Comprehensive Comparative Analysis of Cholesterol Catabolic Genes/Proteins in Mycobacterial Species.

Rochelle Van Wyk,David Nelson,Samson Mashele,Mari Van Wyk,Khajamohiddin Syed

doi:10.3390/ijms20051032

Abstract

In dealing with Mycobacterium tuberculosis, the causative agent of the deadliest human disease—tuberculosis (TB)—utilization of cholesterol as a carbon source indicates the possibility of using cholesterol catabolic genes/proteins as novel drug targets. However, studies on cholesterol catabolism in mycobacterial species are scarce, and the number of mycobacterial species utilizing cholesterol as a carbon source is unknown. The availability of a large number of mycobacterial species’ genomic data affords an opportunity to explore and predict mycobacterial species’ ability to utilize cholesterol employing in silico methods. In this study, comprehensive comparative analysis of cholesterol catabolic genes/proteins in 93 mycobacterial species was achieved by deducing a comprehensive cholesterol catabolic pathway, developing a software tool for extracting homologous protein data and using protein structure and functional data. Based on the presence of cholesterol catabolic homologous proteins proven or predicted to be either essential or specifically required for the growth of M. tuberculosis H37Rv on cholesterol, we predict that among 93 mycobacterial species, 51 species will be able to utilize cholesterol as a carbon source. This study’s predictions need further experimental validation and the results should be taken as a source of information on cholesterol catabolism and genes/proteins involved in this process among mycobacterial species.

Highlights

Tuberculosis (TB), is a chronic infectious disease caused by Mycobacterium tuberculosis, and is one of the leading causes of death worldwide, killing an estimated two million people annually [1,2]
It has not been confirmed whether there is a specific order to the degradation reactions regarding the side chain and rings, but for M. tuberculosis it has been suggested that the ring-degrading enzymes KsaAB and HsaA-C act optimally after the side chain has been removed, since blockage of the side chain degradation resulted in accumulation of cholest-4-en-3-one as a major metabolite [19]
Genes/proteins involved in the cholesterol catabolism were identified, and comprehensive comparative analysis of M. tuberculosis H37Rv homologous genes/proteins in different mycobacterial species was performed, using a newly developed software tool to extract homologous protein data

Summary

Introduction

Tuberculosis (TB), is a chronic infectious disease caused by Mycobacterium tuberculosis, and is one of the leading causes of death worldwide, killing an estimated two million people annually [1,2]. It is estimated that one third of the world’s population (approximately two billion people) is infected with this highly pathogenic organism [3]. Once it has entered the human body, and after ingestion by macrophages, this intracellular pathogen can survive in a modified phagosome and cause latent infection for years and sometimes decades without any symptoms [4]. The reactivation of latent phase M. tuberculosis into the active phase is observed among people whose immune systems are weakened by HIV infection, by immunosuppressive drugs or by malnutrition and/or aging [5]. With the documentation of total drug-resistant strains [6], along with the insufficiency of new drug targets, we clearly need more research to discover novel drug targets

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