Facile Removal of Leader Peptides from Lanthipeptides by Incorporation of a Hydroxy Acid

Bindman, Noah A.; Bobeica, Silvia C.; Liu, Wenshe Ray; Donk, Wilfred A. van der

doi:10.1021/jacs.5b04681

Cited by 46 publications

(52 citation statements)

References 42 publications

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“…71, 270 Finally, E. coli has been engineered for the recombinant production of ribosomally synthesized posttranslationally modified peptides (RIPPs) that contain ncAAs, and analogues of the lanthipeptide nisin with altered ring structures and sizes have been produced. 271–275 …”

Section: Applications Of Non-canonical Amino Acidsmentioning

confidence: 99%

Playing with the Molecules of Life

2018

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Our understanding of the complex processes of living organisms at the molecular level is growing exponentially. This knowledge, together with a powerful arsenal of tools for manipulating the structures of macromolecules, is allowing chemists to harness and reprogram the cellular machinery. Here we review one example in which the genetic code itself has been expanded with new building blocks that allow us to probe and manipulate the structures and functions of proteins in ways previously unimaginable

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Section: Applications Of Non-canonical Amino Acidsmentioning

confidence: 99%

Playing with the Molecules of Life

2018

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“…[31][32][33] Depsipeptides are also known for their increased susceptibility to base hydrolysis compared to their peptide counterparts, and some studies have utilized this property within proteins. [34][35][36][37] Conversely, because of their lability most reported Fmoc-based solid phase peptide synthesis (SPPS) methods for depsipeptides typically involve extensive optimization to minimize hydrolysis and reduce racemization observed when the standard protocols are used for ester synthesis. The synthesis of esters also requires longer reaction times that can further complicate the preparation of complex depsipeptides.…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

Probing the role of the backbone carbonyl interaction with the Cu_A center in azurin by replacing the peptide bond with an ester linkage

et al. 2017

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The role of a backbone carbonyl interaction with an engineered Cu A center in azurin was investigated by developing a method of synthesis and incorporation of a depsipeptide where one of the amide bonds in azurin is replaced by an ester bond using expressed protein ligation. Studies by electronic absorption and electron paramagnetic resonance spectroscopic techniques indicate that, while the substitution does not significantly alter the geometry of the site, it weakens the axial interaction to the Cu A center and strengthens the Cu-Cu bond, as evidenced by the blue shift of the near-IR absorption that has been assigned to the Cu-Cu ψ→ψ* transition. Interestingly, the changes in the electronic structure from the replacement did not result in a change in the reduction potential of the Cu A center, suggesting that the diamond core structure of Cu 2 S Cys2 is resistant to variations in axial interactions.Exploring the structure and function of metalloproteins requires intimate knowledge about the roles of residues around the metal-binding sites. Such knowledge forms a strong basis for successful design and engineering of novel metalloproteins with tunable functional properties. [1][2][3][4][5][6] The most common way to acquire such knowledge is site directed mutagenesis (SDM). Because SDM is limited to only ∼20 proteinogenic amino acids, determining the precise role of the residues is difficult, as SDM often simultaneously changes more than one factor, such as electronic and steric effects, at the same time. Therefore, it is nearly impossible to de-convolute the contributions of each individual factor in such instances. To overcome this limitation, non-proteinogenic analogs of natural amino acids have been incorporated into metalloproteins. [7][8][9][10][11] For example, we have previously employed Expressed Protein Ligation (EPL) to replace conserved metal-binding amino acids with their isostructural nonproteinogenic analogs. 12,13 Such replacements allowed us to de-convolute steric factors from other factors such as electronic effects and hydrophobicity, thereby firmly establishing the roles of these residues in metalloprotein function. 12 HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptWhile most residues use side chains to interact with metal centers, increasing numbers of examples have appeared in the literature showing backbone carbonyl oxygens as metalcoordinating ligands. One such example is the Cu A center found in cytochrome c oxidase (CcO) and nitrous oxide reductase (N 2 OR). [17][18][19][20] Cu A contains a dinuclear copper center bridged by two cysteine thiolates wherein each copper is also coordinated by a histidine (Figure 1). More interestingly, perpendicular to this "diamond core" structural plane, are three carbonyl oxygens of the backbone peptide linkage that are within 2.17 to 4.07 Å of the two copper centers, suggesting that these backbone carbonyl oxygens may play a key role in the formation and fine-tuning of the Cu A center. 21 However, their roles in CcO, N 2 OR...

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“…In all cases isolated yields were around 60%. Boc-protected L-tyrosine 3 was synthesized from L-tyrosine 2 by standard methods [44]. Benzylation of the phenolic group of 3 using benzyl bromide and sodium methoxide in methanol produced benzyl ether 4 in 64% yield (Scheme 2) [45].…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

Arjomandi

Hussein

Vella

et al. 2016

European Journal of Medicinal Chemistry

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There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2-fold were observed.

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Facile Removal of Leader Peptides from Lanthipeptides by Incorporation of a Hydroxy Acid

Cited by 46 publications

References 42 publications

Playing with the Molecules of Life

Playing with the Molecules of Life

Probing the role of the backbone carbonyl interaction with the Cu_A center in azurin by replacing the peptide bond with an ester linkage

Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

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Facile Removal of Leader Peptides from Lanthipeptides by Incorporation of a Hydroxy Acid

Cited by 46 publications

References 42 publications

Playing with the Molecules of Life

Playing with the Molecules of Life

Probing the role of the backbone carbonyl interaction with the CuA center in azurin by replacing the peptide bond with an ester linkage

Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

Contact Info

Product

Resources

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Probing the role of the backbone carbonyl interaction with the Cu_A center in azurin by replacing the peptide bond with an ester linkage