Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

• Lena Huck,
• Juan F. González,
• Elena de la Cuesta and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2016, 12, 1772–1777, doi:10.3762/bjoc.12.166

• for the preparation of peptides [2][3] and the synthesis of peptide-like compounds comprising the aziridine motif [4][5]. Furthermore, the incorporation of an electrophilic aziridine moiety in peptide or peptidomimetic frameworks is an interesting strategy for the design of active site-directed drugs

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

• to a histidine or an asparagine residue in their active site. This exchange avoids the dehydration reaction and might facilitate the activation of the hydroxy group for nucleophilic attack on the Michael system by proton abstraction. PS domains also form a distinct phylogenetic clade compared to DH

• proposed mechanism also proceeds via a dehydration–oxa-Michael addition cascade. A crystal structure revealed two crucial aspartic acid residues as candidates for the acid–base catalysis occurring in the active site [18]. 1.1.2 Processing of hemiacetals: Reduction or alkylation of hemiacetals in the

• and was verified by mutagenesis and kinetic studies. In the active site, Glu141 and His129 activate the C3 keto group by protonation. The pro-S hydride of the reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is then transferred to the C3. The resulting hydroxy group participates in the

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• -containing derivatives are biologically interesting (Figure 1) [7]. In addition, molecular docking studies have been performed and highlighted the importance of three binding areas within the active site of the protein: a hydrophobic clamp (Phe157, His209 and Tyr210) interacting with the nucleobase, a

Artificial Diels–Alderase based on the transmembrane protein FhuA

• Hassan Osseili,
• Daniel F. Sauer,
• Klaus Beckerle,
• Marcus Arlt,
• Tomoki Himiyama,
• Tino Polen,
• Akira Onoda,
• Ulrich Schwaneberg,
• Takashi Hayashi and
• Jun Okuda

Beilstein J. Org. Chem. 2016, 12, 1314–1321, doi:10.3762/bjoc.12.124

• absence of any enantioselectivity suggests that no preferential orientation of the substrate at the active site within the barrel structure is possible. Notably, no protein precipitated during catalysis, showing the advantageous feature of membrane proteins in terms of robustness as compared to soluble

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

• , given that the active site Zn2+ is proposed to activate the cysteine side chains for cyclisation. The identification of the labyrinthopeptins [59] (Figure 4C) led to the discovery of a subset of class III lanthipeptides that contain an additional carbocyclic ring, which features the labionin (Lab) amino

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

• within the superfamily of polyisoprenyl-phosphate N-acetyl hexosamine 1-phosphate transferases (PNPT). Mutation of these three aspartate residues (D115, D116 and D267 in the E. coli protein) resulted in a complete loss of catalytic activity. This led to a proposed model for the active site of MraY in

• protein E from bacteriophage X174, Bugg et al. reported a different site of inhibition in pronounced distance to the proposed active site. It has been demonstrated before that mutation of phenylalanine 288 (F288L) in helix 9 of MraY caused resistance against lysis protein E [72][73]. An interaction

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• option would be to obtain the ligand geometries inside an enzyme active site. Since conformational search inside a receptor normally gives the mode of interaction between substrate and enzyme, as well as the intermolecular interaction energy (related to the ligand–receptor affinity and, consequently, to

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

• exquisitely shaped hydrophobic pocket/active site. Ronald Breslow was asking similar questions and addressing it with cyclodextrin derivatives as enzyme mimics, but as I neared the end of my Ph.D. degree I confess I knew nothing of this facet of supramolecular chemistry. In 1991, as lab work started to be

• project on the synthesis of deep-cavity cavitands. The first was inspired by Murray Goodman’s work [13] on the covalent templation of small, stable collagen-like triple-helices, and involved positioning a metal-ion coordinating template into a collagen structure such that the “active site” was situated in

