Various mechanisms in cyclopeptide production from precursors synthesized independently of non-ribosomal peptide synthetases

Xu, Wenyan; Li, Liling; Du, Liangcheng; Tan, Ning‐Hua

doi:10.1093/abbs/gmr062

Cited by 14 publications

(17 citation statements)

References 49 publications

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“…The formation of the peptideb ond is common to macrocyclization of other peptide substrates, namely other cyanobactins. [9,36] This new mechanism differs from that proposed previously (Schemes 1and 2); [9] the central differencei sthat His618u ndergoes ac onformational rearrangement and does not protonate the leaving group. Rather,i ti st he incoming substrate amino terminus that protonates the leaving group.…”

Section: Resultsmentioning

confidence: 64%

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The Catalytic Mechanism of the Marine‐Derived Macrocyclase PatGmac

Brás

Ferreira

Calixto

et al. 2016

Chemistry A European J

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Cyclic peptides are a class of compounds with high therapeutic potential, possessing bioactivities including antitumor and antiviral (including anti-HIV). Despite their desirability, efficient design and production of these compounds has not been achieved to date. The catalytic mechanism of patellamide macrocyclization by the PatG macrocyclase domain has been computationally investigated by using quantum mechanics/molecular mechanics methodology, specifically ONIOM(M06/6-311++G(2d,2p):ff94//B3LYP/6-31G(d):ff94). The mechanism proposed herein begins with a proton transfer from Ser783 to His 618 and from the latter to Asp548. Nucleophilic attack of Ser783 on the substrate leads to the formation of an acyl-enzyme covalent complex. The leaving group Ala-Tyr-Asp-Gly (AYDG) of the substrate is protonated by the substrate's N terminus, leading to the breakage of the P1-P1' bond. Finally, the substrate's N terminus attacks the P1 residue, decomposing the acyl-enzyme complex forming the macrocycle. The formation and decomposition of the acyl-enzyme complex have the highest activation free energies (21.1 kcal mol(-1) and 19.8 kcal mol(-1) respectively), typical of serine proteases. Understanding the mechanism behind the macrocyclization of patellamides will be important to the application of the enzymes in the pharmaceutical and biotechnological industries.

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Section: Resultsmentioning

confidence: 64%

“…The formation of the peptide bond is common to macrocyclization of other peptide substrates, namely other cyanobactins. [9, 36]…”

Section: Resultsmentioning

confidence: 99%

The Catalytic Mechanism of the Marine‐Derived Macrocyclase PatGmac

Brás

Ferreira

Calixto

et al. 2016

Chemistry A European J

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“…[135] Nature produces most cyclic peptides through ribosomal synthesis, involving mRNA translation to peptide chains of l-amino acids, often post-translationally modified and cyclized by enzymes. [136] However, nature also extensively uses nonribosomal synthesis, involving enzymes to catalyse assembly of non-proteinogenic amino acids and derivatives followed by cyclization. [137] Every point of an amino acid has been used as a linker to cyclize peptides.…”

Section: Unusual Helix Mimicrymentioning

confidence: 99%

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

et al. 2014

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Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.

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“…30 After cleavage of the mature cyclotide domain, backbone cyclization, and oxidative folding, it is easy to note the conserved molecular patterns of peptide tridimensional structure, like the CCK motif, with b-sheet secondary structures and several loops. 29,36,41,45 In summary, the current model for natural processing of cyclotide precursors suggests that oxidative folding occurs prior to cyclization in the endoplasmic reticulum, where the oxidation of cysteine residues and formation of disulfide bonds within the endoplasmic reticulum happens primarily, with the excision and cyclization of the cyclotide domain from the precursor in a secretory pathway taking place later ( Figure 3). 41 However, the details of precursor processing, including the order of events, are not fully understood.…”

Section: From Precursor Biosynthesis To Cyclotide Maturationmentioning

confidence: 95%

Cyclotides

Pinto

Almeida

Porto

et al. 2011

J Evid Based Complementary Altern Med

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In recent years, a number of peptides containing a cyclic structural fold have been described. Among them, the cyclotides family was widely reported in different plant tissues, being composed of small cyclic peptides containing 6 conserved cysteine residues connected by disulfide bonds and forming a cysteine-binding cyclic structure known as a cyclic cysteine knot. This structural scaffold is responsible for an enhanced structural stability against chemical, thermal, and proteolytic degradation. Because of the observed stability and multifunctionality, including insecticidal, antimicrobial, and anti-HIV (human immunodeficiency virus) action, much effort has gone into trying to elucidate the structural-function relations of cyclotide compounds. This review focuses on the novelties involving gene structure, precursor formation and processing, and protein folding of the cyclotide family, shedding some light on molecular mechanisms of cyclotide production. Because cyclotides are clear targets for drug development and also biotechnology applications, their chemical synthesis, heterologous systems production, and protein grafting are also addressed.

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Various mechanisms in cyclopeptide production from precursors synthesized independently of non-ribosomal peptide synthetases

Cited by 14 publications

References 49 publications

The Catalytic Mechanism of the Marine‐Derived Macrocyclase PatGmac

The Catalytic Mechanism of the Marine‐Derived Macrocyclase PatGmac

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Cyclotides

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