Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• the anaerobic bacteria, Sulfurospiririllum multivorans, uses 1,1,2,2-tetrarchloroethene as a terminal electron acceptor to be reduced to trichloroethene (Scheme 8a) [87]. In electron transport chains, reductases reduce the Co(II) species of the B12 cofactor to the Co(I) species in the active site of

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• simultaneously bind to amino acid residues present in both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. The CAS is located deeply inside the narrow gorge and is responsible for ACh hydrolysis. On the other hand the PAS is located around the entrance of the active site gorge and

• is responsible for transient substrate binding before reaching the active site. Especially PAS plays a crucial role in β-amyloid (Aβ) fibrillogenesis in AD patients by forming stable AChE–Aβ complexes [3][4]. Thus, these types of effects may render them potential therapeutic agents for AD treatment

• program [19] was used to investigate the orientation of the compounds in the rhAChE binding site. Compounds 4a, 9a, 9b, 9e, 9h, 9i, and 10a were selected as representatives for the docking study. The active site of human AChE, which is at the bottom of a deep and narrow gorge, consists of several major

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• -hydroxynicotine in the active site is followed by hydrolysis of the oxidized amine in a second site to yield 6-hydroxypseudooxynicotine (Scheme 3) [15]. However, a recent analysis of the structure of the product of the LHNO reaction utilizing NMR and continuous-flow mass spectrometry established that the enzyme

Spectroelectrochemical studies on the effect of cations in the alkaline glycerol oxidation reaction over carbon nanotube-supported Pd nanoparticles

• Dennis Hiltrop,
• Steffen Cychy,
• Karina Elumeeva,
• Wolfgang Schuhmann and
• Martin Muhler

Beilstein J. Org. Chem. 2018, 14, 1428–1435, doi:10.3762/bjoc.14.120

• -donating effect of the embedded nitrogen species [35]. Pd0 is also considered the active site in glycerol electrooxidation, and the observed lower overpotential may originate from the same interaction with the nitrogen-doped support. Furthermore, the thermal treatment of the oxygen-functionalized CNTs in

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

• among AHL synthases is observed. The preference for unsubstituted, 3-oxo or 3-hydroxyacyl precursors is mediated by binding interactions inside the active site of AHL synthases [18][21]. Investigations on the chain-length selectivity of the AHL synthases are limited. BjaI can accept substrates ranging

• distribution of the saturated AHLs as for the first experiment was observed with none of the additional substrates showing a significantly higher conversion. These results point to a very flexible active site of the investigated AHL synthase PgaI2, which converts a variety of substrates. The highest conversion

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• observed that the conjugates with alkynyl side chains show excellent E. coli DNA topoisomerase I inhibition properties with IC50 values of <5.0 μM, which was attributed to critical interactions between the inhibitor side chain and amino acids of the active site of DNA topoisomerase I, as suggested by the

Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies

• Elias Christoforides,
• Andreas Papaioannou and
• Kostas Bethanis

Beilstein J. Org. Chem. 2018, 14, 838–848, doi:10.3762/bjoc.14.69

• of the [FeFe]-H2ase active site, (μ-SCH2NH(C6H4SO3−)CH2S)[FeI(CO)3]2, within the cavity of a 1·2 β-CD sodium salt clathrate. 28 water molecules are also found in the asymmetric unit. The incorporation of charged functional groups into the guest molecule of cyclodextrin host/guest system provides a

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• of catalysts in a nanoreactor facilitates one-pot tandem reactions that, in most cases, require two or more incompatible catalysts [22][57]. Catalyst confinement leads to a high local concentration of the substrate at the active site, which results in higher reaction rates and better conversion [9

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• increased steric bulk of the fluorinated amino acid, meaning protection from protease degradation is a result of the steric occlusion of the peptide from the active site [23][28]. In contrast, the Marsh lab found that the introduction of HfLeu into the antimicrobial peptide MSI-78 only renders it more

• binds in an extended conformation to the enzyme’s active site [42]. The positions P2, P1’ and P2’ at or adjacent to the cleavage site [41] carry the key residues for the recognition of the substrate by the protease and serve as substitution sites. The alanines at P2, P1’ or P2’ positions were

