Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• enzymes belong to the family of oxidoreductases with NAD+ or NADP+ as electron acceptor. This oxidation is a mandatory step for removing the OH functionality at C12. In all the chemoenzymatic routes reported by Eggert et al. [20], the carbonyl group resulting from the oxidation of the 12-OH group was

• leptum [48] and Clostridium group P strain C 48–50 [49][52]). Furthermore, on the other side, the NAD+-dependent 12α-HSDHs activity was observed and reported in Eubacterium lentum and Clostridium perfringens [50][51]. A NAD+ dependent process for the production of 12-oxo-CDCA was patented in 2006 [53

• presented in the next paragraphs. 7α-Hydroxysteroid dehydrogenases (7α-HSDH) These enzymes are able to oxidise specifically the α-hydroxy group at C7 together with the concomitant reduction of NAD+ or NADP+ (Figure 5). All of them are part of the group of the short chain dehydrogenases/reductases (SDR

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• ], NAD-capped RNAs [23][24], 3'-dephospho-CoA linked RNA [25] or methylphosphate capping [26][27] we refer to the indicated articles. Review Enzymatic preparation of capped mRNA Enzymatic preparation of capped mRNA is based on in vitro transcription (IVT) of a DNA template. While RNA synthesized via

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• nucleophile (Figure 6) [54]. Rarer mechanisms have also been discovered, like for example the one of i) myrosinases in plants that are retaining GHs that lack a general acid and use an exogenous base [55], or ii) some GHs from families 4 and 109 which follow a NAD-dependent hydrolysis [56][57]. Even if the

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• during system preparation was still necessary and it speaks against a separate evolution of the system parts. In the case of fatty acid experiments [90], fatty acid vesicles were formed on/around titanium oxide particles and the irradiation of the photosensitizer powered the reduction of NAD+ to NADH

Synthesis and enzymatic ketonization of the 5-(halo)-2-hydroxymuconates and 5-(halo)-2-hydroxy-2,4-pentadienoates

• Tyler M. M. Stack,
• William H. Johnson Jr. and
• Christian P. Whitman

Beilstein J. Org. Chem. 2017, 13, 1022–1031, doi:10.3762/bjoc.13.101

• to the position of the ring fission (shown on 1 in Scheme 1). An extradiol dioxygenase processes catechol 1 to 2-hydroxymuconate semialdehyde 2, which is oxidized by an NAD+-dependent dehydrogenase to yield 2-hydroxymuconate (3a) [6][7]. Ketonization of 3a to 2-oxo-3-hexenedioate (4a) is catalyzed by

• ]. VPH catalyzes the addition of water to the C-4 position of 5a to produce (S)-2-keto-4-hydroxypentanoate (6a) [9][10][11]. A retro-aldol cleavage of 6a by pyruvate aldolase yields pyruvate and acetaldehyde (7a). Pyruvate aldolase is tightly coupled with an acetaldehyde dehydrogenase, which uses NAD

Investigation of the action of poly(ADP-ribose)-synthesising enzymes on NAD⁺ analogues

• Sarah Wallrodt,
• Edward L. Simpson and
• Andreas Marx

Beilstein J. Org. Chem. 2017, 13, 495–501, doi:10.3762/bjoc.13.49

• labelling approaches comprising different reporter-modified NAD+ building blocks have stimulated and enriched proteomic studies and imaging applications of ADP-ribosylation processes. Herein, we compare the substrate scope and applicability of different NAD+ analogues for the investigation of the polymer

• -synthesising enzymes ARTD1, ARTD2, ARTD5 and ARTD6. By varying the site and size of the NAD+ modification, suitable probes were identified for each enzyme. This report provides guidelines for choosing analogues for studying poly(ADP-ribose)-synthesising enzymes. Keywords: ARTD; click chemistry; NAD+; poly(ADP

• of ADP-ribosylation [3][4]. This posttranslational modification received considerable attention within the last decade [5][6] and has been linked to tumour biology, oxidative stress, inflammatory, and metabolic diseases [7]. Using NAD+ as a substrate, ARTDs covalently transfer ADP-riboses onto

