scholarly journals Modifications of diketopiperazines assembled by cyclodipeptide synthases with cytochrome P450 enzymes

2021 ◽  
Vol 105 (6) ◽  
pp. 2277-2285
Author(s):  
Lauritz Harken ◽  
Shu-Ming Li
Keyword(s):  
Cyclic Peptides ◽  
Structural Basis ◽  
Cytochrome P450 Enzymes ◽  
Peptide Bonds ◽  
Peptide Synthetases ◽  
Key Points ◽  
Enzyme Families ◽  
Tailoring Enzymes ◽  
Significant Attention ◽  
Nitrogen Bond

Abstract2,5-Diketopiperazines are the smallest cyclic peptides comprising two amino acids connected via two peptide bonds. They can be biosynthesized in nature by two different enzyme families, either by nonribosomal peptide synthetases or by cyclodipeptide synthases. Due to the stable scaffold of the diketopiperazine ring, they can serve as precursors for further modifications by different tailoring enzymes, such as methyltransferases, prenyltransferases, oxidoreductases like cyclodipeptide oxidases, 2-oxoglutarate-dependent monooxygenases and cytochrome P450 enzymes, leading to the formation of intriguing secondary metabolites. Among them, cyclodipeptide synthase-associated P450s attracted recently significant attention, since they are able to catalyse a broader variety of astonishing reactions than just oxidation by insertion of an oxygen. The P450-catalysed reactions include hydroxylation at a tertiary carbon, aromatisation of the diketopiperazine ring, intramolecular and intermolecular carbon-carbon and carbon-nitrogen bond formation of cyclodipeptides and nucleobase transfer reactions. Elucidation of the crystal structures of three P450s as cyclodipeptide dimerases provides a structural basis for understanding the reaction mechanism and generating new enzymes by protein engineering. This review summarises recent publications on cyclodipeptide modifications by P450s.Key Points• Intriguing reactions catalysed by cyclodipeptide synthase-associated cytochrome P450s• Homo- and heterodimerisation of diketopiperazines• Coupling of guanine and hypoxanthine with diketopiperazines Graphical abstract

scholarly journals Specific reduction of carboxyl groups in peptides and proteins by diborane

1969 ◽  
Vol 111 (4) ◽  
pp. 593-601 ◽  
Author(s):  
M. Z. Atassi ◽  
Arthur F. Rosenthal
Keyword(s):  
Cyclic Peptides ◽  
Acid Amide ◽  
Sperm Whale ◽  
Biological Properties ◽  
Carboxyl Groups ◽  
Peptide Bonds ◽  
Human Haemoglobin ◽  
Horse Heart Cytochrome ◽  
Egg White Lysozyme ◽  
Horse Heart Cytochrome C

1. The reaction of several peptides and proteins with diborane was studied under different conditions to determine those most suitable for the specific reduction of carboxyl groups. 2. In the reaction of model peptides and the cyclic peptides bacitracin and tyrocidin, reduction at 0° was entirely specific for the carboxyl groups without affecting the peptide bonds. Acid amide residues were not reduced. Some tripeptides showed anomalous results in that the C-terminal residue was quite resistant to reduction. 3. Specific reduction of carboxyl groups was achieved in each of the following proteins: human serum albumin, egg albumin, adult human haemoglobin, sperm-whale apomyoglobin, horse heart cytochrome c and egg-white lysozyme. The C-terminal amino acid was usually reduced. 4. Conditions for specific reduction of all available carboxyl groups are not easily found and may vary from one substance to another. Specific reduction of a limited number of available carboxyl groups may be generally accomplished by reactions at −10°. 5. It is suggested that this chemical modification, which has the advantage of permanence, may be useful in studying the role of carboxyl groups in the conformation of proteins and in the biological properties of peptides and proteins.

scholarly journals Structural basis of ribosomal peptide macrocyclization in plants

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Joel Haywood ◽  
Jason W Schmidberger ◽  
Amy M James ◽  
Samuel G Nonis ◽  
Kirill V Sukhoverkov ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Peptide Bond ◽  
Binding Mode ◽  
Structural Basis ◽  
Plant Genes ◽  
Ph Conditions ◽  
The Common ◽  
New Generation ◽  
Drug Leads

