Mechanistic studies of mycobacterial glycolipid biosynthesis by the mannosyltransferase PimE

Yaqi Liu, Chelsea M. Brown, Nuno Borges, Rodrigo N. Nobre, Satchal Erramilli, Meagan Belcher Dufrisne, Brian Kloss, Sabrina Giacometti, Ana M. Esteves, Cristina G. Timóteo, Piotr Tokarz, Rosemary J. Cater, Todd L. Lowary, Yasu S. Morita, Anthony A. Kossiakoff, Helena Santos (), Phillip J. Stansfeld (), Rie Nygaard () and Filippo Mancia ()
Additional contact information
Yaqi Liu: Columbia University Irving Medical Center
Chelsea M. Brown: University of Warwick
Nuno Borges: Universidade Nova de Lisboa
Rodrigo N. Nobre: Universidade Nova de Lisboa
Satchal Erramilli: University of Chicago
Meagan Belcher Dufrisne: Columbia University Irving Medical Center
Brian Kloss: Columbia University Irving Medical Center
Sabrina Giacometti: Columbia University Irving Medical Center
Ana M. Esteves: Universidade Nova de Lisboa
Cristina G. Timóteo: Universidade Nova de Lisboa
Piotr Tokarz: University of Chicago
Rosemary J. Cater: Columbia University Irving Medical Center
Todd L. Lowary: Academia Sinica
Yasu S. Morita: University of Massachusetts
Anthony A. Kossiakoff: University of Chicago
Helena Santos: Universidade Nova de Lisboa
Phillip J. Stansfeld: University of Warwick
Rie Nygaard: Columbia University Irving Medical Center
Filippo Mancia: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Tuberculosis (TB), a leading cause of death among infectious diseases globally, is caused by Mycobacterium tuberculosis (Mtb). The pathogenicity of Mtb is largely attributed to its complex cell envelope, which includes a class of glycolipids called phosphatidyl-myo-inositol mannosides (PIMs). These glycolipids maintain the integrity of the cell envelope, regulate permeability, and mediate host-pathogen interactions. PIMs comprise a phosphatidyl-myo-inositol core decorated with one to six mannose residues and up to four acyl chains. The mannosyltransferase PimE catalyzes the transfer of the fifth PIM mannose residue from a polyprenyl phosphate-mannose (PPM) donor. This step contributes to the proper assembly and function of the mycobacterial cell envelope; however, the structural basis for substrate recognition and the catalytic mechanism of PimE remain poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of PimE from Mycobacterium abscessus in its apo and product-bound form. The structures reveal a distinctive binding cavity that accommodates both donor and acceptor substrates/products. Key residues involved in substrate coordination and catalysis were identified and validated via in vitro assays and in vivo complementation, while molecular dynamics simulations delineated access pathways and binding dynamics. Our integrated approach provides comprehensive insights into PimE function and informs potential strategies for anti-TB therapeutics.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57843-1

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DOI: 10.1038/s41467-025-57843-1

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