Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• , aminoacyl adenylate is released from the enzyme to be hydrolyzed by water. This process is called pretransfer editing. Cysteine is an amino acid that has a similar molecular volume to proline, and therefore cysteine can undergo activation and transfer by ProRS. To correct for this error, the transfer step

• is followed by the swinging of the charged tRNA to another pocket that is meant for the recognition of Cys-tRNAPro (the yeaK editing domain). If the amino acid is correct, the charged tRNA is released from the enzyme, and if cysteine is loaded on it, it is hydrolyzed. This process is called

• faster amide rotation kinetics, has been reported for fluoroproline containing cysteine-rich minicollagen domains [141], green fluorescent protein [117][142], ubiquitin [133], β2-microglobulin [136], thioredoxin A [119][143] and red fluorescent protein [137]. In addition, the effects of the fluoroproline

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• -phase peptide synthesis (SPPS) methods (15 and 16, Figure 1). A second well-established methodology for the 19F isotopic labelling of protein and peptides involves the post-translational chemical conjugation of an 19F probe to specific amino acids present within the protein, typically cysteine and

• combined with the aforementioned chemical approaches based on cysteine and lysine modification. It is worth noting that for small proteins and peptides the chemical incorporation of the desired fluorinated amino acids using SPPS protocols still remains the method of choice, as it enables the site-specific

• experiments using multi-site labelled proteins can be used to provide information on changes in the chemical environment of the protein surface, which can be used to characterize binding-sites and/or conformational changes upon binding. For example, 19F NMR studies on cysteine-labelled ß2-adrenergic receptor

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• interactions but have a high propensity to form interprotein interactions. In contrast, serine, threonine, asparagine (polar uncharged), alanine, valine, isoleucine (hydrophobic), cysteine, proline, and glycine are less likely to form interprotein interactions and bifurcated interactions. The binding mode in

Chemical constituents of Chaenomeles sinensis twigs and their biological activity

• Joon Min Cha,
• Dong Hyun Kim,
• Lalita Subedi,
• Zahra Khan,
• Sang Un Choi,
• Sun Yeou Kim and
• Chung Sub Kim

Beilstein J. Org. Chem. 2020, 16, 3078–3085, doi:10.3762/bjoc.16.257

• 1a (1 mg). To the dried water-soluble phase were added pyridine (0.5 mL) and ʟ-cysteine methyl ester hydrochloride (0.5 mg), and the reaction mixture was stirred at 60 °C for 1 h. Then, o-tolyl isothiocyanate (0.1 mL) was added and the mixture stirred at 60 °C for another 1 h. The reaction mixture

Semiautomated glycoproteomics data analysis workflow for maximized glycopeptide identification and reliable quantification

• Steffen Lippold,
• Arnoud H. de Ru,
• Jan Nouta,
• Peter A. van Veelen,
• Magnus Palmblad,
• Manfred Wuhrer and
• Noortje de Haan

Beilstein J. Org. Chem. 2020, 16, 3038–3051, doi:10.3762/bjoc.16.253

• compared to Skyline, and GlycopeptideGraphMS. All quantification packages resulted in comparable glycosylation profiles but featured differences in terms of robustness and data quality control. Partial cysteine oxidation was identified as an unexpectedly abundant peptide modification and impaired the

• quantification. Keywords: bioinformatics; cysteine oxidation; glycoproteomics; immunoglobulins; mass spectrometry; Introduction Protein glycosylation mainly occurs in the form of N- and O-glycosylation. N-Glycans are attached to Asn within an amino acid consensus sequence (Asn-Xxx-Ser/Thr, Xxx ≠ Pro) and O

• a fixed modification for cysteine residues. Methionine oxidation was enabled as a variable modification. The search for N- and O-glycopeptides was separately performed. For this purpose, either the database “N-glycan 309 mammalian no sodium” (Supporting Information File 7) or “O-glycan 78 mammalian

Enzyme-instructed morphological transition of the supramolecular assemblies of branched peptides

