Sandbox Reserved 1051: Difference between revisions
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[[Image:Substrate_Catalytic_Triad.jpg|300 px|right|thumb|'''Figure 3:''' Relation of the catalytic triad to the octylthioglucoside analog in [http://www.rcsb.org/pdb/explore/explore.do?structureId=1VA5 Ag85C]]] | [[Image:Substrate_Catalytic_Triad.jpg|300 px|right|thumb|'''Figure 3:''' Relation of the catalytic triad to the octylthioglucoside analog in [http://www.rcsb.org/pdb/explore/explore.do?structureId=1VA5 Ag85C]]] | ||
Mutagenesis studies<ref name="Favrot2014"> PMID:25028518 </ref> have confirmed the the catalytic function of Ag85C is dependent upon a Glu-His-Ser <scene name='69/694220/Catalytic_triad/4'>catalytic triad</scene>, similar to that of [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin]. By modifying each of the catalytic residues separately and then testing the variant enzyme’s relative activity, it has been shown that mutation of any one of these residues dramatically reduces activity. The S124 alcohol’s nucleophilicity is inductively strengthened | Mutagenesis studies<ref name="Favrot2014"> PMID:25028518 </ref> have confirmed the the catalytic function of Ag85C is dependent upon a Glu-His-Ser <scene name='69/694220/Catalytic_triad/4'>catalytic triad</scene>, similar to that of [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin]. By modifying each of the catalytic residues separately and then testing the variant enzyme’s relative activity, it has been shown that mutation of any one of these residues dramatically reduces activity. The S124 alcohol’s nucleophilicity is inductively strengthened via deprotonation by H260 and E224, which allows the S124 residue to catalyze the reaction, shown in '''Figure 4''' below. | ||
[[Image:Ag85CCatalyticMechanism.jpg|800 px|center|thumb|'''Figure 4:''' Catalytic mechanism]] | [[Image:Ag85CCatalyticMechanism.jpg|800 px|center|thumb|'''Figure 4:''' Catalytic mechanism]] | ||
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The formation of the functional catalytic triad relies on upon Van der Waals interaction between C209 and the peptide bond between L232 and T231. This interaction results in a kinked conformation of the α9 helix, which promotes that activity of the catalytic triad. As a result, Ag85C, a mycolyl transferase, can facilitate the modification of trehalose monomycolates to trehalose dimycolates, which are then transported to the bacterial cell wall. | |||
[[Image:C209.jpeg|200 px|left|thumb|'''Figure 5:''' Cys209 stabilizing kinked formation of alpha-9 helix in the native [http://www.rcsb.org/pdb/explore/explore.do?structureId=1dqz Ag85C] enzyme ]] | |||
== Methods of Inhibition == | == Methods of Inhibition == | ||
Due to the importance of Ag85C enzymatic activity in maintaining the integrity of the ''Mycobacteria tuberculosis'' cell wall though mycolic acid modifications, the Ag85C enzyme represents a potentially effective avenue for inhibiting cell growth. The conformational sensitivity of the active site residues, H260, E228, and S124, relies entirely upon Van der Waals interaction between <scene name='69/694220/C209/1'>C209 and L232-T 23</scene>, which can be seen in both the scene and '''Figure 4'''. The C209 facilitated interaction causes the <scene name='69/694220/Alpha_9_helix/2'>α9 helix</scene> to acquire a kinked conformation that promotes optimal interaction distances between catalytic residues. As a result, C209 has been a specific target residue for Ag85C inhibition. | Due to the importance of Ag85C enzymatic activity in maintaining the integrity of the ''Mycobacteria tuberculosis'' cell wall though mycolic acid modifications, the Ag85C enzyme represents a potentially effective avenue for inhibiting cell growth. The conformational sensitivity of the active site residues, H260, E228, and S124, relies entirely upon Van der Waals interaction between <scene name='69/694220/C209/1'>C209 and L232-T 23</scene>, which can be seen in both the scene and '''Figure 4'''. The C209 facilitated interaction causes the <scene name='69/694220/Alpha_9_helix/2'>α9 helix</scene> to acquire a kinked conformation that promotes optimal interaction distances between catalytic residues. As a result, C209 has been a specific target residue for Ag85C inhibition. | ||