2a7s: Difference between revisions

New page: left|200px<br /><applet load="2a7s" size="450" color="white" frame="true" align="right" spinBox="true" caption="2a7s, resolution 2.90Å" /> '''Crystal Structure of...
 
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[[Image:2a7s.gif|left|200px]]<br /><applet load="2a7s" size="450" color="white" frame="true" align="right" spinBox="true"  
[[Image:2a7s.gif|left|200px]]<br /><applet load="2a7s" size="350" color="white" frame="true" align="right" spinBox="true"  
caption="2a7s, resolution 2.90&Aring;" />
caption="2a7s, resolution 2.90&Aring;" />
'''Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis'''<br />
'''Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis'''<br />


==Overview==
==Overview==
Mycolic acids and multimethyl-branched fatty acids are found uniquely in, the cell envelope of pathogenic mycobacteria. These unusually long fatty, acids are essential for the survival, virulence, and antibiotic resistance, of Mycobacterium tuberculosis. Acyl-CoA carboxylases (ACCases) commit, acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other, organisms such as Escherichia coli or humans that have only one or two, ACCases, M. tuberculosis contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in the pathogen are not well defined., Previous studies indicate that AccD4, AccD5, and AccD6 are important for, cell envelope lipid biosynthesis and that its disruption leads to pathogen, death. We have determined the 2.9-Angstroms crystal structure of AccD5, whose sequence, structure, and active site are highly conserved with, respect to the carboxyltransferase domain of the Streptomyces coelicolor, propionyl-CoA carboxylase. Contrary to the previous proposal that AccD4-5, accept long-chain acyl-CoAs as their substrates, both crystal structure, and kinetic assay indicate that AccD5 prefers propionyl-CoA as its, substrate and produces methylmalonyl-CoA, the substrate for the, biosyntheses of multimethyl-branched fatty acids such as mycocerosic, phthioceranic, hydroxyphthioceranic, mycosanoic, and mycolipenic acids., Extensive in silico screening of National Cancer Institute compounds and, the University of California, Irvine, ChemDB database resulted in the, identification of one inhibitor with a K(i) of 13.1 microM. Our results, pave the way toward understanding the biological roles of key ACCases that, commit acyl-CoAs to the biosynthesis of cell envelope fatty acids, in, addition to providing a target for structure-based development of, antituberculosis therapeutics.
Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell envelope of pathogenic mycobacteria. These unusually long fatty acids are essential for the survival, virulence, and antibiotic resistance of Mycobacterium tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms such as Escherichia coli or humans that have only one or two ACCases, M. tuberculosis contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in the pathogen are not well defined. Previous studies indicate that AccD4, AccD5, and AccD6 are important for cell envelope lipid biosynthesis and that its disruption leads to pathogen death. We have determined the 2.9-Angstroms crystal structure of AccD5, whose sequence, structure, and active site are highly conserved with respect to the carboxyltransferase domain of the Streptomyces coelicolor propionyl-CoA carboxylase. Contrary to the previous proposal that AccD4-5 accept long-chain acyl-CoAs as their substrates, both crystal structure and kinetic assay indicate that AccD5 prefers propionyl-CoA as its substrate and produces methylmalonyl-CoA, the substrate for the biosyntheses of multimethyl-branched fatty acids such as mycocerosic, phthioceranic, hydroxyphthioceranic, mycosanoic, and mycolipenic acids. Extensive in silico screening of National Cancer Institute compounds and the University of California, Irvine, ChemDB database resulted in the identification of one inhibitor with a K(i) of 13.1 microM. Our results pave the way toward understanding the biological roles of key ACCases that commit acyl-CoAs to the biosynthesis of cell envelope fatty acids, in addition to providing a target for structure-based development of antituberculosis therapeutics.


==About this Structure==
==About this Structure==
2A7S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Active as [http://en.wikipedia.org/wiki/Propionyl-CoA_carboxylase Propionyl-CoA carboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.4.1.3 6.4.1.3] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2A7S OCA].  
2A7S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Active as [http://en.wikipedia.org/wiki/Propionyl-CoA_carboxylase Propionyl-CoA carboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.4.1.3 6.4.1.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A7S OCA].  


==Reference==
==Reference==
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[[Category: Melgar, M.]]
[[Category: Melgar, M.]]
[[Category: Purdon, J.]]
[[Category: Purdon, J.]]
[[Category: Tsai, S.C.]]
[[Category: Tsai, S C.]]
[[Category: Tseng, T.]]
[[Category: Tseng, T.]]
[[Category: acetyl-coa carboxylase]]
[[Category: acetyl-coa carboxylase]]
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[[Category: propionyl-coa carboxylase]]
[[Category: propionyl-coa carboxylase]]


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