have been used to characterize these GalfTs and it was demonstrated that a single active site in GalfT2 is responsible for both activities [15]. The crystal structures of both, free and UDP-bound GalfT2 have been recently determined [16

Studies on the substrate specificity of a GDP-mannose pyrophosphorylase from Salmonella enterica

• Lu Zou,
• Ruixiang Blake Zheng and
• Todd L. Lowary

Beilstein J. Org. Chem. 2012, 8, 1219–1226, doi:10.3762/bjoc.8.136

• positions, in turn suggesting that these positions are buried inside the enzyme active site. Additionally, both the 6-methoxy and 6-deoxy Manp-1P derivatives are good or moderate substrates for GDP-ManPP, thus indicating that the C-6 hydroxy group of the Manp-1P substrate is not required for binding to the

• , because the 2-methoxy, 3-methoxy, and 4-methoxy compounds all showed a large decrease in activity, it is likely that these positions are bound tightly in the active site of the enzyme. A graphical summary of the substrate specificity for GDP-ManPP is shown in Figure 6. Kinetic analysis of Manp-1P

• from S. enterica was evaluated. All the derivatives acted as substrates for GDP-ManPP, but with uniformly lower activity than the natural substrate Man-1P. The results suggest that the C-2, C-3, and C-4 hydroxy groups of Manp-1P are bound within the active site of GDP-ManPP and the addition of a methyl

Control over molecular motion using the cis–trans photoisomerization of the azo group

• Estíbaliz Merino and
• María Ribagorda

Beilstein J. Org. Chem. 2012, 8, 1071–1090, doi:10.3762/bjoc.8.119

• glutamate head. Only the cis form of the azobenzene allows the approach of the fragment and the interaction of glutamate with the active site of the protein. When this interaction occurs, the protein folds as a clamshell, triggering the opening of the ion channel (Figure 5b). Another recent example was