Natural Product Reports

Natural Product Reports View Article Online REVIEW View Journal | View Issue The many faces and important roles of protein– protein interactions during non-ribosomal peptide Cite this: Nat. Prod. Rep.,2018,35, 1120 synthesis ab abc Thierry Izore´ and Max J. Cryle * Covering: up to July 2018 Non-ribosomal peptide synthetase (NRPS) machineries are complex, multi-domain proteins that are responsible for the biosynthesis of many important, peptide-derived compounds. By decoupling peptide synthesis from the ribosome, NRPS assembly lines are able to access a significant pool of amino acid monomers for peptide synthesis. This is combined with a modular protein architecture that allows for great variation in stereochemistry, peptide length, cyclisation state and further modifications. The architecture of Creative Commons Attribution 3.0 Unported Licence. NRPS assembly lines relies upon a repetitive set of catalytic domains, which are organised into modules responsible for amino acid incorporation. Central to NRPS-mediated biosynthesis is the carrier protein (CP) domain, to which all intermediates following initial monomer activation are bound during peptide synthesis up until the final handover to the thioesterase domain that cleaves the mature peptide from the NRPS. This mechanism makes understanding the protein–protein interactions that occur between different NRPS domains during peptide biosynthesis of crucial importance to understanding overall NRPS function. This endeavour is also highly challenging due to the inherent flexibility and dynamics of NRPS systems. In this Received 25th April 2018 review, we present the current state of understanding of the protein–protein interactions that govern DOI: 10.1039/c8np00038g This article is licensed under a NRPS-mediated biosynthesis, with a focus on insights gained from structural studies relating to CP domain rsc.li/npr interactions within these impressive peptide assembly lines. 1. Introduction Open Access Article. Published on 12 September 2018. Downloaded 1/11/2019 2:00:53 AM. 1. Introduction 2. PCP – the central domain in NRPS mediated synthesis 3. Activation of the PCP-domain through interaction with Non-ribosomal peptide synthetases (NRPSs) are ribosomally a PPTase independent macromolecular machineries involved in the 4. A-domains – amino acid selection and activation production of many different classes of peptide-derived natural 4.1 Function of adenylation domains products.1 The utility of NRPS machineries for producing 4.2 Structure of adenylation domains bioactive peptides stems from two main sources – rstly, the 4.3 Adenylation domain interactions with PCPs ability to select a wide range of monomers for use in peptide 5. Condensation and epimerisation domains synthesis, and secondly the signicant modications able to be 6. Thioesterase domains performed to the peptide by a range of catalytic domains found 7. Other NRPS interactions within a specic NRPS. Unlike ribosomes that strictly use 8. Conclusions adened set of amino acids to produce peptides and proteins, 9. Conicts of interest the NRPS system has evolved to become extremely versatile 10. Acknowledgements regarding the substrate monomers that it accepts. Indeed, it has 11. References been reported that more than 500 different substrates are accepted by NRPS assembly lines.2 In addition to the 20 well- known L-a-amino acids incorporated in proteins, these building blocks include a broad range of non-proteinogenic a- aThe Monash Biomedicine Discovery Institute, Department of Biochemistry and b 3 Molecular Biology and ARC Centre of Excellence in Advanced Molecular Imaging, and -amino acids (including examples such as phenyl- Monash University, Clayton, Victoria 3800, Australia. E-mail: [email protected] glycines, cyclic guanidines, alkene-, alkyne-, halo-, hydroxyl- or 2 bEMBL Australia, Monash University, Clayton, Victoria 3800, Australia cyclopropyl-containing amino acids) and extend even to cDepartment of Biomolecular Mechanisms, Max-Planck Institute for Medical Research, homologated amino acids or monomers derived from 69120 Heidelberg, Germany. E-mail: [email protected] 1120 | Nat. Prod. Rep.,2018,35,1120–1139 This journal is © The Royal Society of Chemistry 2018 View Article Online Review Natural Product Reports aminobenzoic acid residues:4 this variety of potential substrates harbour additional domains: examples include epimerisation leads to a vast number of conceivable nal peptide products. domains (E-domains), S-adenosylmethionine (SAM)-dependent Together with the related polyketide synthase (PKS) systems, methyltransferase domains or formylation domains,8 adding yet megasynthase machineries represent one of the best sources of further potential diversity to the structure of the nal NRPS biologically active