The control of fatty acid uptake in mycobacteria

Biochemists from the National University of Singapore (NUS) have discovered a regulatory mechanism for a fatty acid transporter in mycobacteria, which plays a critical role in the survival of these pathogens.

Mycobacteria are known to cause serious human diseases, including tuberculosis, one of the leading causes of death from infectious diseases worldwide. These pathogens have evolved various strategies to infect and survive within host cells, one of which involves their ability to absorb fatty acids from the host as a nutrient source, However, the details of this uptake process have not been well understood.

Using a combination of molecular genetics, protein structural prediction, membrane protein biochemistry, and functional assays, the research team, led by Associate Professor Shu Sin CHNG from the Department of Chemistry at NUS and the Singapore Centre for Environmental Life Sciences Engineering successfully characterised the Mce1 fatty acid transport system in mycobacteria. This system provides a vital mechanism that enables mycobacterial pathogens to absorb fatty acids from the host, supporting their survival and pathogenicity. In particular, they identified two new protein components that are important for the function and regulation of Mce1 systems, providing valuable insights into this class of lipid transporters and informing future anti-mycobacterial strategies.

The team have discovered that certain mycobacterial species possess two related Mce1 systems, a detail that had previously gone unnoticed. In addition, they have identified a negative protein regulator of these fatty acid transport systems within the large family of ATP-binding cassette (ABC) transporters. This regulator inhibits the Mce1 transporter by physically removing the protein component that uses ATP to energise it.

Prof Chng said, “Such a regulatory mechanism has not been reported for ABC transporters, which serve pivotal functions in all living organisms. We will continue to study how this novel regulatory element responds to external factors to better understand when Mce1 systems are turned on or off in mycobacteria.”

The research work was published in the journal Nature Communications.

Following this work, Dr Yushu CHEN*, a research fellow in the team and the first author of the paper, is now focused on identifying other proteins that may also be involved in fatty acid transport in mycobacteria. He has recently received an Open Fund-Young Individual Research Grant (OF-YIRG) from the National Medical Research Council (NMRC) of Singapore to investigate one such system.

Dr Chen said, “This new project aims to answer a fundamental and longstanding question about how fatty acids cross biological membranes in cells.”

Figure illustrates the proposed model of Mce1 complexes, which are ATP-binding cassette (ABC) transporters responsible for fatty acid transport. Two variants of the Mce1 complex exist in Mycobacterium smegmatis., containing either MSMEG_6540 or Mce1A. The regulatory protein Mce1N negatively controls the activities of these complexes by preventing the association of MceG, the ATP-hydrolysing enzyme, with the rest of the transporter. This inhibition likely prevents the efflux of fatty acids, potentially playing a role in mycobacterial physiology and virulence. [Credit: Nature Communications]

*Dr Yushu Chen is a former graduate student of Associate Professor Shu Sin Chng.

Reference

Chen Y, Wang Y, Chng SS*, “A conserved membrane protein negatively regulates Mce1 complexes in mycobacteria” Nature Communications Volume: 14 Issue:1 Pages: 5897 DOI: 10.1038/s41467-023-41578-y Published: 2023.