Document Detail

A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages.
MedLine Citation:
PMID:  17264217     Owner:  NLM     Status:  MEDLINE    
Rhodococcus sp. strain RHA1, a soil bacterium related to Mycobacterium tuberculosis, degrades an exceptionally broad range of organic compounds. Transcriptomic analysis of cholesterol-grown RHA1 revealed a catabolic pathway predicted to proceed via 4-androstene-3,17-dione and 3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (3,4-DHSA). Inactivation of each of the hsaC, supAB, and mce4 genes in RHA1 substantiated their roles in cholesterol catabolism. Moreover, the hsaC(-) mutant accumulated 3,4-DHSA, indicating that HsaC(RHA1), formerly annotated as a biphenyl-degrading dioxygenase, catalyzes the oxygenolytic cleavage of steroid ring A. Bioinformatic analyses revealed that 51 rhodococcal genes specifically expressed during growth on cholesterol, including all predicted to specify the catabolism of rings A and B, are conserved within an 82-gene cluster in M. tuberculosis H37Rv and Mycobacterium bovis bacillus Calmette-Guérin. M. bovis bacillus Calmette-Guérin grew on cholesterol, and hsaC and kshA were up-regulated under these conditions. Heterologously produced HsaC(H37Rv) and HsaD(H37Rv) transformed 3,4-DHSA and its ring-cleaved product, respectively, with apparent specificities approximately 40-fold higher than for the corresponding biphenyl metabolites. Overall, we annotated 28 RHA1 genes and proposed physiological roles for a similar number of mycobacterial genes. During survival of M. tuberculosis in the macrophage, these genes are specifically expressed, and many appear to be essential. We have delineated a complete suite of genes necessary for microbial steroid degradation, and pathogenic mycobacteria have been shown to catabolize cholesterol. The results suggest that cholesterol metabolism is central to M. tuberculosis's unusual ability to survive in macrophages and provide insights into potential targets for novel therapeutics.
Robert Van der Geize; Katherine Yam; Thomas Heuser; Maarten H Wilbrink; Hirofumi Hara; Matthew C Anderton; Edith Sim; Lubbert Dijkhuizen; Julian E Davies; William W Mohn; Lindsay D Eltis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-01-30
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  104     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-07     Completed Date:  2007-03-22     Revised Date:  2010-09-15    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1947-52     Citation Subset:  IM    
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9751 NN, Groningen, The Netherlands.
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MeSH Terms
Cholesterol / genetics*,  metabolism*
Hydrolases / genetics*,  metabolism
Macrophages / microbiology*
Multigene Family*
Mycobacterium tuberculosis / genetics*,  growth & development*,  metabolism
RNA, Messenger / metabolism
Rhodococcus / genetics*,  metabolism
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/RNA, Messenger; 57-88-5/Cholesterol; EC 3.-/Hydrolases; EC 3.7.-/HsaD protein, Mycobacterium tuberculosis

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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