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Function of the target enzyme HSaD within Tuberculosis (TB)
According to Lack et al., (2007, pp 2-7), tuberculosis is one of the major cause of mortality across the world, especially in underdeveloped countries. This huge epidemic makes it very essential to understand the etiopathogenesis of the disease and the organism causing it i.e., Mycobacterium Tuberculosis. The identification and analysis of this bacterium has been accentuated by gene studies and the necessary genetic machinery required by this organism to survive the macrophage milieu. One such gene is responsible for the synthesis of an enzyme called HSaD, a hydrolase. It is responsible for the cleavage of inter-carbon atoms bond in the metabolism of cholesterol. According to Bhakta et al., (2004), a gene called nat gene has shown crucial importance for survival within a macrophage for a variant of mycobacterium called Mycobacterium bovis. Similarly, according to Rengarajan et al. (2005), HSaD is essential for the survival of M.Tuberculosis within a macrophage.
According to a research conducted by Diamond Light Source (2008), HSaD has a strong role in the pathogenesis of tuberculosis inside human body. This enzyme provides protection from the strong immunogenic products within the human cells and eventually manifests as a disease that takes thousands of life each year. The scientists, through recombinant technology, studied the structure of this enzyme and concluded that it has the same structure as of a typical meta-cleavage protein. The only difference HSaD has is an extra large active site which clarifies its role in the cholesterol metabolism.
According to Lack et al. (2009, pp. 443), the mechanisms by which Mycobacterium Tuberculosis survive within the strong checks and balances of the human body are not very elucidated. Although, it has been postulated through well structured research that it since it is a saprophytic bacteria, it can very well feed off of the cholesterol reserves within a human cell. Another evidence linking the use of cholesterol as a growth substrate by the M.Tuberculosis bacterium within a cell is that lare quantities of cholesterol has been found in the caseating granulomas formed in TB. Also, few genetically engineered bacteria were made devoid of their cholesterol metabolising capacity, showed drastically decreased virulence and therefore, decreased survival.
According to Ryan et al. (2013, pp. 42), another very big issue in treating, managing and controlling TB is development of single drug and even multi drug resistant strains. This advent has called for the need to develop highly prioritized anti tubercular drugs that can aid in containing and eradicating this illness. These researchers tried to engineer a drug that could specifically target this enzyme or the genetic machinery involved to reduce the virulence of the organism and make it vulnerable to killing. These classes of drugs are serine protease inhibitors, monoglyceride lipase (MGL) inhibitors and anti cholinesterase. Although, no single drug showed promising results but this study elucidated the fact that HSaD is responsible for the hydrolytic cleavage of the Carbon-Carbon bond.
In a nut shell, it is very evident that HSaD has a very crucial role in the survival of the macrophage inside the human system and if researched upon, it could give a new horizon in the treatment modalities for the TB. It will eventually decrease the disease burden globally, significantly decrease mortality and save millions of dollars wasted in the treatment and prevention of TB.
References
Bhakta, S., Besra, G., Upton, A., Parish, T., Sholto-Douglas-Vernon, C., Gibson, K., Knutton, S., Gordon, S., daSilva, R., Anderton, M. and Sim, E. (2004). Arylamine N -Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target. The Journal of Experimental Medicine, [online] 199(9), pp.1191-1199. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211905/ [Accessed 29 Feb. 2016].
Diamond Light Source, (2008). An intelligent weapon to combat tuberculosis - Diamond Light Source. [online] Available at: http://www.diamond.ac.uk/Home/News/LatestNews/12January2008.html [Accessed 29 Feb. 2016].
Lack, N., Yam, K., Lowe, E., Horsman, G., Owen, R., Sim, E. and Eltis, L. (2009). Characterization of a Carbon-Carbon Hydrolase from Mycobacterium tuberculosis Involved in Cholesterol Metabolism. Journal of Biological Chemistry, [online] 285(1), pp.434-443. Available at: http://www.jbc.org/content/285/1/434.full [Accessed 29 Feb. 2016].
Lack, N., Lowe, E., Liu, J., Eltis, L., Noble, M., Sim, E. and Westwood, I. (2007). Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis. Acta Cryst Sect F, [online] 64(1), pp.2-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373992/ [Accessed 29 Feb. 2016].
Rengarajan, J., Bloom, B. and Rubin, E. (2005). From The Cover: Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proceedings of the National Academy of Sciences, [online] 102(23), pp.8327-8332. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142121/ [Accessed 29 Feb. 2016].
Ryan, A., Keany, S., Eleftheriadou, O., Ballet, R., Cheng, H.-Y. and Sim, E. (2013) “Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage,” FEMS Microbiol Lett FEMS Microbiology Letters, 350(1), pp. 42–47. Available at: http://onlinelibrary.wiley.com/doi/10.1111/1574-6968.12302/epdf