Constrained, cyclic peptides encoded by plant genes represent a new generation of drug leads. Evolution has repeatedly recruited the Cys-protease asparaginyl endopeptidase (AEP) to perform their head-to-tail ligation. These macrocyclization reactions use the substrates amino terminus instead of water to deacylate, so a peptide bond is formed. How solvent-exposed plant AEPs macrocyclize is poorly understood. Here we present the crystal structure of an active plant AEP from the common sunflower, Helianthus annuus. The active site contained electron density for a tetrahedral intermediate with partial occupancy that predicted a binding mode for peptide macrocyclization. By substituting catalytic residues we could alter the ratio of cyclic to acyclic products. Moreover, we showed AEPs from other species lacking cyclic peptides can perform macrocyclization under favorable pH conditions. This structural characterization of AEP presents a logical framework for engineering superior enzymes that generate macrocyclic peptide drug leads.

scholarly journals Novel Cyclic Peptides in Seed of Annona muricata are Ribosomally Synthesized

2019 ◽  
Author(s):  
Mark F. Fisher ◽  
Jingjing Zhang ◽  
Oliver Berkowitz ◽  
James Whelan ◽  
Joshua S. Mylne
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Cyclic Peptides ◽  
De Novo ◽  
Peptide Sequence ◽  
Tandem Mass ◽  
Annona Muricata ◽  
Peptide Synthetases ◽  
Precursor Proteins ◽  
Bacteria And Fungi

ABSTRACTSmall, cyclic peptides are reported to have many bioactivities. In bacteria and fungi they can be made by non-ribosomal peptide synthetases, but in plants they are exclusively ribosomal. Cyclic peptides from the Annona genus possess cytotoxic and anti-inflammatory activities, but their biosynthesis is unknown. The medicinal soursop plant, Annona muricata, contains annomuricatins A (cyclo-PGFVSA) and B (cyclo-PNAWLGT). Here, using de novo transcriptomics and tandem mass spectrometry, we identify a suite of short transcripts for precursor proteins for ten validated annomuricatins, nine of which are novel. In their precursors, annomuricatins are preceded by an absolutely conserved Glu and each peptide sequence has a conserved proto-C-terminal Pro, revealing parallels with the segetalin orbitides from the seed of Vaccaria hispanica, which are processed through ligation by a prolyl oligopeptidase in a transpeptidation reaction.

scholarly journals The Desotamide Family of Antibiotics

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 452 ◽  
Author(s):  
Asif Fazal ◽  
Michael E. Webb ◽  
Ryan F. Seipke
Keyword(s):  
Natural Products ◽  
Cyclic Peptides ◽  
Clinical Use ◽  
Antimicrobial Compounds ◽  
Peptide Antibiotics ◽  
New Family ◽  
Concise Review ◽  
Major Class ◽  
Microbial Natural Products ◽  
Significant Attention

Microbial natural products underpin the majority of antimicrobial compounds in clinical use and the discovery of new effective antibacterial treatments is urgently required to combat growing antimicrobial resistance. Non-ribosomal peptides are a major class of natural products to which many notable antibiotics belong. Recently, a new family of non-ribosomal peptide antibiotics were discovered—the desotamide family. The desotamide family consists of desotamide, wollamide, surugamide, ulleungmycin and noursamycin/curacomycin, which are cyclic peptides ranging in size between six and ten amino acids in length. Their biosynthesis has attracted significant attention because their highly functionalised scaffolds are cyclised by a recently identified standalone cyclase. Here, we provide a concise review of the desotamide family of antibiotics with an emphasis on their biosynthesis.

scholarly journals Structural basis for collagen recognition by the immune receptor OSCAR

Blood ◽  
2016 ◽  
Vol 127 (5) ◽  
pp. 529-537 ◽  
Author(s):  
Long Zhou ◽  
Jennifer M. Hinerman ◽  
Michal Blaszczyk ◽  
Jeanette L. C. Miller ◽  
Deborah G. Conrady ◽  
...  
Keyword(s):  
Primary Site ◽  
Structural Basis ◽  
Immune Receptor ◽  
Receptor Cluster ◽  
Terminal Domain ◽  
Helical Peptide ◽  
Key Points

Key Points OSCAR has 2 immunoglobulin-like domains with an obtuse interdomain angle, differing from other members of the leukocyte receptor cluster. Each domain of OSCAR binds a collagen triple-helical peptide; the primary site is on the C-terminal domain in contrast to GPVI and LAIR-1.

scholarly journals Discovery and Heterologous Production of New Cyclic Depsibosamycins

2021 ◽  
Vol 9 (7) ◽  
pp. 1396
Author(s):  
Marc Stierhof ◽  
Maksym Myronovskyi ◽  
Josef Zapp ◽  
Andriy Luzhetskyy
Keyword(s):  
Cyclic Peptides ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Side Chain ◽  
Biological Functions ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Species ◽  
Peptide Synthetases ◽  
Major Interest ◽  
In Silico Identification

