Structural, functional and evolutionary perspectives on effective re-engineering of non-ribosomal peptide synthetase assembly lines

2018 ◽  
Vol 35 (11) ◽  
pp. 1210-1228 ◽  
Author(s):  
Alistair S. Brown ◽  
Mark J. Calcott ◽  
Jeremy G. Owen ◽  
David F. Ackerley
Keyword(s):  
Protein Interactions ◽  
Recent Progress ◽  
Protein Protein Interactions ◽  
Assembly Lines ◽  
Effective Strategies ◽  
Peptide Synthetase ◽  
Evolutionary Perspectives

Salutary lessons from recent progress in re-engineering non-ribosomal peptide synthetase assembly lines, emphasizing effective strategies and key protein–protein interactions.

Protein–protein interactions in polyketide synthase–nonribosomal peptide synthetase hybrid assembly lines

2018 ◽  
Vol 35 (11) ◽  
pp. 1185-1209 ◽  
Author(s):  
Akimasa Miyanaga ◽  
Fumitaka Kudo ◽  
Tadashi Eguchi
Keyword(s):  
Protein Interactions ◽  
Polyketide Synthase ◽  
Nonribosomal Peptide Synthetase ◽  
Hybrid Assembly ◽  
Protein Protein Interactions ◽  
Assembly Lines ◽  
Nonribosomal Peptide ◽  
Peptide Synthetase

The protein–protein interactions in polyketide synthase–nonribosomal peptide synthetase hybrids are summarized and discussed.

scholarly journals Coevolution-based prediction of protein–protein interactions in polyketide biosynthetic assembly lines

2020 ◽  
Vol 36 (19) ◽  
pp. 4846-4853 ◽  
Author(s):  
Yan Wang ◽  
Miguel Correa Marrero ◽  
Marnix H Medema ◽  
Aalt D J van Dijk
Keyword(s):  
Protein Interactions ◽  
Antitumor Agents ◽  
Acyl Carrier Protein ◽  
Specific Protein ◽  
Combinatorial Biosynthesis ◽  
Supplementary Information ◽  
Protein Protein Interactions ◽  
Assembly Lines ◽  
Specific Order ◽  
Encoding Genes

Abstract Motivation Polyketide synthases (PKSs) are enzymes that generate diverse molecules of great pharmaceutical importance, including a range of clinically used antimicrobials and antitumor agents. Many polyketides are synthesized by cis-AT modular PKSs, which are organized in assembly lines, in which multiple enzymes line up in a specific order. This order is defined by specific protein–protein interactions (PPIs). The unique modular structure and catalyzing mechanism of these assembly lines makes their products predictable and also spurred combinatorial biosynthesis studies to produce novel polyketides using synthetic biology. However, predicting the interactions of PKSs, and thereby inferring the order of their assembly line, is still challenging, especially for cases in which this order is not reflected by the ordering of the PKS-encoding genes in the genome. Results Here, we introduce PKSpop, which uses a coevolution-based PPI algorithm to infer protein order in PKS assembly lines. Our method accurately predicts protein orders (93% accuracy). Additionally, we identify new residue pairs that are key in determining interaction specificity, and show that coevolution of N- and C-terminal docking domains of PKSs is significantly more predictive for PPIs than coevolution between ketosynthase and acyl carrier protein domains. Availability and implementation The code is available on http://www.bif.wur.nl/ (under ‘Software’). Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The mechanism of sperm–oocyte fusion in mammals

Reproduction ◽  
2004 ◽  
Vol 127 (4) ◽  
pp. 423-429 ◽  
Author(s):  
Keisuke Kaji ◽  
Akira Kudo
Keyword(s):  
Membrane Protein ◽  
Sexual Reproduction ◽  
Gene Targeting ◽  
Molecular Mechanism ◽  
Protein Interactions ◽  
Recent Progress ◽  
Research Field ◽  
Protein Protein Interactions ◽  
Long Time ◽  
Adams Family

