Conformational flexibility of coenzyme A and its impact on the post‐translational modification of acyl carrier proteins by 4′‐phosphopantetheinyl transferases

• Published in: The FEBS journal Vol. 287; no. 21; pp. 4729 - 4746
• Main Authors: Nguyen, Minh Chau, Saurel, Olivier, Carivenc, Coralie, Gavalda, Sabine, Saitta, Stéphane, Tran, Mai Phuong, Milon, Alain, Chalut, Christian, Guilhot, Christophe, Mourey, Lionel, Pedelacq, Jean‐Denis
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2020; Wiley
• Subjects: ACP; Acyl carrier protein; Biochemistry, Molecular Biology; Biosynthesis; Coenzyme A; complex; Fatty acids; Flexibility; Life Sciences; mechanism of action; Metal ions; modular PKS; moieties; Mycobacterium abscessus; Natural products; pH effects; Physiology; post-translational modification; PPTase; protein dynamics; Protein structure; Proteins; Structural Biology; Structure-function relationships; transferases; Translation; modular PKS; PPTase; ACP; complex; protein dynamics
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.15273

One central question surrounding the biosynthesis of fatty acids and polyketide‐derived natural products is how the 4′‐phosphopantetheinyl transferase (PPTase) interrogates the essential acyl carrier protein (ACP) domain to fulfill the initial activation step. The triggering factor of this study was the lack of structural information on PPTases at physiological pH, which could bias our comprehension of the mechanism of action of these important enzymes. Structural and functional studies on the family II PPTase PptAb of Mycobacterium abscessus show that pH has a profound effect on the coordination of metal ions and on the conformation of endogenously bound coenzyme A (CoA). The observed conformational flexibility of CoA at physiological pH is accompanied by a disordered 4′‐phosphopantetheine (Ppant) moiety. Finally, structural and dynamical information on an isolated mycobacterial ACP domain, in its apo form and in complex with the activator PptAb, suggests an alternate mechanism for the post‐translational modification of modular megasynthases. Phosphopantetheinyl transferases (PPTases) are required for activating acyl carrier protein (ACP) domains of megasynthases. Structural studies on PptAb of Mycobacterium abscessus reveal that pH has a profound effect on the coordination of metal ions and the conformation of bound coenzyme A (CoA). The high mobility of CoA at physiological pH in PptAb alone and in complex with ACP sheds light on possible reaction intermediates underlying the mechanism of ACP activation.