Sandbox Reserved 321: Difference between revisions

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The enzyme InhA is coded from the INHA gene that is similar in sequence to the ''[http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium]''gene which plays a role in [http://en.wikipedia.org/wiki/Fatty_acid_synthesis fatty acid synthesis], and is part of a short chain dehydrogenase/reductase family<ref name ="making drugs for inhA">Sacchettini, James (New Rochelle, NY) 1999 INHA crystals and three dimensional structure United States Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) 5882878 http://www.freepatentsonline.com/5882878.html</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>. Inha is an [http://en.wikipedia.org/wiki/NADH NADH] dependent trans enoyl-acyl ACP carrier protein that is part of the fatty acid biosynthesis system: fatty acid synthase two (FASII), and plays a role in the synthesis of [http://en.wikipedia.org/wiki/Mycolic_acid Mycolic Acid]<ref name ="mech of thioamide drug action">PMID:17227913</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>. Mycolic acids are long chain fatty acids (C54 to C63)that are essential in cell wall formation of the human pathogen ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]''as well as other mycobateria such as ''[http://en.wikipedia.org/wiki/Mycobacterium_leprae Mycobacterium leprae]'', and are associated with virulence<ref name ="TB">PMID2568869:</ref>. InhA has been proposed as the target of the [http://en.wikipedia.org/wiki/Thioamidedrugs thioamide] drugs, ethionamide (ETH) and isoniazid (INH), which have been used in treatment of mycobacterial infections <ref name ="phosphorylation of inhA">PMID:21143326</ref>.

=Structure of InhA=

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The primary target of the thioamide drugs PTH and ETH have been shown to be InhA <scene name='Sandbox_Reserved_321/Structural_progresion/1'>(go to original scene)</scene> in both genetic 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 [http://en.wikipedia.org/wiki/In_vitro in vitro]<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 ETH and PTH activation<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"/>. Currently studies are being carried out to determine other methods of treatment for mycobaterial infections that dont require activation by cellular constituents, due to the incerease of drug resistant cases world wide.

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 the rotation 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. Developmentaly this is important, for InhA is no longer active an 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 <scene name='Sandbox_Reserved_321/K218_and_m_155/1'>(K218 and M155)</scene> 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 the rotation 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. Developmentaly this is important, for InhA is no longer active an 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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 [[Image:Stero veiw.png|thumb|left|upright=2.5|alt=Secondary Structure Succession of InhA. Secondary structure residues are ordered from blue to red.|Stero view of the homotetramer structure of InhA with secondary structure succession outlined]]
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 The enzyme InhA is coded from the INHA gene that is similar in sequence to the ''[http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium]''gene which plays a role in [http://en.wikipedia.org/wiki/Fatty_acid_synthesis fatty acid synthesis], and is part of a short chain dehydrogenase/reductase family<ref name ="making drugs for inhA">Sacchettini, James (New Rochelle, NY) 1999 INHA crystals and three dimensional structure United States Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) 5882878 http://www.freepatentsonline.com/5882878.html</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>. Inha is an [http://en.wikipedia.org/wiki/NADH NADH] dependent trans enoyl-acyl ACP carrier protein that is part of the fatty acid biosynthesis system: fatty acid synthase two (FASII), and plays a role in the synthesis of [http://en.wikipedia.org/wiki/Mycolic_acid Mycolic Acid]<ref name ="mech of thioamide drug action">PMID:17227913</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>. Mycolic acids are long chain fatty acids (C54 to C63)that are essential in cell wall formation of the human pathogen ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]''as well as other mycobateria such as ''[http://en.wikipedia.org/wiki/Mycobacterium_leprae Mycobacterium leprae]'', and are associated with virulence<ref name ="TB">PMID2568869:</ref>. InhA has been proposed as the target of the [http://en.wikipedia.org/wiki/Thioamidedrugs thioamide] drugs, ethionamide (ETH)  and isoniazid (INH), which have been used in treatment of mycobacterial infections <ref name ="phosphorylation of inhA">PMID:21143326</ref>.
 =Structure of InhA=
@@ Line 52: / Line 54: @@
 The primary target of the thioamide drugs PTH and ETH have been shown to be InhA <scene name='Sandbox_Reserved_321/Structural_progresion/1'>(go to original scene)</scene> in both genetic 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 [http://en.wikipedia.org/wiki/In_vitro in vitro]<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 ETH and PTH activation<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"/>.  Currently studies are being carried out to determine other methods of treatment for mycobaterial infections that dont require activation by cellular constituents, due to the incerease of drug resistant cases world wide.
-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 the rotation 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.  Developmentaly this is important, for InhA is no longer active an 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 <scene name='Sandbox_Reserved_321/K218_and_m_155/1'>(K218 and M155)</scene> 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 the rotation 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.  Developmentaly this is important, for InhA is no longer active an the mycolic acids nessasary in cell wall compostion of various mycobacteria will not be formed.