A sterol biosynthetic pathway in Mycobacterium.

The genome sequence of Mycobacterium tuberculosis (and also M. leprae) revealed a significant number of homologies to Saccharomyces cerevisiae sterol biosynthetic enzymes. We addressed the hypothesis of a potential sterol biosynthetic pathway existing in Mycobacterium using cultures of Mycobacterum smegmatis. Non-saponifiable lipid extracts subjected to analysis by gas chromatography-mass spectrometry (GC-MS) showed cholesterol was present. Sterol synthesis by M. smegmatis was confirmed using 14C-radiolabelled mevalonic acid and incorporation into C4-desmethyl sterol co-migrating with authentic cholesterol on TLC. The sterol biosynthetic pathway has provided a rich source of targets for commercially important bioactive molecules and such agents represent new opportunities for Mycobacteria chemotherapy.

Indirect assay of beta hydroxy beta methyl glutaryl CoA reductase in the sera of leprosy patients--a further probe into cholesterol metabolism.

With an aim to study the cholesterol biosynthetic capacity of the leprosy patients, the enzyme Beta hydroxy methyl glutaryl CoA reductase (HMG CoA) has been indirectly determined in the sera of leprosy patients and their family members by assaying the circulating levels of HMG CoA and mevalonate and finding out the ratio between two. The ratio was around 1 in leprosy patients indicating a normal HMG CoA reductase activity and approximately the same values were obtained in cases of healthy controls. The results suggest that cholesterol biosynthetic capacity of leprosy patients is normal. Whether cholesterol, the final product or intermediates like mevalonate are utilised by the invading M. leprae, thereby causing a lowered cholesterol level remains to be seen.

Cholesterol dynamics in macrophages implication for the bacteriology and pathology of leprosy.

M. leprae in the host multiplies abundantly in macrophages rich in cholesterol. Host-grown leprosy bacilli have an extremely high cholesterol content and in this respect they occupy a unique place among procariotic cells. M. leprae takes up cholesterol from the environment and it is not clear whether it can synthesize cholesterol and if so from which precursors. Mycobacteria can be grown from leprous tissues in primary cultures only in the presence of cholesterol. These strains quickly adapt to in vitro substrates and are able to synthesize cholesterol from still-unknown chemical entities, which are also sources of carbon and energy. These still unknown substrates will probably have to be discovered before cultivation of these elusive microorganisms is achieved and we approach a better understanding of the chemical mediators in the cellular defence and/or pathology of leprosy.