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

• genetic molecule RNA (see below) and is also an important component of coenzymes (ATP, FAD and NAD). In 1992, Aoyama et al. reported on the selective complexation of pentoses and hexoses by β-CD [95]. Based on competitive inhibition of the 8-anilinonaphthalene-1-sulfonate binding followed by fluorescence

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

• 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

• ’-oxoaverantin (101) into averufin (102) by intramolecular acetal formation [87]. To date, it is not clear, how exactly the OAVN cyclase participates in this process [88]. Interestingly, the OAVN cyclase operates cofactor-free, although it contains a NAD(P)+-binding Rossman fold. Furthermore, this enzyme is also

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

• Matthias Bender,
• Henrik Mouritsen and
• Jens Christoffers

Beilstein J. Org. Chem. 2016, 12, 912–917, doi:10.3762/bjoc.12.89

• coenzymes like NAD+ or FAD – discovered relatively late (in 1972) [3]. Its biosynthetic precursor, 7,8-didemethyl-8-hydroxy-5-deazariboflavin (1, Scheme 1) without a phosphodiester extension is called FO and came into our focus of interest because it was for instance suggested to function as an antenna

Highly stable and reusable immobilized formate dehydrogenases: Promising biocatalysts for in situ regeneration of NADH

• Barış Binay,
• Dilek Alagöz,
• Deniz Yildirim,
• Ayhan Çelik and
• S. Seyhan Tükel

Beilstein J. Org. Chem. 2016, 12, 271–277, doi:10.3762/bjoc.12.29

• a great potential in the enantioselective reduction of ketones [1][2] and/or carbon–carbon double bonds [3][4] to produce optically active compounds. However, most dehydrogenases use an expensive cofactor such as NAD(H) or NADP(H) [5]. Therefore, the regeneration of the cofactor is required to

• decrease operational costs. NAD+-dependent formate dehydrogenase (FDH, EC 1.2.1.2) catalyzes oxidation of formate to carbon dioxide (CO2) [6]. FDH is industrially used as coenzyme for the regeneration of NADH [7][8], as sensor for the determination of formic acid [9], and as catalyst for the production of

• conditions. Hence, the use of a proper immobilization technique and support could stabilize its dimeric form. In this study, NAD+-dependent FDH from Candida methylica was covalently immobilized onto Immobead 150, an epoxy group containing commercial support, and Immobead 150 support modified with

Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

• Ahmed Mahal,
• Stefano D’Errico,
• Nicola Borbone,
• Brunella Pinto,
• Agnese Secondo,
• Valeria Costantino,
• Valentina Tedeschi,
• Giorgia Oliviero,
• Vincenzo Piccialli and
• Gennaro Piccialli

Beilstein J. Org. Chem. 2015, 11, 2689–2695, doi:10.3762/bjoc.11.289

• [17]. Using the Aplysia ADP-ribosyl cyclase many metabolite analogues of cADPR have been produced starting from NAD+ and NADP+ [18][19][20][21]. However, the specificity of the enzymatic cyclization mechanism drastically limits its applicability for enzymatic or chemo-enzymatic procedures. For this

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

• hydrolysis of phosphoanhydride bonds [25][26][27]. For reductases or dehydrogenases operating in reverse, the electrons required to reduce CO2 are provided through oxidation of reduced forms of redox cofactors, either directly or through electron driving protein mediation (NAD(P)H or equivalents). For a

• two steps catalysed by NAD(P)H dependent dehydrogenases. Later in the pathway, propionyl-CoA (17) is the substrate for a second carboxylation with HCO3− to methylmalonyl-CoA (18), performed by the same ATP-dependent bifunctional carboxylase that carries out the first step [71][72]. Succinyl-CoA (5) is

