1kph: Difference between revisions

Revision as of 14:36, 21 February 2008

Crystal Structure of mycolic acid cyclopropane synthase CmaA1 complexed with SAH and DDDMAB

OverviewOverview

Mycolic acids are major components of the cell wall of Mycobacterium tuberculosis. Several studies indicate that functional groups in the acyl chain of mycolic acids are important for pathogenesis and persistence. There are at least three mycolic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that are responsible for these site-specific modifications of mycolic acids. To derive information on the specificity and enzyme mechanism of the family of proteins, the crystal structures of CmaA1, CmaA2, and PcaA were solved to 2-, 2-, and 2.65-A resolution, respectively. All three enzymes have a seven-stranded alpha/beta fold similar to other methyltransferases with the location and interactions with the cofactor S-adenosyl-l-methionine conserved. The structures of the ternary complexes demonstrate the position of the mycolic acid substrate binding site. Close examination of the active site reveals electron density that we believe represents a bicarbonate ion. The structures support the hypothesis that these enzymes catalyze methyl transfer via a carbocation mechanism in which the bicarbonate ion acts as a general base. In addition, comparison of the enzyme structures reveals a possible mechanism for substrate specificity. These structures provide a foundation for rational-drug design, which may lead to the development of new inhibitors effective against persistent bacteria.

About this StructureAbout this Structure

1KPH is a Single protein structure of sequence from Mycobacterium tuberculosis with , and as ligands. Active as Cyclopropane-fatty-acyl-phospholipid synthase, with EC number 2.1.1.79 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis., Huang CC, Smith CV, Glickman MS, Jacobs WR Jr, Sacchettini JC, J Biol Chem. 2002 Mar 29;277(13):11559-69. Epub 2001 Dec 26. PMID:11756461

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-[[Image:1kph.gif|left|200px]]<br /><applet load="1kph" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1kph.gif|left|200px]]<br /><applet load="1kph" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1kph, resolution 2.00&Aring;" />
 '''Crystal Structure of mycolic acid cyclopropane synthase CmaA1 complexed with SAH and DDDMAB'''<br />
 ==Overview==
-Mycolic acids are major components of the cell wall of Mycobacterium, tuberculosis. Several studies indicate that functional groups in the acyl, chain of mycolic acids are important for pathogenesis and persistence., There are at least three mycolic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that are responsible for these site-specific modifications of, mycolic acids. To derive information on the specificity and enzyme, mechanism of the family of proteins, the crystal structures of CmaA1, CmaA2, and PcaA were solved to 2-, 2-, and 2.65-A resolution, respectively. All three enzymes have a seven-stranded alpha/beta fold, similar to other methyltransferases with the location and interactions, with the cofactor S-adenosyl-l-methionine conserved. The structures of the, ternary complexes demonstrate the position of the mycolic acid substrate, binding site. Close examination of the active site reveals electron, density that we believe represents a bicarbonate ion. The structures, support the hypothesis that these enzymes catalyze methyl transfer via a, carbocation mechanism in which the bicarbonate ion acts as a general base., In addition, comparison of the enzyme structures reveals a possible, mechanism for substrate specificity. These structures provide a foundation, for rational-drug design, which may lead to the development of new, inhibitors effective against persistent bacteria.
+Mycolic acids are major components of the cell wall of Mycobacterium tuberculosis. Several studies indicate that functional groups in the acyl chain of mycolic acids are important for pathogenesis and persistence. There are at least three mycolic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that are responsible for these site-specific modifications of mycolic acids. To derive information on the specificity and enzyme mechanism of the family of proteins, the crystal structures of CmaA1, CmaA2, and PcaA were solved to 2-, 2-, and 2.65-A resolution, respectively. All three enzymes have a seven-stranded alpha/beta fold similar to other methyltransferases with the location and interactions with the cofactor S-adenosyl-l-methionine conserved. The structures of the ternary complexes demonstrate the position of the mycolic acid substrate binding site. Close examination of the active site reveals electron density that we believe represents a bicarbonate ion. The structures support the hypothesis that these enzymes catalyze methyl transfer via a carbocation mechanism in which the bicarbonate ion acts as a general base. In addition, comparison of the enzyme structures reveals a possible mechanism for substrate specificity. These structures provide a foundation for rational-drug design, which may lead to the development of new inhibitors effective against persistent bacteria.
 ==About this Structure==
-KPH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with CO3, SAH and 10A as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cyclopropane-fatty-acyl-phospholipid_synthase Cyclopropane-fatty-acyl-phospholipid synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.79 2.1.1.79] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1KPH OCA].
+KPH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with <scene name='pdbligand=CO3:'>CO3</scene>, <scene name='pdbligand=SAH:'>SAH</scene> and <scene name='pdbligand=10A:'>10A</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cyclopropane-fatty-acyl-phospholipid_synthase Cyclopropane-fatty-acyl-phospholipid synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.79 2.1.1.79] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KPH OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Mycobacterium tuberculosis]]
 [[Category: Single protein]]
-[[Category: Glickman, M.S.]]
+[[Category: Glickman, M S.]]
-[[Category: Huang, C.C.]]
+[[Category: Huang, C C.]]
-[[Category: Jr., W.R.Jacobs.]]
+[[Category: Jr., W R.Jacobs.]]
-[[Category: Sacchettini, J.C.]]
+[[Category: Sacchettini, J C.]]
-[[Category: Smith, C.V.]]
+[[Category: Smith, C V.]]
-[[Category: TBSGC, TB.Structural.Genomics.Consortium.]]
+[[Category: TBSGC, TB Structural Genomics Consortium.]]
 [[Category: 10A]]
 [[Category: CO3]]
@@ Line 30: / Line 30: @@
 [[Category: tbsgc]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 19:34:32 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:36:33 2008''