“Polar patch” proteases as glycopeptiligases

Doores, Katie J.; Davis, Benjamin G.

doi:10.1039/b412030b

Cited by 15 publications

(11 citation statements)

References 21 publications

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“…Indeed, the specific targeting to glycan structures, as observed for the three M60-like O-glycopeptidase members studied here, lends itself to the idea of using such enzymes as unique molecular tools to study glycoprotein structure. Furthermore, O-glycopeptidases may find application as glycopeptiligases where their native specificity for O-glycosylated peptides could be harnessed to ligate peptides and glycopeptides to generate designed glycosylated products without the need to significantly engineer the active site environment of the peptidase (24,25). The mechanism we have described by which these three M60-like peptidases recognize substrate reveals the intimate utilization of posttranslationally added glycans as a substrate recognition determinant.…”

Section: Discussionmentioning

confidence: 99%

Recognition of protein-linked glycans as a determinant of peptidase activity

Noach

Ficko-Blean

Pluvinage

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

137

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The vast majority of proteins are posttranslationally altered, with the addition of covalently linked sugars (glycosylation) being one of the most abundant modifications. However, despite the hydrolysis of protein peptide bonds by peptidases being a process essential to all life on Earth, the fundamental details of how peptidases accommodate posttranslational modifications, including glycosylation, has not been addressed. Through biochemical analyses and X-ray crystallographic structures we show that to hydrolyze their substrates, three structurally related metallopeptidases require the specific recognition of O-linked glycan modifications via carbohydrate-specific subsites immediately adjacent to their peptidase catalytic machinery. The three peptidases showed selectivity for different glycans, revealing protein-specific adaptations to particular glycan modifications, yet always cleaved the peptide bond immediately preceding the glycosylated residue. This insight builds upon the paradigm of how peptidases recognize substrates and provides a molecular understanding of glycoprotein degradation.

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Section: Discussionmentioning

confidence: 99%

Recognition of protein-linked glycans as a determinant of peptidase activity

Noach

Ficko-Blean

Pluvinage

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

137

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“…The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc/petroleum ether to give white crystals of (2S) -2-{[(benzyloxy)carbonyl]amino}-3-[( tert -butyldimethylsilyl)oxy]propanoic acid. Yield 87% [79]; Mp 80–82 °C; 1 H NMR (CDCl 3 ) δ: 7.31–7.40 (m, 5 H), 5.62 (d, J = 8.23 Hz, 1 H), 5.14 (d, J = 5.03 Hz, 2 H), 4.46 (d, J = 7.78 Hz, 1 H), 4.13 (dd, J = 10.06, 2.29 Hz, 1 H), 3.86 (dd, J = 10.06, 3.20 Hz, 1 H), 0.87 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (CDCl 3 ) δ: 175.0, 156.1, 136.1, 128.5, 128.2, 128.1, 67.2, 63.3, 55.6, 25.7, 18.2, −5.6; IR (cm −1 ): 3651w, 3437w, 3241w, 2992 w, 2782w, 1706s, 1567m, 1467w, 1378w, 1282w, 1229m, 1090s, 894s, 781m; HR-MS: for C 17 H 28 NO 5 Si [M + H] + calculated 354.1731 m/z , found 354.1733 m/z .…”

Section: Methodsmentioning

confidence: 99%

“…Benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-nitrophenyl)carbamoyl]ethyl]carbamate [79] ( 25 ): Yield 51%; Mp 111–115 °C; 1 H NMR (CDCl 3 ) δ: 8.86 (s, 1 H), 8.19–8.24 (m, 2 H), 7.66 (d, J = 8.69 Hz, 2 H), 7.33–7.42 (m, 5 H), 5.73 (s, 1 H), 5.18 (t, J = 12.35 Hz, 2 H), 4.37 (br s, 1 H), 4.18 (dd, J = 10.06, 3.66 Hz, 1 H), 3.77 (dd, J = 9.83, 7.55 Hz, 1 H), 0.92 (s, 9 H), 0.13 (s, 6 H); 13 C NMR (CDCl 3 ) δ: 169.0, 156.3, 143.7, 143.0, 135.8, 128.6, 128.5, 125.1, 119.2, 67.5, 63.0, 56.5, 25.8, 18.1, −5.5; IR (cm −1 ): 3391w, 3230w, 2977w, 2871w, 2831w, 2831w, 1695m, 1635s, 1578m, 1514m, 1453s, 1375s, 1282s, 1204m, 1133s, 1079s, 1044m, 880s, 798s, 759m; HR-MS: for C 23 H 31 N 3 O 6 Si [M + H] + calculated 474.2055 m/z , found 474.2067 m/z .…”

Section: Methodsmentioning

confidence: 99%

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors

Bąk

Pizova

Kozik

et al. 2019

IJMS

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A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure–activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity–activity landscape index for BChE inhibitory response values. The ‘indirect’ ligand-based and ‘direct’ protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an ‘average’ 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).

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“…Recently however, the Davis group reported that chemical modification of the of the subtilisin SBL active site alters the enzyme in such a way that glycosylation is tolerated at the ligation junction. 30 The power of this method is exemplified by a relay synthesis of RNase B (Fig. 8).…”

Section: Protease Catalyzed Ligationmentioning

confidence: 99%

Chemoenzymatic approaches to glycoprotein synthesis

Bennett

Wong

2007

Chem. Soc. Rev.

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The construction of homogeneous glycoproteins presents a formidable challenge to the synthetic chemist. Over the past few years there has been an explosion in the number of methods developed to address this problem. These methods include the development of novel ligation technologies for the synthesis of the protein backbone, as well chemical and enzymatic approaches for introducing complex glycans into the peptide backbone. This tutorial review discusses the application of these techniques to the synthesis of peptides and proteins possessing well defined glycans.

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“Polar patch” proteases as glycopeptiligases

Cited by 15 publications

References 21 publications

Recognition of protein-linked glycans as a determinant of peptidase activity

Recognition of protein-linked glycans as a determinant of peptidase activity

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors

Chemoenzymatic approaches to glycoprotein synthesis

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