Sandbox Reserved 321: Difference between revisions

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The primary target of the thioamide drugs PTH and ETH has been shown to be InhA in both gentic and molecular experiments<ref name ="mech of thioamide drug action"/>. Both PTH and ETH require activation by various cellular componets to form the NAD adduct that acts to inhibit InhA, and therefore connot be studied in vivo]<ref name ="mech of thioamide drug action"/>. The exacct mechanism of their activation is still under speculation, however a flavin monooxygenase (EthA) has been shown to participate in it<ref name ="mech of thioamide drug action"/>. In fact, strains of ''M. tuberculosis'' that have mutations in the gene which express EthA exhibit resistance to thioamide drugs<ref name ="mech of thioamide drug action"/>. Curently studies are being carried out to determine other methods of treatment for mycobaterial infections that dont require activation by cellular constituents, due to the incereasing in drug resistant cases world wide.

The ETH-NAD adduct (EAD), and the PTH-NAD adducts (P1H) have been found to occupy the same hydrophobic pocket of InhA as NADH and exhibit the same van der Waal interactions between K218 and M155 and the ethyl or proply group with distances of 3.3Å and 3.2Å respectively<ref name ="mech of thioamide drug action"/>. EAD or P1H binding forces rotaion of F149 by 90° which causes a ring stacking interation with the pyridine ring on the adduct. In addtion π stacking interactions form between the propyl group of P1H and the ethyl group of <scene name='Sandbox_Reserved_321/Pi_stacking/1'>EAD with Y158</scene>at distance of ~3.3Å. These interations and conformational changes in InhA contribute to its inactivation. If InhA is no longer active then the mycolic acids nessasary in cell wall compostion of various mycobacteria will not be formed.

The ETH-NAD adduct <scene name='Sandbox_Reserved_321/Ligand/1'>(EAD)</scene>, and the PTH-NAD adducts (P1H) have been found to occupy the same hydrophobic pocket of InhA as NADH and exhibit the same van der Waal interactions between K218 and M155 and the ethyl or proply group with distances of 3.3Å and 3.2Å respectively<ref name ="mech of thioamide drug action"/>. EAD or P1H binding forces rotaion of F149 by 90° which causes a ring stacking interation with the pyridine ring on the adduct. In addtion π stacking interactions form between the propyl group of P1H and the ethyl group of <scene name='Sandbox_Reserved_321/Pi_stacking/1'>EAD with Y158</scene>at distance of ~3.3Å. These interations and conformational changes in InhA contribute to its inactivation. If InhA is no longer active then the mycolic acids nessasary in cell wall compostion of various mycobacteria will not be formed.

Sandbox Reserved 321: Difference between revisions

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Revision as of 23:48, 3 April 2011 view source Kelly Hrywkiw (talk \| contribs) 155 edits No edit summary ← Older edit		Revision as of 00:00, 4 April 2011 view source Kelly Hrywkiw (talk \| contribs) 155 edits No edit summary Newer edit →
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	The primary target of the thioamide drugs PTH and ETH has been shown to be InhA in both gentic and molecular experiments<ref name ="mech of thioamide drug action"/>. Both PTH and ETH require activation by various cellular componets to form the NAD adduct that acts to inhibit InhA, and therefore connot be studied in vivo]<ref name ="mech of thioamide drug action"/>. The exacct mechanism of their activation is still under speculation, however a flavin monooxygenase (EthA) has been shown to participate in it<ref name ="mech of thioamide drug action"/>. In fact, strains of ''M. tuberculosis'' that have mutations in the gene which express EthA exhibit resistance to thioamide drugs<ref name ="mech of thioamide drug action"/>. Curently studies are being carried out to determine other methods of treatment for mycobaterial infections that dont require activation by cellular constituents, due to the incereasing in drug resistant cases world wide.		The primary target of the thioamide drugs PTH and ETH has been shown to be InhA in both gentic and molecular experiments<ref name ="mech of thioamide drug action"/>. Both PTH and ETH require activation by various cellular componets to form the NAD adduct that acts to inhibit InhA, and therefore connot be studied in vivo]<ref name ="mech of thioamide drug action"/>. The exacct mechanism of their activation is still under speculation, however a flavin monooxygenase (EthA) has been shown to participate in it<ref name ="mech of thioamide drug action"/>. In fact, strains of ''M. tuberculosis'' that have mutations in the gene which express EthA exhibit resistance to thioamide drugs<ref name ="mech of thioamide drug action"/>. Curently studies are being carried out to determine other methods of treatment for mycobaterial infections that dont require activation by cellular constituents, due to the incereasing in drug resistant cases world wide.

	The ETH-NAD adduct (EAD), and the PTH-NAD adducts (P1H) have been found to occupy the same hydrophobic pocket of InhA as NADH and exhibit the same van der Waal interactions between K218 and M155 and the ethyl or proply group with distances of 3.3Å and 3.2Å respectively<ref name ="mech of thioamide drug action"/>. EAD or P1H binding forces rotaion of F149 by 90° which causes a ring stacking interation with the pyridine ring on the adduct. In addtion π stacking interactions form between the propyl group of P1H and the ethyl group of <scene name='Sandbox_Reserved_321/Pi_stacking/1'>EAD with Y158</scene>at distance of ~3.3Å. These interations and conformational changes in InhA contribute to its inactivation. If InhA is no longer active then the mycolic acids nessasary in cell wall compostion of various mycobacteria will not be formed.		The ETH-NAD adduct <scene name='Sandbox_Reserved_321/Ligand/1'>(EAD)</scene>, and the PTH-NAD adducts (P1H) have been found to occupy the same hydrophobic pocket of InhA as NADH and exhibit the same van der Waal interactions between K218 and M155 and the ethyl or proply group with distances of 3.3Å and 3.2Å respectively<ref name ="mech of thioamide drug action"/>. EAD or P1H binding forces rotaion of F149 by 90° which causes a ring stacking interation with the pyridine ring on the adduct. In addtion π stacking interactions form between the propyl group of P1H and the ethyl group of <scene name='Sandbox_Reserved_321/Pi_stacking/1'>EAD with Y158</scene>at distance of ~3.3Å. These interations and conformational changes in InhA contribute to its inactivation. If InhA is no longer active then the mycolic acids nessasary in cell wall compostion of various mycobacteria will not be formed.