• enzyme reported to catalyse both formate oxidation and CO2 reduction under appropriate conditions, using substrate amounts of NAD+/NADH [119]. This enzyme was later used in the seminal work of Parkinson and Weaver [120], where electrons were supplied through a semiconductor photoelectrode using light in

Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines A, B and C and taste evaluation

• Marco G. Rigamonti and
• Francesco G. Gatti

Beilstein J. Org. Chem. 2015, 11, 2117–2124, doi:10.3762/bjoc.11.228

• dehydrogenases (ADHs) was screened [17], the regeneration of the NAD(P)+ cofactor was carried out using a glucose dehydrogenase (GDH from Bacillus megaterium), with glucose as co-substrate [18]. The product distributions are reported in Table 1. However, most of these ADHs gave low conversions and selectivity

• and conditions: (a) Jones reagent, acetone, 0 °C, 3 h; (b) DIBALH, 2-propanol, toluene, 0 °C/rt, 6 h; (c) L-selectride, THF, −78 °C/rt, 16 h; (d) ADH, cofactor NAD(P)H+, GDH, glucose, water, 30 °C, 24 h; (e) p-nitrobenzoic acid, PPh3, DIAD, toluene, 0 °C, 24 h; (f) MeONa, MeOH, rt, 5 h. Reagents and

Engineering Pichia pastoris for improved NADH regeneration: A novel chassis strain for whole-cell catalysis

• Martina Geier,
• Christoph Brandner,
• Gernot A. Strohmeier,
• Mélanie Hall,
• Franz S. Hartner and
• Anton Glieder

Beilstein J. Org. Chem. 2015, 11, 1741–1748, doi:10.3762/bjoc.11.190

• the recent years, a broad range of cofactor regeneration systems based on enzymatic, chemical, photochemical or electrochemical processes have been developed [3]. In living (growing) cells, NAD(P)H can be recycled via the cellular metabolism of a co-substrate such as glucose. Alternatively, cofactor

• oxidized by alcohol oxidase (AOX) to formaldehyde, which is further metabolized either in the assimilatory or in the dissimilatory pathway. In the latter one, formaldehyde spontaneously reacts with glutathione to S-hydroxymethylglutathione which is oxidized in a first step by the glutathione- and NAD

• +-dependent enzyme formaldehyde dehydrogenase (FLD) to S-formylglutathione. S-Formylglutathione hydrolase (FGH) then hydrolyses this compound to formate and glutathione. In a second NAD+-dependent step, formate is oxidized to CO2 by formate dehydrogenase (FDH). Thus, 2 equivalents of the cofactor NADH are

Gold(I)-catalysed synthesis of a furan analogue of thiamine pyrophosphate

• Amjid Iqbal,
• El-Habib Sahraoui and
• Finian J. Leeper

Beilstein J. Org. Chem. 2014, 10, 2580–2585, doi:10.3762/bjoc.10.270

• to NAD+ is monitored by UV spectroscopy at 340 nm. In order to follow the time-course of binding of furan 17, various concentrations (1–8 µM) were incubated with apo-PDC in a Mg2+-containing buffer and aliquots were taken out at timed intervals (1–30 min) and added to the assay solution containing

An integrated photocatalytic/enzymatic system for the reduction of CO₂ to methanol in bioglycerol–water

• Michele Aresta,
• Angela Dibenedetto,
• Tomasz Baran,
• Antonella Angelini,
• Przemysław Łabuz and
• Wojciech Macyk

Beilstein J. Org. Chem. 2014, 10, 2556–2565, doi:10.3762/bjoc.10.267

• . For the approach discussed here, the production of one mol of CH3OH from CO2 requires three enzymes and the consumption of three mol of NADH. Regeneration of the cofactor NADH from NAD+ was achieved by using visible-light-active, heterogeneous, TiO2-based photocatalysts. The efficiency of the

• regeneration process is enhanced by using a Rh(III)-complex for facilitating the electron and hydride transfer from the H-donor (water or a water–glycerol solution) to NAD+. This resulted in the production of 100 to 1000 mol of CH3OH from one mol of NADH, providing the possibility for practical application

