Next Article in Journal
Heart Failure Associated with Giant Uterine Leiomyoma: A Case Report
Previous Article in Journal
Immediate and Long-Term Effects of Breathing Exercises on Reaction Time
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of Mycobacterium tuberculosis

1
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi Arabia
2
Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Qassim, Saudi Arabia
3
Department of Anatomy, College of Medicine, University of Hail, Hail 55476, Hail, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Medicina 2024, 60(11), 1891; https://doi.org/10.3390/medicina60111891
Submission received: 10 September 2024 / Revised: 2 November 2024 / Accepted: 8 November 2024 / Published: 18 November 2024
(This article belongs to the Section Infectious Disease)

Abstract

Background and Objective: ATP-binding cassette (ABC) transporters are prominent drug targets due to their highly efficient trafficking capabilities and their significant physiological and clinical roles. Gaining insight into their biophysical and biomechanistic properties is crucial to maximize their pharmacological potential. Materials and Methods: In this study, we present the biochemical and biophysical characterization, and phylogenetic analysis of the domains of Mycobacterium tuberculosis (M. tuberculosis) ABC transporters: the exporter Rv1348 (IrtA) and the importer system Rv1349-Rv2895c (IrtB-Rv2895c), both involved in siderophore-mediated iron uptake. Results: Our findings reveal that the substrate-binding domain (SBD) of IrtA functions as an active monomer, while Rv2895c, which facilitates the uptake of siderophore-bound iron, exists in a dynamic equilibrium between dimeric and monomeric forms. Furthermore, ATP binding induces the dimerization of the ATPase domains in both IrtA (ATPase I) and IrtB (ATPaseII), but only the ATPase domain of IrtA (ATPase I) is active independently. We also analyzed the stability of substrate binding to the domains of the two transporters across varying temperature and pH ranges, revealing significant shifts in their activity under different conditions. Our study highlights the conformational changes that accompany substrate interaction with the transporter domains, providing insights into the fundamental mechanism required for the translocation of siderophore to the extracytoplasmic milieu by IrtB and, subsequently, import of their ferrated forms by the IrtB-Rv2895c complex. Phylogenetic analyses based on ATPase domains reveal that IrtA shares features with both archaeal and eukaryotic transporters, while IrtB is unique to mycobacterial species. Conclusions: Together, these findings provide valuable insights, which could accelerate the development of intervention strategies for this critical pathway pivotal in the progression of M. tuberculosis infection.
Keywords: Mycobacterium tuberculosis; siderophore-iron uptake; ABC transporters; Rv1348 (IrtA) and Rv2895c (IrtB); evolutionary linkage of transporters; drug targeting Mycobacterium tuberculosis; siderophore-iron uptake; ABC transporters; Rv1348 (IrtA) and Rv2895c (IrtB); evolutionary linkage of transporters; drug targeting

Share and Cite

MDPI and ACS Style

Farhana, A.; Alsrhani, A.; Ejaz, H.; Alruwaili, M.; Alameen, A.A.M.; Manni, E.; Rasheed, Z.; Khan, Y.S. Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of Mycobacterium tuberculosis. Medicina 2024, 60, 1891. https://doi.org/10.3390/medicina60111891

AMA Style

Farhana A, Alsrhani A, Ejaz H, Alruwaili M, Alameen AAM, Manni E, Rasheed Z, Khan YS. Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of Mycobacterium tuberculosis. Medicina. 2024; 60(11):1891. https://doi.org/10.3390/medicina60111891

Chicago/Turabian Style

Farhana, Aisha, Abdullah Alsrhani, Hasan Ejaz, Muharib Alruwaili, Ayman A. M. Alameen, Emad Manni, Zafar Rasheed, and Yusuf Saleem Khan. 2024. "Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of Mycobacterium tuberculosis" Medicina 60, no. 11: 1891. https://doi.org/10.3390/medicina60111891

APA Style

Farhana, A., Alsrhani, A., Ejaz, H., Alruwaili, M., Alameen, A. A. M., Manni, E., Rasheed, Z., & Khan, Y. S. (2024). Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of Mycobacterium tuberculosis. Medicina, 60(11), 1891. https://doi.org/10.3390/medicina60111891

Article Metrics

Back to TopTop