• Dongsik Yang,
• Hongjian He and
• Bing Xu

Beilstein J. Org. Chem. 2020, 16, 2709–2718, doi:10.3762/bjoc.16.221

• in a polymeric hydrogel for a responsiveness to thermolysin [35]. Dong et al. reported the branching of an oligopeptide via a cysteine linkage to result in multivalence [37]. During our studies on enzyme-instructed self-assembly (EISA) [38][39][40] of branched peptides for hydrogelation [32], we

pH- and concentration-dependent supramolecular self-assembly of a naturally occurring octapeptide

• Goutam Ghosh and
• Gustavo Fernández

Beilstein J. Org. Chem. 2020, 16, 2017–2025, doi:10.3762/bjoc.16.168

• in mind, we synthesized an octapeptide, PEP-1, which contains two valine (Val) units and one leucine (Leu) unit as the hydrophobic residues and one glutamic acid (Glu) residue, two arginine (Arg) units, and one cysteine (Cys) substituent as polar moieties (Scheme 1). This choice of amino acids

• temperature, and this was stirred for 2 hours following the same procedure as before. At the final stage, we cleaved the peptide from the resin by using a proper cleavage cocktail: TFA/phenol/water/TIPS 88:5:5:2. DTT was included, as this peptide contains cysteine. After adding the cleavage cocktail to the

A dynamic combinatorial library for biomimetic recognition of dipeptides in water

• Florian Klepel and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2020, 16, 1588–1595, doi:10.3762/bjoc.16.131

• CXC peptide building block design (single-letter code) were the terminal amino acids are cysteine (C) and the X can be any amino acid (Scheme 1a). This allows for rapid synthesis of various new building bocks by standard Fmoc based SPPS using Trt protecting groups for cysteine, which are subsequently

• cleaved (see Supporting Information File 1 for details). It also enables easy incorporation of nonnatural amino acids if desired [21]. We prepared a DCL by dissolving CFC, CEC, CSC and CAC (C for cysteine, F for phenylalanine, E for glutamic acid, S for serine, A for alanine) in an equimolar ratio in a

• SPPS. Thus one cysteine moiety is left deprotected and can be addressed selectively either by dimerization with another CFC(Acm) or with inversely substituted tripeptide (C(Acm)FC). These linear peptide dimers were subsequently cyclized by oxidative cleavage of the Acm groups to give a(CFC)2 and p(CFC

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• glutathione. However, attempts to conjugate with a cysteine on a genetically modified nicotinic acetylcholine receptor did not afford the expected light-responsive channel. Our data indicate that the 4FAB photoswitch can be derivatized bifunctionally for genetically-targeted photopharmacology whilst

• temperature. The maleimide-substituted compound 1 reacted with the cysteine of glutathione, however, we found that this "4FAB version" of MAHoCh (Scheme 1) did not enable significant perturbation of nicotinic acetylcholine receptor currents used with MAHoCh [16]. However, when 4FABTA analog 2 was tested as a

• maintains the near-ideal chemical properties of Hecht’s 4FAB chromophores [12][13] (see below). The final synthetic challenge was the installation of a maleimide onto chromophore 2. The original AB photoswitchable probes which were cross-linked to cysteine mutants had amides with a reverse orientation [19

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• cysteine sulfhydryl side chain to electrophilic Cβ of an O-acetylated Morita–Baylis–Hillman (MBH) adduct residue (Scheme 1). Despite reports describing the use of amino acid residues with nucleophilic side chains to prompt the macrocyclization of peptides and their mimetics, to the best of our knowledge

• on the compound can be a q or t, integrating for one hydrogen, assigned to C3 methine hydrogen. The 1H,13C-HMBC spectra allows us to observe an important strong correlation between the signals assigned to the protons on C1 and the carbon Cβ of the cysteine, which strongly suggest the formation of the

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• cysteine residue in the immediate proximity to the active site and the enone moiety of AbC. The PABA pathway is essential in bacteria but absent in humans, making AbC a promising compound for further development towards an antibiotic drug candidate. Because of its intriguing structure and antibacterial

