| Structural highlights
Function
AFTA_MYCTU Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the addition of the first key arabinofuranosyl (Araf) residue from the sugar donor decaprenyl-phospho-arabinose (DPA) on the C-5 of a 6-linked galactofuranosyl (Galf) of the galactan domain, thus 'priming' the galactan for further elaboration by other arabinofuranosyltransferases. It is not able to add an Araf residue to a terminal Galf.[1] [2]
Publication Abstract from PubMed
Arabinogalactan (AG) is an essential cell wall component in mycobacterial species, including the deadly human pathogen Mycobacterium tuberculosis. It plays a pivotal role in forming the rigid mycolyl-AG-peptidoglycan core for in vitro growth. AftA is a membrane-bound arabinosyltransferase and a key enzyme involved in AG biosynthesis which bridges the assembly of the arabinan chain to the galactan chain. It is known that AftA catalyzes the transfer of the first arabinofuranosyl residue from the donor decaprenyl-monophosphoryl-arabinose to the mature galactan chain (i.e., priming); however, the priming mechanism remains elusive. Herein, we report the cryo-EM structure of Mtb AftA. The detergent-embedded AftA assembles as a dimer with an interface maintained by both the transmembrane domain (TMD) and the soluble C-terminal domain (CTD) in the periplasm. The structure shows a conserved glycosyltransferase-C fold and two cavities converging at the active site. A metal ion participates in the interaction of TMD and CTD of each AftA molecule. Structural analyses combined with functional mutagenesis suggests a priming mechanism catalyzed by AftA in Mtb AG biosynthesis. Our data further provide a unique perspective into anti-TB drug discovery.
Structure of the priming arabinosyltransferase AftA required for AG biosynthesis of Mycobacterium tuberculosis.,Gong Y, Wei C, Wang J, Mu N, Lu Q, Wu C, Yan N, Yang H, Zhao Y, Yang X, Gurcha SS, Veerapen N, Batt SM, Hao Z, Da L, Besra GS, Rao Z, Zhang L Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2302858120. doi: , 10.1073/pnas.2302858120. Epub 2023 May 30. PMID:37252995[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Alderwick LJ, Seidel M, Sahm H, Besra GS, Eggeling L. Identification of a novel arabinofuranosyltransferase (AftA) involved in cell wall arabinan biosynthesis in Mycobacterium tuberculosis. J Biol Chem. 2006 Jun 9;281(23):15653-61. PMID:16595677 doi:10.1074/jbc.M600045200
- ↑ Shi L, Zhou R, Liu Z, Lowary TL, Seeberger PH, Stocker BL, Crick DC, Khoo KH, Chatterjee D. Transfer of the first arabinofuranose residue to galactan is essential for Mycobacterium smegmatis viability. J Bacteriol. 2008 Aug;190(15):5248-55. PMID:18556798 doi:10.1128/JB.00028-08
- ↑ Gong Y, Wei C, Wang J, Mu N, Lu Q, Wu C, Yan N, Yang H, Zhao Y, Yang X, Gurcha SS, Veerapen N, Batt SM, Hao Z, Da L, Besra GS, Rao Z, Zhang L. Structure of the priming arabinosyltransferase AftA required for AG biosynthesis of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2302858120. PMID:37252995 doi:10.1073/pnas.2302858120
|