Sperm–oocyte fusion is one of the most impressive events in sexual reproduction, and the elucidation of its molecular mechanism has fascinated researchers for a long time. Because of the limitation of materials and difficulties in analyzing membrane protein–protein interactions, many attempts have failed to reach this goal. Recent studies involving gene targeting have clearly demonstrated the various molecules that are involved in sperm–oocyte binding and fusion. Sperm ADAMs (family of proteins with a disintegrin and metalloprotease domain), including fertilin α, fertilin β and cyritestin, have been investigated and found to be important for binding rather than for fusion and painstaking studies have raised suspicions that their putative receptors, oocyte integrins, are necessary for the sperm–oocyte interaction. Recently, several studies have focused the spotlight on CD9 and glycosylphosphatidylinositol (GPI)-anchored proteins on oocytes, and epididymal protein DE on sperm, as candidate molecules involved in sperm–oocyte fusion. Lack of, or interference with the function of, these proteins can disrupt the sperm–oocyte fusion without changing the binding. In this review we highlight the candidate molecules involved in the sperm–oocyte interaction suggested from the recent progress in this research field.

scholarly journals Manipulating Protein–Protein Interactions in Nonribosomal Peptide Synthetase Type II Peptidyl Carrier Proteins

Biochemistry ◽  
2017 ◽  
Vol 56 (40) ◽  
pp. 5269-5273 ◽  
Author(s):  
Matt J. Jaremko ◽  
D. John Lee ◽  
Ashay Patel ◽  
Victoria Winslow ◽  
Stanley J. Opella ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Nonribosomal Peptide Synthetase ◽  
Type Ii ◽  
Carrier Proteins ◽  
Protein Protein Interactions ◽  
Nonribosomal Peptide ◽  
Peptide Synthetase

scholarly journals Mapping the biosynthetic pathway of a hybrid polyketide-nonribosomal peptide in a metazoan

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Likui Feng ◽  
Matthew T. Gordon ◽  
Ying Liu ◽  
Kari B. Basso ◽  
Rebecca A. Butcher
Keyword(s):  
Protein Interactions ◽  
Biosynthetic Pathway ◽  
Polyketide Synthase ◽  
Carrier Protein ◽  
Nonribosomal Peptides ◽  
Direct Transfer ◽  
Protein Protein Interactions ◽  
Nonribosomal Peptide ◽  
Peptide Synthetase ◽  
Complex Protein

AbstractPolyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) hybrid systems typically use complex protein-protein interactions to facilitate direct transfer of intermediates between these multimodular megaenzymes. In the canal-associated neurons (CANs) of Caenorhabditis elegans, PKS-1 and NRPS-1 produce the nemamides, the only known hybrid polyketide-nonribosomal peptides biosynthesized by animals, through a poorly understood mechanism. Here, we use genome editing and mass spectrometry to map the roles of individual PKS-1 and NRPS-1 enzymatic domains in nemamide biosynthesis. Furthermore, we show that nemamide biosynthesis requires at least five additional enzymes expressed in the CANs that are encoded by genes distributed across the worm genome. We identify the roles of these enzymes and discover a mechanism for trafficking intermediates between a PKS and an NRPS. Specifically, the enzyme PKAL-1 activates an advanced polyketide intermediate as an adenylate and directly loads it onto a carrier protein in NRPS-1. This trafficking mechanism provides a means by which a PKS-NRPS system can expand its biosynthetic potential and is likely important for the regulation of nemamide biosynthesis.

scholarly journals Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 445
Author(s):  
Rosario González-Muñiz ◽  
María Ángeles Bonache ◽  
María Jesús Pérez de Vega
Keyword(s):  
Protein Interactions ◽  
Recent Progress ◽  
Cell Penetrating Peptides ◽  
Protein Protein Interactions ◽  
Future Mission ◽  
Protein Interfaces ◽  
Peptide Derivatives ◽  
Macrocyclic Peptides ◽  
Synthetic Methodologies ◽  
Macrocyclic Peptide

Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes.

scholarly journals The many faces and important roles of protein–protein interactions during non-ribosomal peptide synthesis

2018 ◽  
Vol 35 (11) ◽  
pp. 1120-1139 ◽  
Author(s):  
Thierry Izoré ◽  
Max J. Cryle
Keyword(s):  
Peptide Synthesis ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Current State ◽  
Peptide Synthetase ◽  
The Many

Non-ribosomal peptide synthetase (NRPS) machineries are complex, multi-domain proteins that are responsible for the biosynthesis of many important, peptide-derived compounds. In this review, we present the current state of understanding of the protein–protein interactions that govern NRPS-mediated biosynthesis.

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