• docking of known and proposed ligands. The crystal structure contains a tryptophan molecule in the active site. Restrained molecular dynamics [20][21] was employed to position the active site cysteine (Cys-263) in a position that would allow covalent binding of the ligands in the active site. The

• , which suggests a suitable level of structural truncation of compound 2. Further docking studies, using covalent docking, also showed that both atrop-O-benzyl-desmethyl-abyssomicin C and 2 can bind to the active site cysteine via a Michael addition to the α,β-unsaturated ketone, still maintaining the

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• biosynthetic precedence, MicH is responsible for the assembly of a thiazoline ring through condensation of a cysteine residue and subsequent cyclization [16]. The lack of MicH would hence indicate the absence of the corresponding thiazoline motif in the corresponding natural product. Based upon the assumption

• stereochemistry at the C2 position derived from L-cysteine. This is because the MicC homolog from Massilia sp. NR 4-1 features only a single adenylation domain for the activation of L-cysteine, which corresponds to the micacocidin and yersiniabactin assembly lines [13][16]. An inspection of the ketoreductase (KR

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• -free click reactions) [14]. The second functional unit, the maleimide moiety, is a reactive probe for mercaptane, which could be, e.g., a protein holding a cysteine residue on its surface [15][16][17]. The successful ligation by conjugated addition can be followed by the changes of the fluorescence

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• shock protein from M. Jannaschii (MjHSP) [71]. The authors reported a HG-II-type catalyst modified on its NHC backbone with an α-bromoacetyl unit (68) that is reacted with the unique cysteine of the modified MjHSP variant (G41C) to afford ArM 4 (Scheme 15). The hybrid catalyst ArM 4 was then tested for

• variant of the β-barrel protein FhuA [73][74]. To do so, the authors duplicated multiple β-barrel strands to enlarge the cavity of the protein. HG-type catalysts bearing a maleimide moiety with different spacer lengths (69–71) were covalently anchored to a cysteine of the expanded nitrobindin variant

• -selective protein modification through aqueous CM [83], thus expanding the catalytic repertoire of protein modification with transition-metal catalysts [84][85][86][87]. A variant of subtilisin from Bacillus lentus containing a single cysteine (SBL-S156C) was modified by direct allylation to install an

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• -1)-βA),F7,L17,P34]-hNPY (8), was synthesized by reacting the tubugi-1-SSPy (3) with the free thiol function of a β-alanine–cysteine dipeptide (βAC) linked to the side chain of Lys4 of the targeting peptide. For this purpose, 1 mol equiv of the tubugi-1-SSPy building block 3 and one molar equivalent

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• human C-type mannose receptor 2, the sequence identity was 28%. Identical amino acids are highlighted in grey, amino acids with a small/polar side chain: orange, hydrophobic side chain: green, charged side chain: red, aromatic amino acids and cysteine: violet. β-Sheets of the secondary structure are

Green synthesis of new chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones from the corresponding α-amino acid arylhydrazides in aqueous medium

• Nadia Bouzayani,
• Jamil Kraїem,
• Sylvain Marque,
• Yakdhane Kacem,
• Abel Carlin-Sinclair,
• Jérôme Marrot and
• Béchir Ben Hassine

Beilstein J. Org. Chem. 2018, 14, 2923–2930, doi:10.3762/bjoc.14.271

• (3d), (L)-cysteine phenylhydrazide (3g), (L)-tyrosine phenylhydrazide (3j), (L)-alanine 4-chlorophenylhydrazide (3k), (L)-phenylglycine 4-chlorophenylhydrazide (3l) and (L)-phenylalanine 4-chlorophenylhydrazide (3m) were synthesized for the first time in this work. Verardo et al. [29] have shown that

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• post-expressional protein modifications [10][11][12]. For example, a single cysteine mutant of subtilisin from Bacilus lentus (SBL-S156C) was modified via sulfide bond formation with allyl cysteine displaying an allyl function on the protein surface. This allyl group was modified with a GH-type

• . Engineered variants of NB were used to construct artificial metatheases [56]. The cavity of NB was enlarged by introducing five mutations compared to the NB wild-type. Two histidines were substituted by leucine or alanine. Furthermore, a cysteine was introduced allowing covalent anchoring, and the two

