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, Ces petits éléments structuraux, situés aux extrémités C-et N-terminales des sous-unités de PKS, sont responsables de leur bon appariement et donc du transfert correct de l'intermédiaire polycétidique. Pour approfondir nos connaissances sur les DD, nous avons étudié plusieurs interfaces entre sous-unités de PKS trans-AT et cis-AT. Ces travaux ont notamment conduit à l'identification de la première classe de DD chez les PKS trans-AT, et nous avons pu caractériser une interface complète, formée entre deux sous-unités consécutives au sein de la PKS virginiamycine. De plus, nous avons montré qu'au moins un des DD de paires appariées est souvent une région intrinsèquement désordonnée (IDR), ce mode de reconnaissance permet d'assurer une interaction spécifique couplée à une affinité moyenne. En effet, chez l'enacyloxine synthase, une PKS hybride cis-AT/trans-AT, les six interfaces de docking sont médiées par une IDR C-terminal. En outre, nous avons démontré que ce système présentait plusieurs classes structurales de DD, mais que des variations du code électrostatique au sein d'une classe individuelle pouvaient également être utilisées pour garantir la spécificité. Ensemble, ces résultats fournissent des indications importantes pour les futures tentatives d'utilisation des DD en ingénierie des sous-unités de PKS. Une autre stratégie innovante permettant d'obtenir de nouveaux dérivés polycétidiques, consiste à utiliser des enzymes post-PKS. Ces dernières modifient de manière extensive l'intermédiaire et lui confèrent bien souvent son activité biologique. Dans ce contexte, nous avons étudié LkcE, une enzyme bi-fonctionnelle qui catalyse une réaction rare d'oxydation d'amide, suivie d'une réaction de Mannich intramoléculaire. Nous avons résolu quatre structures cristallographiques de l'enzyme et ces données couplées aux études cinétiques, nous ont permis de proposer un mécanisme catalytique détaillé pour LkcE, > Les polycétides sont des métabolites secondaires produits par divers organismes et présentant un large spectre d'activité thérapeutique. L'organisation modulaire des enzymes responsables de leur synthèse, les polycétides synthases (PKS), en font des cibles attrayantes pour la biologie synthétique visant l'obtention de nouvelles structures de polycétides. L'une des stratégies les plus prometteuses à ce jour consiste à échanger des sous-unités entières entre différents systèmes PKS

R. Pks and S. , One of the most promising strategies to date consists in swapping of whole sub-units between different PKS systems. However, the success of this strategy critically depends on understanding and exploiting 'docking domains' -the protein sequences at the C-and N-terminal extremities of the subunits which are responsible for correctly ordering the polypeptides, and therefore for faithful chain transfer. To increase our knowledge of DDs, we investigated several interfaces in both trans-AT and cis-AT PKSs. This work led notably to the identification of the first family of DDs from trans-AT PKSs, and we were further able to characterize a complete interface formed between two consecutive subunits within the virginiamycin PKS. In addition, we showed that at least one DD of matched pairs is often an intrinsically disordered region (IDR), as this type of interaction motif allows for specific but medium affinity contacts. Indeed, in the enacyloxin hybrid cis-AT/trans-AT PKS which we also investigated extensively, docking at every interface is mediated by a C-terminal IDR. In addition, we demonstrated that multiple structural classes of DD are present within the system, but that variations of the electrostatic 'code' within an individual structural class can also be used to ensure specificity. Taken together, these results provide important guidelines for future attempts to deploy DDs in subunit engineering. Another attractive target for synthetic biology are the so-called 'post-PKS' enzymes, which chemically decorate the initially-formed structure, and are often essential for their bioactivity. In this context, we studied LkcE, a bi-functional enzyme that catalyzes a rare amide oxidation followed by an intramolecular Mannich reaction to yield the lankacidin macrocycle -both to understand its unusual mechanism and to evaluate its suitability as a general polyketide modifying enzyme. We solved four crystal structures of the enzyme, Complex polyketides are secondary metabolites which are produced by a range of different organisms, and which present a broad spectrum of therapeutic activity. The modular organization of the enzymes responsible for their synthesis, the polyketide synthases (PKS), makes them attractive targets for synthetic biology aimed at obtaining new polyketide structures

, Moreover, we showed that LkcE displays a certain tolerance toward its substrate structures, suggesting its usefulness as a general catalyst for cyclisation/ligation reaction in synthetic biology and chemical synthesis. Key words: polyketide, polyketide synthases, docking domains