• enzymes in humans. It exhibits specificity for hydrophobic, especially aromatic residues like Phe, Trp, and Tyr at the P1 and P1’ positions [50][51][52][53][54]. It has an extended active site that can bind at least seven residues [66][67], and peptide bond cleavage occurs N-terminal to the residue at

Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes

• Hui Hong,
• Markiyan Samborskyy,
• Katsiaryna Usachova,
• Katharina Schnatz and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2017, 13, 2408–2415, doi:10.3762/bjoc.13.238

• each of the characteristic active site sequence motifs for the ketosynthase (KS), acyltransferase (AT), ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) domains of each of the 27 extension modules, including the newly-recognised YGP motif of active DH domains [8] between the three PKS

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• ) and the NSE triad NDXXSXX(R,K)(E,D), modified to a DTE triad in plants, for binding of the Mg2+ cofactor that forms a trinuclear (Mg2+)3 cluster to which the diphosphate portion of the substrate binds. Upon substrate binding the active site closes, resulting in hydrogen bonds between the substrate’s

2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of ß-barrel hybrid catalyst for phenylacetylene polymerization

• Julia Kinzel,
• Daniel F. Sauer,
• Marco Bocola,
• Marcus Arlt,
• Tayebeh Mirzaei Garakani,
• Andreas Thiel,
• Klaus Beckerle,
• Tino Polen,
• Jun Okuda and
• Ulrich Schwaneberg

Beilstein J. Org. Chem. 2017, 13, 1498–1506, doi:10.3762/bjoc.13.148

• the choice of the stabilization reagent. In case of PE–PEG, FhuA ΔCVFtev precipitation is observed. Filtering of the solution shows similar results as the reaction with the precipitate present, indicating a deactivation of the catalyst or restricted access of the substrate to the active site. The

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

• consideration for animal FAS (again abstracted as spanning a cylindrical reaction space, two full sets of active sites) gives a virtual active site concentration of 1.2 mM. Accordingly, both scaffolds of FA type I synthesis facilitate reactions at high virtual concentration of enzymatic domains. PKS

• megasynthases share basic principles with the mammalian FAS fold (Figure 2c) [6][7], and it is valid to assume that active site concentrations lie in the similar range. Bacterial and mitochondrial FA synthesis comprises separate enzymes. To compensate for the lower organizational level, key enzymes occur at

• “preserve-and-adapt”. While the adaptation of active sites will remain as a challenging task in such an approach, the generally profound description of substrate/active site complexes, the conservation of active sites beyond protein families, and their susceptibility for biophysical assays makes the

Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• expanded substrate scope [18]. Moreover, our recent structural characterizations of WelO5 in the absence and presence of 2 have shown residues 215-232 of WelO5 encode an α-helical motif that helps keeping the small molecular substrate in the active site by undergoing a dramatic conformational change upon

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• variants of these folds), namely GT-A and GT-B (Figure 8). Different folds are nevertheless observed for GTs that use lipid phosphate donor substrates. The achievement of the enzyme-transition state complex requires a particular arrangement of the active site that is the result of concomitant protein

• crystalline glycosyl transferase. The four steps of the “freeze-trigger” process could be validated throughout by elucidation of the crystal structure of the glycosyl transferase, which has the active site occupied in a semi-closed conformation of the substrate with various levels of ordering of the internal

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• active site. This is further supported by Wildeboer’s study from 2005 who reported a much lower affinity of desmethoxy-βE compared to the parent DHβE [27]. Conclusion In summary, we have successfully developed a strategy to construct the CD ring system of DHβE and to efficiently access the synthetically

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• committed step in synthesis of these Class I enzymes is the abstraction of the diphosphate group from the isoprenyl diphosphate substrate [50] at what the diphosphate group is postulated to remain inside the active site of the enzyme [51][52]. Class II terpene synthases harbor a distinct DXDD-motif [52] and

• , combinatorial enzyme design and microbial engineering. Mutational engineering of terpene synthases Site-directed mutagenesis of diterpene cyclases is conventionally applied to elucidate structure–function relationships and mostly targets the active site of the enzyme in order to change the polarity or dimension

• to phytotoxic fusicoccin A [60] and its derivative with presumably anticancer potential [61]. Exchange of two amino acid residues in the active site of the Class II peregrinol diphosphate synthase from the horehound Marrubium vulgare (MvCPS1) [58] resulted in an altered neutralization mechanism of a