• wild-type protein). For covalent anchoring, a cysteine residue was introduced at position 545 [59]. This position is suggested to be in a conformationally stable environment within the β-barrel structure. Additionally, mutation N548V was introduced to enable access of the metal catalyst to position

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• amino acid cysteine is also cumbersome and challenging. Recently, Low et al. reported synthesis of various targeted conjugates in which fluorescent tag [37] has been attached in a solution phase reaction. Also, they have reported the synthesis of ligand-conjugated peptides containing a radiotracer

• commonly available and less expensive cysteine-labelled 2-chlorotrityl resin (Figure 1b). The methodology is general and can be significantly useful for acid-sensitive resins that contain acid-labile orthogonal amino acids with 4-methoxytrityl (Mmt) and 4-methyltrityl (Mtt) protecting groups. Results and

• . This is compensated by introduction of dibasic amino acid like diaminopropionic acid (Dap), acidic amino acids like aspartic acid (Asp) and polar cysteine amino acid (Cys) that makes up the chelating core. In the case of FR targeted fluorescent conjugate 17, the targeting ligand, folic acid, is

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• sub-micromolar IC50 (318 nM). Compound 11 was originally designed by the Meijler lab to react with a cysteine in the AHL-binding pocket of LasR, thereby acting as an irreversible inhibitor [44]. SdiA does have a cysteine in the binding pocket (Cys45, see Figure 1D), but it is positioned near carbons 3

• identified that can be used for developing second-generation AHL-type ligands with enhanced potencies in SdiA: using electrophilic groups to target the cysteine in the SdiA binding pocket (taking a possible cue from 11); delineating the SARs for activity by the POHL class, with an eye toward examining bulky

• ), and a cysteine that potentially could be involved in inhibition (purple, see discussion below). Overview of SdiA agonism and antagonism single-point screening results in the S. Typhimurium reporter. Agonists are indicated in green. Antagonists are indicated in red. Compounds with less than 10% agonism

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• -CoA) is then transferred to an active-site cysteine of the β-ketoacyl-ACP synthase III (FabH)-type enzyme PqsD [26][27]. Subsequently, another CoA-activated substrate comes into play. In analogy to fatty acid synthesis, malonyl-CoA is reacted with the enzyme-bound thioester to yield 2

• formed by action of the heterodimeric complex PqsBC. This time, CoA-activated octanoic acid is used to preload an active-site cysteine of PqsC with the fatty acid via a thioester linkage [30][31]. The previously produced 2-ABA is then consumed to from HHQ under decarboxylative condensation [30]. Finally

• docking [51]. These inhibitors appeared to bind in the substrate channel in a slightly remote position from the active site cysteine and, hence, termed channel blockers [51]. Optimised hits exhibited a potency in the single-digit micromolar range (12, Figure 6). However, it has been found that similar

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• the aryl substitution resulted in a flat SAR with only little variation in potency among the substituents analyzed [30][36][37][38][39]. Just recently, in an attempt to search for new pharmacophores, Titz et al. have reported the synthesis of the epoxyheptose derivative 11 targeting a cysteine residue

Functionalization of graphene: does the organic chemistry matter?

• Artur Kasprzak,
• Agnieszka Zuchowska and
• Magdalena Poplawska

Beilstein J. Org. Chem. 2018, 14, 2018–2026, doi:10.3762/bjoc.14.177

• -cysteine has been proposed or discussed. Most plausibly, the attack of cysteine’s highly nucleophilic sulfur on GO’s epoxides did occur in this case [30][31], based on the changes observed in the IR spectrum of the product. The material’s structure would include free amino and carboxyl groups forming the

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• converted to the epoxide 123, which upon thiolysis with a strategically protected cysteine, gave the regioisomeric hydroxy sulfides 124 and 125 (Scheme 43). Each of these was then converted to natural pteriatoxin A (7) and its analog 126. Epoxide opening to yield β-hydroxy sulfides of unnatural (artificial