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

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

• of these proteins and their PDB IDs are provided in Supporting Information File 2). The Surflex-dock module of the Sybyl software was employed for protein preparation and docking of the β-carboline library [14][15]. Water molecules and ligands were removed from the protein structures and the active

• site of each protein was defined by the corresponding residues around the cocrystallized ligands. In-house algorithms were used to evaluate ligand-docking efficiency, and docking scores were used to assess and rank the protein targets. A portion of the protein-scoring matrix is illustrated in Figure 3

Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system

• Caterina Fraschetti,
• Matthias C. Letzel,
• Antonello Filippi,
• Maurizio Speranza and
• Jochen Mattay

Beilstein J. Org. Chem. 2012, 8, 539–550, doi:10.3762/bjoc.8.62

• life's supramolecular systems in which the guest molecule (e.g., amino acids, neurotransmitters, drugs) is selectively captured into the host macromolecular structure (molecular recognition) and transformed catalytically at a specific “active site” (enzyme catalysis) [1][2][3]. Furthermore, the

• biorecognition may require the partial or complete desolvation of the guest molecule and of the polar groups of the active site by greatly enhancing its reactivity [4]. An important step towards the elucidation of enzyme mechanisms requires a comprehensive study of the structure, dynamics, and reactivity of

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• action and chemical topography of the active site of the enzyme under consideration. We proposed the synthesis of a small set of iminosugar derivatives, which in some cases resulted in selective inhibitors of trehalases of different origin, despite the fact that their activity was in the micromolar range

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• presence of metal cations such as Zn2+, Mg2+ and Mn2+ in the active site [9]. It is generally assumed that the coordination of the metal cations to the phosphate oxygen atoms reduces the Coulomb repulsion in the transition states or in the intermediates, thus, lowering the activation barrier [10]. In

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• atoms, with the final chain length being solely dependent on the size of the acting FAS’s active site (although FA biosynthesis is catalysed by several discrete enzymes in bacteria, the term FAS, strictly speaking short for fatty acid synthase and thereby implying the action of only one single enzyme

Dependency of the regio- and stereoselectivity of intramolecular, ring-closing glycosylations upon the ring size

• Patrick Claude,
• Christian Lehmann and
• Thomas Ziegler

Beilstein J. Org. Chem. 2011, 7, 1609–1619, doi:10.3762/bjoc.7.189

• donors and acceptors (prearranged glycosides) resembles to some extent enzyme-catalyzed glycosylation reactions where the glycosyl donor and glycosyl acceptor are first bound in the active site of an enzyme and thus, the glycosidic bond forms intramolecularly. Three different concepts for the

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

• Michael Zengerle,
• Florian Brandhuber,
• Christian Schneider,
• Franz Worek,
• Georg Reiter and
• Stefan Kubik

Beilstein J. Org. Chem. 2011, 7, 1543–1554, doi:10.3762/bjoc.7.182

• the phosphonylation of this nucleophilic group, similar to the phosphonylation of the serine residue in the active site of AChE during OP-mediated inhibition of this enzyme. If the compound thus formed is hydrolytically unstable, it will be cleaved in the aqueous medium, releasing the original

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope

• Aélig Robin,
• Valentin Köhler,
• Alison Jones,
• Afruja Ali,
• Paul P. Kelly,
• Elaine O'Reilly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2011, 7, 1494–1498, doi:10.3762/bjoc.7.173

• , presumably because it opens up the active site. S. Flitsch, L.-L Wong and coworkers for example showed that P450cam (Y96A) was able to hydroxylate diphenylmethane to 4-hydroxydiphenylmethane, an activity that was not observed with the wild-type enzyme [15]. For the present study, incorporation of the Y96A

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• activity [50], and the possibility that the inhibitor is actually binding not to the enzyme active site, but to this lectin domain instead, is not ruled out at present. Conclusion Unsaturated carbohydrate derived electrophiles react readily with carbohydrate nitrogen nucleophiles to form amine-linked

Metathesis access to monocyclic iminocyclitol-based therapeutic agents

• Ileana Dragutan,
• Valerian Dragutan,
• Carmen Mitan,
• Hermanus C.M. Vosloo,
• Lionel Delaude and
• Albert Demonceau

Beilstein J. Org. Chem. 2011, 7, 699–716, doi:10.3762/bjoc.7.81

• binding with the active site of enzymes. The unusual spatial distribution of the hydroxy groups in these compounds should generate new inhibitory profiles. According to in vitro assays, seven-membered ring iminocyclitols are noted inhibitors of α-mannosidase, an enzyme that plays important roles in