• ‘dangles’ above the zinc-bound water in the crystal structure of the enzyme. In addition to synthesis, the project also involved a good deal of potentiometry, and this began to teach me that synthesizing enzyme mimics was a difficult challenge of balancing the need to create functionality for the active

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• mechanism for CorB and MxnB closely resembles each other, but certain differences have also been proposed, as will be discussed here. First, one chain is transferred and covalently linked to the active-site cysteine. This results in an activation of the cysteine-tethered chain. In the second step, the other

• -oxohexanoyl thioester and different thioesters of straight-chain and iso-branched chain fatty acids [14]. The mechanism proposal also includes the catalytic cysteine. The first chain, i.e., thioester-activated 9-methyldecanoic acid, gets covalently tethered to that important residue within the active site

• chains are positioned face to face. A) Transacylation of the eastern chain to C121 of CorB. The simplified mimic of the eastern chain (shown in bold) was placed into the active site on the basis of its unbiased (F0–Fc)-difference electron density. The remaining portion of the eastern chain was modeled

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• analogues complexed inside the model ribosomal active site. Sampling the lowest energy wells in a 40 kJ/mol energy window the lowest enthalpy minimum was used to assess the relevant terms in Equation 1 below. Since the linezolid complex represents the zero point of our relative binding energy scale, a

• . In a second step, models of different size were cut out from this working shell in order to find the smallest model still including all relevant moieties affected by linezolid inside the active site (working shell I). The resulting ribosomal model still characterized by 1) the reproduction of

• , induced by subtle chemical differences (H vs CH3) favoring 5 over 6 by more than 13 kJ/mol. An inspection of our obtained minima reveals that, whereas the flexible terminal N-glycinyl chain is capable of making different water mediated H-bonds or with the residues from the active site entrance directly

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• indicated that the bornyl cation also has a short lifetime in the active site of the enzyme, but one – 185 fs on average – that is longer (by approximately a factor of 4) than in the absence of the enzyme and complexed diphosphate. Take home messages: • Secondary carbocations, which often correspond to

Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds

• Sophie Letort,
• Sébastien Balieu,
• William Erb,
• Géraldine Gouhier and
• François Estour

Beilstein J. Org. Chem. 2016, 12, 204–228, doi:10.3762/bjoc.12.23

• ions in the solvent. Acting as the active site, the substitution of secondary hydroxy groups might impact the hydrolysis rate. This was investigated comparing the effect of β-CD, DIMEB and TRIMEB on the alkaline hydrolysis of parathion, methyl parathion, and fenitrothion [53][54]. In all host–guest

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• , ranging from the use of carboxylated cofactors [28][32] to complex extended metabolic pathways in C4 and CAM plants [17][33][34] and substrate channelling. In addition, a number of enzymes accept HCO3− as a substrate, which is converted to CO2 close to the active site before the reductive step [26][28

Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• monooxygenases are useful biocatalysts for C–H activation, and there is a need to expand the range of these enzymes beyond what is naturally available. A panel of 93 variants of active self-sufficient P450cam[Tyr96Phe]-RhFRed fusion enzymes with a broad diversity in active site amino acids was developed by

• hydroxylations. Keywords: active site mutagenesis; biotransformation; C–H activation; cytochrome P450cam monooxygenase; hydroxylation; Introduction Selective C–H activation and oxyfunctionalisation of hydrocarbons offers a route to chiral alcohols and other industrially important synthetic building blocks from

• –alkyl compounds [3], olefins [4], polycyclic aromatic hydrocarbons [5], terpenes [6][7][8] and alkanes as small as ethane [9]. Over the years a number of active site mutants of P450cam have been generated by rational re-design, but the active site has not been explored in a comprehensive and systematic

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

• diacid derivative of oleic acid catalyzed by dibutyltin oxide and Novozyme 435 (Figure 10) [59]. Dibutyltin oxide catalysis resulted in cross-linking and gel formation. This was not observed by enzyme catalysis, presumably due to steric hindrance which may be imposed by the active site of the enzyme

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