compounds for exploitation in medicine. peptide product. The nal module of most NRPS machineries Along with the classic example of peptide production by ACV contains a terminal thioesterase domain (or TE-domain) that synthase during penicillin biosynthesis,5 other NRPS- exerts its catalytic activity in releasing the nal PCP-bound assembled peptides have been found to play diverse roles, peptide: this process can also serve to introduce yet further with examples including those that act as siderophores, anti- diversity into the nal peptide structure, with one common biotics (including clinically relevant examples like the glyco- example the cyclisation of a linear peptide. NRPS assembly lines peptide antibiotics (GPAs) and daptomycin), cytostatic agents or range from a single module as in the Pseudomonas pyreudione as regulators in bacterial quorum sensing.6,7 synthetase9 upto18modulesinlengthandcanbeencodedbyone The structure of an NRPS plays a vital role in its function. A or more genes. The two longest NRPS machineries encoded in typical linear NRPS machinery is composed of multiple a single gene are kolossin A synthase from Photorhabdus lumi- modules (100–200 kDa, depending on domain composition), nescens, an impressive 15 module-long NRPS enzyme,10 and the with each module in the assembly line responsible for the peptaibol synthetase from Trichoderma virens with 18 modules.11 incorporation of one amino acid monomer into the nal Although NRPSs are mostly found in bacteria and fungi and peptide (Fig. 1). Differing architectures to linear systems where the product peptides provide a tness advantage to the include iterative and non-linear NRPS systems: iterative systems producing host, some rare examples of NRPS-like enzymes do possess a limited number of modules with the nal peptide exist in higher eukaryotes. However, those that have been being the result of several copies of a shorter peptide fragment, identied display altered architectures when compared to whilst non-linear systems are more complex and less easily standard NRPS machineries, since such machineries are typi- 1 Creative Commons Attribution 3.0 Unported Licence. de ned in terms of traditional modules. Whilst both iterative cally composed of an A-domain, PCP-domain and a dedicated C- and non-linear NRPS machineries are intriguing from a mech- terminal catalytic domain that is specic to each NRPS.12 anistic standpoint, the vast majority of medicinally important Examples of those eukaryotic NRPS are the 2-aminoadipic 6- NRPS-products are produced by linear NRPS machineries. Each semialdehyde dehydrogenases (AASDH) involved in lysine module within a linear NRPS can be further described as metabolism13 and the carcinine and b-alanyl-dopamine a series of at least three different domains: the adenylation synthetase Ebony involved in neurotransmitter recycling and domain (or A-domain) is responsible for the selection and the cuticle sclerotisation in insects.14 activation of amino acids; the peptidyl carrier protein domain Given that some of our most critical medicines such as last- (PCP, also known as a thiolation domain) whose role is to resort antibiotics (e.g. vancomycin, daptomycin), anti-tumour This article is licensed under a shuttle substrates between different domains; and the drugs (bleomycin, cryptophycin) or immune modulatory condensation domain (or C-domain) that catalyses peptide compounds (cyclosporine) are NRPS-produced and remain tied bond formation between PCP bound amino acid monomers to biosynthesis for their production, great interest exists in and peptides (or amino acids for the initial NRPS module). In understanding their biosynthesis.15 Furthermore, the potential Open Access Article. Published on 12 September 2018. Downloaded 1/11/2019 2:00:53 AM. addition to these three essential domains, a module can to produce new derivatives of such compounds in the future TI completed his Ph.D. at the MJC obtained his Ph.D. in University of Grenoble where he chemistry from the University of focussed on structural studies of Queensland in 2006. He then bacterial virulence factors moved to the Max Planck Insti- (mainly Gram+ pilus and type III tute for Medical Research in secretion systems) under the Heidelberg Germany as an HFSP supervision of Andréa Dessen. Cross-Disciplinary Fellow and He then joined the group of Jan later as an Emmy Noether group Lowe¨ at the Laboratory of leader funded by the DFG. Since Molecular Biology in Cambridge 2016 he is an EMBL Australia to study bacterial and archaeal group leader based within the cytoskeletons using Cryo- Biomedicine Discovery Institute Electron microscopy. In at Monash University, where his November 2016 he moved to Monash University in Australia to team focusses on understanding

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