Structural and Functional Characterization of Phosphatidylinositol-Phosphate Biosynthesis in Mycobacteria.
CDP-alcohol phosphotransferase
crystallography
inositol-phosphate
tuberculosis
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
21 08 2020
21 08 2020
Historique:
received:
31
01
2020
revised:
23
04
2020
accepted:
28
04
2020
pubmed:
12
5
2020
medline:
26
1
2021
entrez:
12
5
2020
Statut:
ppublish
Résumé
In mycobacteria, phosphatidylinositol (PI) acts as a common lipid anchor for key components of the cell wall, including the glycolipids phosphatidylinositol mannoside, lipomannan, and lipoarabinomannan. Glycolipids in Mycobacterium tuberculosis, the causative agent of tuberculosis, are important virulence factors that modulate the host immune response. The identity-defining step in PI biosynthesis in prokaryotes, unique to mycobacteria and few other bacterial species, is the reaction between cytidine diphosphate-diacylglycerol and inositol-phosphate to yield phosphatidylinositol-phosphate, the immediate precursor to PI. This reaction is catalyzed by the cytidine diphosphate-alcohol phosphotransferase phosphatidylinositol-phosphate synthase (PIPS), an essential enzyme for mycobacterial viability. Here we present structures of PIPS from Mycobacterium kansasii with and without evidence of donor and acceptor substrate binding obtained using a crystal engineering approach. PIPS from Mycobacterium kansasii is 86% identical to the ortholog from M. tuberculosis and catalytically active. Functional experiments guided by our structural results allowed us to further characterize the molecular determinants of substrate specificity and catalysis in a new mycobacterial species. This work provides a framework to strengthen our understanding of phosphatidylinositol-phosphate biosynthesis in the context of mycobacterial pathogens.
Identifiants
pubmed: 32389689
pii: S0022-2836(20)30330-2
doi: 10.1016/j.jmb.2020.04.028
pmc: PMC7483940
mid: NIHMS1594392
pii:
doi:
Substances chimiques
Bacterial Proteins
0
Phosphatidylinositol Phosphates
0
CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase
EC 2.7.8.11
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5137-5151Subventions
Organisme : NCRR NIH HHS
ID : S10 RR029205
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM132120
Pays : United States
Organisme : NCRR NIH HHS
ID : P41 RR015301
Pays : United States
Organisme : NIGMS NIH HHS
ID : K99 GM123228
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM116799
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM111980
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI119672
Pays : United States
Organisme : NIGMS NIH HHS
ID : R00 GM123228
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no financial conflict of interest.
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