Academic Journal
HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II : A singular structure for a unique function
| العنوان: | HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II : A singular structure for a unique function |
|---|---|
| المؤلفون: | Bories, Pascaline, Rima, Julie, Tranier, Samuel, Marcoux, Julien, Grimoire, Yasmina, Tomaszczyk, Mathilde, Launay, Anne, Fata, Karine, Marrakchi, Hedia, Burlet-Schiltz, Odile, Mourey, Lionel, Ducoux-Petit, Manuelle, Bardou, Fabienne, Bon, Cécile, Quémard, Annaïk |
| المساهمون: | Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), MSDAVENIR, FIGHT-TB: Unconventional Strategies for Tuberculosis Treatment, French Ministry of Research, Investissement d'Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08)., ANR-14-CE16-0012,FASMY,Une étude intégrée du système Fatty acid Synthase de type II mycobactérien, une cible stratégique pour de nouveaux médicaments antituberculeux.(2014) |
| المصدر: | ISSN: 0961-8368. |
| بيانات النشر: | HAL CCSD Wiley |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | (3R)-hydroxyacyl-ACP dehydratase HadBD, catalytic subunit, crystal structure, fatty acid synthase type II system, hotdog helix, Mycobacterium tuberculosis, mycolic acids, structure– function relationships, substrate-binding subunit, ultra-long-chain substrates, [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; Abstract Worldwide, tuberculosis is the second leading infectious killer and multidrug resistance severely hampers disease control. Mycolic acids are a unique category of lipids that are essential for viability, virulence, and persistence of the causative agent, Mycobacterium tuberculosis ( Mtb ). Therefore, enzymes involved in mycolic acid biosynthesis represent an important class of drug targets. We previously showed that the (3 R )‐hydroxyacyl‐ACP dehydratase (HAD) protein HadD is dedicated mainly to the production of ketomycolic acids and plays a determinant role in Mtb biofilm formation and virulence. Here, we discovered that HAD activity requires the formation of a tight heterotetramer between HadD and HadB, a HAD unit encoded by a distinct chromosomal region. Using biochemical, structural, and cell‐based analyses, we showed that HadB is the catalytic subunit, whereas HadD is involved in substrate binding. Based on HadBD Mtb crystal structure and substrate‐bound models, we identified determinants of the ultra‐long‐chain lipid substrate specificity and revealed details of structure–function relationship. HadBD Mtb unique function is partly due to a wider opening and a higher flexibility of the substrate‐binding crevice in HadD, as well as the drastically truncated central α‐helix of HadD hotdog fold, a feature described for the first time in a HAD enzyme. Taken together, our study shows that HadBD Mtb , and not HadD alone, is the biologically relevant functional unit. These results have important implications for designing innovative antivirulence molecules to fight tuberculosis, as they suggest that the target to consider is not an isolated subunit, but the whole HadBD complex. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/pro.4964 |
| الاتاحة: | https://hal.science/hal-04764850 https://hal.science/hal-04764850v1/document https://hal.science/hal-04764850v1/file/texte%20integral.pdf https://doi.org/10.1002/pro.4964 |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.911CE528 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/pro.4964 |
|---|