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• at full conversion) [119]. No justification for this evidence was proposed, however, a lower stability of the active site-adsorbed alkene intermediate with increasing steric hindrance may be hypothesized, which results in fewer interactions with hydrogen species, thus in enhanced the selectivity of

• from a diffusion-controlled to kinetic-limited regime [163][181]. The non-accumulation of co-products adsorbed on the catalyst surface may also significantly contribute to the minimization of active site inhibition under the conditions of continuous flow [27]. Flow reactor design. Performance

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

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

• ][32][33][34][35][36][37], in combination with structure elucidation at high resolution of AT5 from the DEBS PKS, which was solved in the presence of acetate (Figure 7) [38]. For example, extender unit-specific ATs contain positively charged residues in the active site (R667 and H745, DEBS AT5

• numbering) capable of forming salt bridges with the carboxyl group of the building block, while these are non-polar amino acids in starter-unit specific ATs. The choice of methylmalonyl-CoA over malonyl-CoA is correlated with a YASH motif some 100 residues downstream of the active site serine, whereas

• malonyl-CoA specific ATs exhibit an alternative HAFH sequence (Figure 7a) [38]. In the AT5 crystal structure, the Tyr, Ser and His all lie within the active site (the His is the second member of the catalytic dyad). This leads to a model in which the C-2-methyl of methylmalonyl-CoA forms favorable

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

• -domain likely hinders reorganisation of the P450/NRPS complex and hence can be trapped in states that display sub-optimal substrate orientation in the P450 active site [12]. In the case of StaF, it now seems clear that the natural X-domain is in fact the best system for peptide cyclisation, although

• reactions and provide further indication that its role appears to be more than just recruitment of the P450 to the substrate, but also ensuring proper substrate orientation via the PCP-domain in the P450 active site. Structure and active site architecture of StaF In order to gain insight into the structure

• feature of StaF is the long A’ helix at the N-terminus, which forms the ceiling of the active site. This helix seems to be specific for D-O-E ring catalysing P450s as it was only observed once before in OxyAtei, the D-O-E ring forming P450 from teicoplanin biosynthesis [14]. The centre of the active site

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

• developed a library of cysteine reactive chemical probes with an alkyne handle for fluorescence tagging and report the selective and highly sensitive in vitro labelling of the active site cysteine of this important enzyme. Interestingly, only one type of probe, with a reactive α-chloroacetamide was capable

• of covalently reacting with the active site. We demonstrated the potential of our probes in a competitive labelling platform where we screened a library of synthetic HHQ and PQS analogues with heteroatom replacements and found several inhibitors of probe binding that may represent promising scaffolds

• for the development of customized PqsD inhibitors as well as a chemical toolbox to investigate the activity and active site specificity of the enzyme. Keywords: activity-based probes; PqsD; protein labelling; Pseudomonas aeruginosa; quinolones; Introduction The emergence of multi-drug resistant

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• reported for HIV integrase. MD simulations that were performed with the holo-structure of HIV integrase bound to a known ligand showed signs of a novel binding pocket opening in close proximity to its active site [183]. RCS ligand docking showed that this binding site is a possible binding pocket for drug

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• plays a dominant role in catalysis [3][4][5]. Also for the pistol ribozyme, evidence exists that an adenine-N3 in the active site is significant for the cleavage activity, most likely by 5’-O-leaving group stabilization through proton shuttling [6][7]. Another example for a specific role of an adenine

Radical polymerization by a supramolecular catalyst: cyclodextrin with a RAFT reagent

• Kohei Koyanagi,
• Yoshinori Takashima,
• Takashi Nakamura,
• Hiroyasu Yamaguchi and
• Akira Harada

Beilstein J. Org. Chem. 2016, 12, 2495–2502, doi:10.3762/bjoc.12.244

• sites and catalytic active sites have been designed for polymerization reactions, relatively few reports have described a catalytic design in which the catalytic active site does not leave the CD monomer recognition site during the growing step. In a previous design of radical initiators with CDs, the

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• and achiral precursors such as geranyl diphosphate (GPP, monoterpenes), farnesyl diphosphate (FPP, sesquiterpenes) and geranylgeranyl diphosphate (GGPP, diterpenes). Terpene cyclases (type I) contain a trinuclear (Mg2+)3 cluster in their active site that is stabilised by binding to several highly