Streptomyces are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in the genome of many Streptomyces species. The identification of new peptides and the corresponding biosynthetic gene clusters is of major interest since knowledge can be used to facilitate combinatorial biosynthesis and chemical semisynthesis of natural products. The recently discovered bosamycins are linear octapeptides with an interesting 5-OMe tyrosine moiety and various modifications at the N-terminus. In this study, the new cyclic depsibosamycins B, C, and D from Streptomyces aurantiacus LU19075 were discovered. In comparison to the linear bosamycins B, C, and D, which were also produced by the strain, the cyclic depsibosamycins showed a side-chain-to-tail lactonization of serine and glycine, leading to a ring of four amino acids. In silico identification and heterologous expression of the depsibosamycin (dbm) gene cluster indicated that the cyclic peptides, rather than the linear derivatives, are the main products of the cluster.

scholarly journals Evolution and enrichment of CYP5035 in Polyporales: functionality of an understudied P450 family

2021 ◽  
Vol 105 (18) ◽  
pp. 6779-6792
Author(s):  
Nico D. Fessner ◽  
David R. Nelson ◽  
Anton Glieder
Keyword(s):  
White Rot Fungi ◽  
Fungal Species ◽  
White Rot ◽  
Functional Screening ◽  
Cytochrome P450 Enzymes ◽  
Lentinus Tigrinus ◽  
Detoxification Mechanism ◽  
Key Points ◽  
Functional Profiling ◽  
Polyporus Brumalis

Abstract Bioprospecting for innovative basidiomycete cytochrome P450 enzymes (P450s) is highly desirable due to the fungi’s enormous enzymatic repertoire and outstanding ability to degrade lignin and detoxify various xenobiotics. While fungal metagenomics is progressing rapidly, the biocatalytic potential of the majority of these annotated P450 sequences usually remains concealed, although functional profiling identified several P450 families with versatile substrate scopes towards various natural products. Functional knowledge about the CYP5035 family, for example, is largely insufficient. In this study, the families of the putative P450 sequences of the four white-rot fungi Polyporus arcularius, Polyporus brumalis, Polyporus squamosus and Lentinus tigrinus were assigned, and the CYPomes revealed an unusual enrichment of CYP5035, CYP5136 and CYP5150. By computational analysis of the phylogeny of the former two P450 families, the evolution of their enrichment could be traced back to the Ganoderma macrofungus, indicating their evolutionary benefit. In order to address the knowledge gap on CYP5035 functionality, a representative subgroup of this P450 family of P. arcularius was expressed and screened against a test set of substrates. Thereby, the multifunctional enzyme CYP5035S7 converting several plant natural product classes was discovered. Aligning CYP5035S7 to 102,000 putative P450 sequences of 36 fungal species from Joint Genome Institute-provided genomes located hundreds of further CYP5035 family members, which subfamilies were classified if possible. Exemplified by these specific enzyme analyses, this study gives valuable hints for future bioprospecting of such xenobiotic-detoxifying P450s and for the identification of their biocatalytic potential. Graphical abstract Key points • The P450 families CYP5035 and CYP5136 are unusually enriched in P. arcularius. • Functional screening shows CYP5035 assisting in the fungal detoxification mechanism. • Some Polyporales encompass an unusually large repertoire of detoxification P450s.

scholarly journals A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes

Blood ◽  
2016 ◽  
Vol 127 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Jean M. Watermeyer ◽  
Victoria L. Hale ◽  
Fiona Hackett ◽  
Daniel K. Clare ◽  
Erin E. Cutts ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Structural Basis ◽  
Red Cell ◽  
Shear Forces ◽  
Cell Cytoskeleton ◽  
Key Points ◽  
Infected Cells

Key PointsPlasmodium falciparum–generated cytoadherent knobs on infected erythrocytes contain a spiral framework linked to the red cell cytoskeleton. The findings suggest a structural basis for transmission of shear forces in adhesion of infected cells.

scholarly journals Recent advances in engineering nonribosomal peptide assembly lines

2016 ◽  
Vol 33 (2) ◽  
pp. 317-347 ◽  
Author(s):  
M. Winn ◽  
J. K. Fyans ◽  
Y. Zhuo ◽  
J. Micklefield
Keyword(s):  
Assembly Lines ◽  
New Techniques ◽  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases ◽  
Peptide Assembly ◽  
Recent Advances ◽  
Tailoring Enzymes

This reviews summarises progress towards the engineering of nonribosomal peptide synthetases (NRPS) from the expression of heterologous tailoring enzymes to direct modifications of the assembly lines to produce analogues. New techniques/tools for introducing changes are also examined.

Sign in / Sign up

Export Citation Format

Share Document