Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues

Staś, Monika; Broda, Małgorzata A.; Siodłak, Dawid

doi:10.1007/s00726-021-02974-0

Cited by 7 publications

(11 citation statements)

References 111 publications

(136 reference statements)

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“…Thiazolines and thiazole are replete in natural products 39 − 41 and synthetic drug-like small molecules, 42 , 43 and calculations confirm the expected decrease in conformational freedom that derives from aromatic and/or sp 2 character within the peptide backbone. 44 This finding and the leader-independent nature of MicD-F and ArtGox-mediated thiazol(in)e biosynthesis inspired us to explore substrates in which the site of cyclodehydration/dehydrogenation is embedded within a stable protein fold ( Figure 4 ). We first asked whether MicD-F and ArtGox could install thiazol(in)e linkages within loops and/or at the termini of mCherry.…”

Section: Resultsmentioning

confidence: 99%

Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates

et al. 2022

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products with potent antibiotic, antiviral, and anticancer properties. RiPP enzymes known as cyclodehydratases and dehydrogenases work together to catalyze intramolecular, inter-residue condensation and dehydrogenation reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here, we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers—including aminobenzoic acid derivatives and beta-amino acids—within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse non-α-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond—both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.

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Section: Resultsmentioning

confidence: 99%

Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates

et al. 2022

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“…A comparison of the studied imidazole-alanine to oxazole-alanine (Siodłak et al 2014a) and thiazole-alanine (Staś et al 2021) shows that the set of conformations is similar, which results from structural similarity. However, the energy order, and thus, conformational preferences are different.…”

Section: Imidazole-alanine (1 and 2)mentioning

confidence: 90%

“…The imidazole-alanine, the simplest methyl side chain, was chosen for the studies. Additionally, it has been shown in our previous reports that the α,βdouble bond in the side chain has the main in uence on the conformation of the azole-containing residues (Siodłak et al 2014b;Staś et al 2016aStaś et al , 2021. Hence, the imidazole-dehydroalanine residue, the methylidene side chain, was also investigated.…”

Section: Introductionmentioning

confidence: 99%

Imidazole-amino acids. Conformational switch under tautomer and pH change

Staś

Najgebauer

Siodłak

2022

Preprint

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Azole rings, such as thiazole or oxazole occur in natural peptide and protein main chain as isosteric replacements of the amide group, incorporated into peptide chain by post-translational modification. Residues with imidazole seem to be another tool for the peptide-based drug design, due to their specific prototropic tautomeric as well as amphoteric properties. In this study, we proved that both tautomer and pH change can cause a conformational switch of the studied residues. The studies using the DFT method were conducted in an environment of increasing polarity (gas phase, chloroform, and water) for alanine (1–4) and dehydroalanine (5–8) with adjacent imidazole. The conformational maps (Ramachandram diagrams) are presented and the stability of possible conformations is discussed. The neutral forms of studied compounds, tautomers τ and π, adapt the conformations αRτ (φ, ψ = -75°, -114°) and C7eq (φ, ψ = -75°, 66°), respectively, which are stabilised by the internal N-H···O hydrogen bond. Their torsion angles ψ differ by about 180°, which results in a considerable impact on the peptide chain conformation. The cation form (3) adapts both these conformations, whereas the anion analogue (4) prefers the conformations C5 (φ, ψ ~ -165°, -178°) and β2 (φ, ψ ~ -165°, -3°), in which the N-H···N hydrogen bond is created. Dehydroamino acid analogues, the tautomers τ (5) and π (6) and anion form (8), have a strong tendency towards the conformations β2 (φ, ψ ~ -179°, 0°) and C5 (φ, ψ ~ -180°, 180°), stabilized by the N-H···N hydrogen bond and π-electron conjugation due to the presence of Cα sp2. The preferences of the protonated imidazolium form 7 depend on the environment. The imidazole ring, acting as a donor or acceptor of internal hydrogen bonds, has a profound effect on the type of conformation.

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“…Thiazolines and thiazole are replete in natural products [42][43][44] and synthetic drug-like small molecules, 8,9 and calculations confirm the expected decrease in conformational freedom that derives from aromatic and/or sp 2 character within the peptide backbone. 45 This finding and the leader-independent nature of MicD-F and ArtGox-mediated thiazol(in)e biosynthesis inspired us to explore substrates in which the site of cyclodehydration/dehydrogenation is embedded within a stable protein fold (Figure 4). We first asked whether MicD-F and ArtGox could install thiazol(in)e linkages within loops and/or at the termini of mCherry.…”

Section: Redirecting Ripp Biosynthetic Enzymes To Intact Folded Proteinsmentioning

confidence: 99%

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

Walker¹,

Hamlish²,

Tytla³

et al. 2022

Preprint

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products that include the FDA-approved analgesic ziconotide1,2 as well as compounds with potent antibiotic, antiviral, and anticancer properties.3 RiPP enzymes known as cyclodehydratases and dehydrogenases represent an exceptionally well-studied enzyme class.3 These enzymes work together to catalyze intramolecular, interresidue condensation3,4 and aromatization reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers, including aramids and beta-amino acids, within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse, non-alpha-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond. Both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. Moreover, as thiazoles and thiazoline heterocycles are replete in natural products,5,6,7 small molecule drugs,8,9 and peptide-mimetic therapeutics,10 their installation in protein-based biotherapeutics could improve or augment performance, activity, stability, and/or selectivity. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.

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Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues

Cited by 7 publications

References 111 publications

Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates

Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates

Imidazole-amino acids. Conformational switch under tautomer and pH change

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

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