IpdAB, a Virulence Factor in Mycobacterium Tuberculosis, Is a Cholesterol Ring-Cleaving Hydrolase
This week we profile a recent publication in PNAS from Dr. Lindsay Eltis at the UBC Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
My research is aimed at understanding and harnessing the bacterial degradation of steroids and aromatic compounds, including lignin. Our work on steroid catabolism focuses primarily on the catabolism of cholesterol in Mycobacterium tuberculosis. This catabolism is critical for virulence, and has emerged as a target for urgently needed anti-mycobacterial therapeutics. Our work on lignin catabolism focuses on how this degradation occurs and developing biocatalysts and platforms to transform forest biomass into high-value products.
What is the significance of the findings in this publication?
All steroid-degrading bacteria utilize IpdAB, a predicted CoA transferase (CoT) that has been implicated in the hydrolysis of a carbon-carbon bond; an unprecedented reaction in CoTs. In Mycobacterium tuberculosis, IpdAB is required for virulence where it plays a role in utilizing host cholesterol as a growth substrate. We used a combination of X-ray crystallographic and biochemical studies to elucidate the mechanism of IpdAB. Superposition of the IpdABMtb active site with those of CoTs reveals distinct architectural features which, in conjunction with the biochemical data, indicate that IpdAB catalyzes a retro-Claisen like ring-opening reaction. This is the first such reaction reported for a member of the CoT superfamily. This study provides insights into bacterial steroid catabolism and facilitates the development of potential anti-tuberculosis therapeutics targeting IpdAB.
What are the next steps for this research?
On a fundamental level, we are continuing to characterize cholesterol catabolism by Mycobacterium tuberculosis. Key aspects of this catabolism remain unknown, including its regulation, its impacts the bacterium’s physiology and its role in pathogenesis. On a practical level, we are helping to develop potential anti-tuberculosis therapeutics that target cholesterol catabolism.
This research was funded by:
Canadian Institutes of Health Research, Canada Research Chair
I would also like to acknowledge the important collaboration with Natalie Strynadka for the structural studies.