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| {{Sandbox_Reserved_Butler_CH462_Sp2015_#}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | | {{Sandbox_Reserved_Butler_CH462_Sp2015_#}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> |
| ==Enoyl-ACP Reductase InhA== | | ==Your Protein Name here== |
| <StructureSection load='4OHU' size='240' side='right' caption='Enoyl-ACP Reductase InhA Homotetramer' scene=''> | | <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> |
| | This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs. |
| | You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. |
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| == Introduction == | | == Biological Function == |
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| The Enoyl-ACP Reductase InhA, from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis ''Mycobacterium tuberculosis''], catalyzes the [http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide NADH]-dependent reduction of long-chain ''trans''-2-enoyl-ACP fatty acids in the type II fatty acid biosynthesis pathway of ''M.'' ''tuberculosis''. InhA is a member of the [http://en.wikipedia.org/wiki/Short-chain_dehydrogenase short chain dehydrogenase/reductase] (SDR) family of enzymes. InhA is the only enoyl-ACP reductase found in tuberculosis, making the enzyme a potential drug target.
| | == Structural Overview == |
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| === FAS-II System === | | == Mechanism of Action == |
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| [http://en.wikipedia.org/wiki/Mycolic_acid Mycolic acids] are very long-chain fatty acids (C<sub>60</sub> -C<sub>90</sub>) that are essential components of the mycobacterial cell wall. Mycolic acids are synthesized by at least two known elongation systems, type I and type II [http://en.wikipedia.org/wiki/Fatty_acid_synthase fatty acid synthases] (FAS-I and FAS-II). The FAS-II system prefers C16 as a starting substrate and can extend up to C56. The FAS-II system utilizes the products from the FAS-I system as primers to extend the chain lengths further. The products of the FAS-II system are the precursors of mycolic acids. Elongation by the FAS-II system occurs by a [http://en.wikipedia.org/wiki/Condensation_reaction condensation reaction]of [http://en.wikipedia.org/wiki/Acetyl acetyl] and [http://en.wikipedia.org/wiki/Malonyl-CoA malonyl] substrates, which is achieved in three steps. Step 1 involves transfer of the acyl primer, step 2 involves [http://en.wikipedia.org/wiki/Decarboxylation decarboxylation] of the substrate to yield a [http://en.wikipedia.org/wiki/Carbanion carbanion], and step 3 involves nucleophilic attack of the carbanion to yield the elongated product.
| | == Zinc Ligand(s) == |
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| === Mechanism of Action === | | == Other Ligands == |
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| The InhA gene encodes for the InhA protein. InhA catalyzes the NADH-dependent reduction of the trans double bond between positions C2-C3 of fatty acyl substrates. InhA prefers fatty acyl substrates of C16 or longer, which is consistent of the protein being a member of the FAS-II system. The longer chain length specificity of InhA distinguishes the enzyme from other enoyl-ACP reductase analogues.
| | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. |
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| [[Image:Mechanism-InhA.JPG|thumb|1000px|center|Figure 1. Mechanism of InhA protein]]
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| == Structure ==
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| === Fatty Acyl Binding Crevice ===
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| === Catalytic Triad ===
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| === Hydrogen Bonding Interactions ===
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| == Clinical Applications ==
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| [[Image:Isoniazid.JPG|thumb|300px|right|Figure 5. Isoniazid Mechanism of Action]]
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| === Isoniazid ===
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| Isoniazid is a first-line antibiotic that has been used to treat tuberculosis infections for over 50 years. Isoniazid is known to inhibit mycolic acid biosnthesis, which is the function of InhA. The activated form of isoniazid is covalently attached to the [http://en.wikipedia.org/wiki/Nicotinamide nicotinamide] ring of NADH. However, Isoniazid is still not an ideal antibiotic because many drug-resistant strains of tuberculosis have shown resistance to this inhibitor. Specifically, the mutation Ser<sup>94</sup> to Ala of InhA was sufficient enough to have isoniazid resistance.
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| === Other Inhibitors === | |
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| Drug resistance of ''M. tuberculosis'' has become a huge problem for the development of antibiotics. A drug screen of potential inhibitors of InhA (300 compounds), were composed of inhibitors of the [http://en.wikipedia.org/wiki/Plasmodium_falciparum ''Plasmodium falciparum''] enoyl-reductase, against ''M. tuberculosis''. The enoyl reductases of both bacteria have limited similarities, however two compounds, CD39 and CD117 had activity against drug-susceptible ''M. tuberculosis''. More importantly, both compounds had activity against drug-resistant and multi-drug resistant TB. Treatment of the bacterium with the compounds resulted in the inhibition of mycolic acid and long-chain fatty acid biosynthesis, indicating that these compounds act against enzymes of both the FAS-I and FAS-II system. The benefit of having the compounds have multiple targets is the reduced development of drug resistance, which is the disadvantage of isoniazid. The essential chemical groups that lead to the antimycobacterial properties of the compounds include a [http://en.wikipedia.org/wiki/Thioacetic_acid thioacetate] group, and a [http://en.wikipedia.org/wiki/Butyl t-butyl] group.
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| [[Image:CD39.JPG|thumb|500px|left|Figure 6. CD39 Structure]] [[Image:CD117.JPG|thumb|600 px|center|Figure 7. CD117 Structure]]
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| </StructureSection> | | </StructureSection> |
| == References == | | == References == |
| <references/> | | <references/> |