• cofactors is nicotinamide adenine dinucleotide (NAD+), a cofactor of the oxydoreductase class of enzymes. NAD+, together with its reduced form, 1,4-NADH, plays an essential role in many metabolic processes of living cells. NADH is also important in industrial biocatalysis, namely in the process of reductive

Autonomous assembly of synthetic oligonucleotides built from an expanded DNA alphabet. Total synthesis of a gene encoding kanamycin resistance

• Kristen K. Merritt,
• Kevin M. Bradley,
• Daniel Hutter,
• Mariko F. Matsuura,
• Diane J. Rowold and
• Steven A. Benner

Beilstein J. Org. Chem. 2014, 10, 2348–2360, doi:10.3762/bjoc.10.245

• mM NAD+) and diluted with water (40 μL final volume; final concentrations: 250 nM each oligonucleotide, 5% PEG-6000, 100 mM Tris-HCl, pH 7.5, 10 mM MgCl2, 10 mM DTT, 1 mM NAD+). This mixture was then heated at 95 °C for 5 min, and then slowly cooled (0.1 °C/second) to 42 °C. Aliquots (5 μL) of the

Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect

• Josué M. Silla,
• Claudimar J. Duarte,
• Rodrigo A. Cormanich,
• Roberto Rittner and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2014, 10, 877–882, doi:10.3762/bjoc.10.84

• controlling the gauche effect in 1,2-difluoroethane and derivatives [7][8][9]. Nevertheless, the electrostatic gauche effect has been found to be operative in some β-fluoro-N-ethylpyridinium cations of interest, as well as in the C2'-endo conformation of NAD+ [5]. Since multifluorination represents a relevant

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

• et al. also reported an efficient oxidation of galactitol to L-tagatose through the use of galactitol dehydrogenase (GDH, EC 1.1.1.16) from Rhodobacter sphaeroides D and the overall yield was 78% [55]. This oxidation only requires catalytic amounts of NAD+, which is regenerated in situ through the

• conversion potential [52]. The production yield could reach above 60% in the presence of glycerol [52] which may be responsible for NAD+/NADH regeneration. Large-scale preparation of L-tagatose has not been extensively studied yet due to elaborate routes or expensive starting materials. In our lab, the

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

• of coenzyme NAD{P}). Although these entities are biogenic, the human body is not capable of producing them, thus industrial processes have had to be developed, Lonza and Reilly are historically the key players in this area [23]. The molecule 2-methyl-5-ethylpyridine (1.11) can be prepared directly

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• culture and mouse models of ALS. NSC-34 cells expressing SOD1 G93A were treated with 29 and activation of Nrf2 was tested. In response to treatment, the expression of Nrf2 and the Nrf2 regulated genes, NQO-1 (NAD(P)H quinine oxidoreductase), HO-1 (heme oxygenase-1), and glutathione reductase were

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

• transcriptional repression through both chromatin condensation and chromatin signalling. To date, 18 human genes encoding proven or putative HDACs have been identified [7]. HDACs fall into two categories: the zinc-dependent enzymes (class I, II and IV) and the NAD+-dependent enzymes (class III, also called

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• integrated formyl transferase domain in the initiation module and NAD-dependent halogenase. The formation of Ahp remains to be analyzed. Aeruginosin Aeruginosins are specific inhibitors of serine type proteases and produced by different genera of freshwater cyanobacteria. The strain Planktothrix agardhii

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

• , often with high regio- and stereoselectivity [1], and are therefore attractive candidates for biocatalyst development. However, the need for reconstitution of protein redox partners, the necessary use of expensive NAD(P)H, and the lack of widely applicable high-throughput screening protocols render the

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• BC when the ancient Sumerians and Babylonians practiced the brewing of beer and winemaking [6]. Indeed, in vivo fermentation of sugars to ethanol by yeast is a complex process involving at least 12 enzymes and 2 cofactors, NAD+ and ADP. Nowadays microbial biotransformations have become an