Sandbox Reserved 321: Difference between revisions
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<scene name='Sandbox_Reserved_321/Substructure_2/1'>Substructure 2</scene> contains the c-terminal region of the molecule and consists of a small β strand <scene name='Sandbox_Reserved_321/B-7/1'>(B-7)</scene>, and two α helicies <scene name='Sandbox_Reserved_321/A-6_and_a-7/1'>(A-6 and A-7)</scene> which are conected by a short five residue loop<ref name ="making drugs for inhA"/>. The C-terminal domain consits of two other α helicies <scene name='Sandbox_Reserved_321/A-8_and_a-9/1'>(A-8 and A-9)</scene><ref name ="making drugs for inhA"/>. | <scene name='Sandbox_Reserved_321/Substructure_2/1'>Substructure 2</scene> contains the c-terminal region of the molecule and consists of a small β strand <scene name='Sandbox_Reserved_321/B-7/1'>(B-7)</scene>, and two α helicies <scene name='Sandbox_Reserved_321/A-6_and_a-7/1'>(A-6 and A-7)</scene> which are conected by a short five residue loop<ref name ="making drugs for inhA"/>. The C-terminal domain consits of two other α helicies <scene name='Sandbox_Reserved_321/A-8_and_a-9/1'>(A-8 and A-9)</scene><ref name ="making drugs for inhA"/>. | ||
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[[Image:Pathway2.png|thumb|right|upright=2|alt=Proposed mechanism.|Formulated mechanism of Mycolic acid synthesis as proposed by Wilson et al.<ref name ="Drug Induced Alterations">PMID:10536008</ref>.]] | [[Image:Pathway2.png|thumb|right|upright=2|alt=Proposed mechanism.|Formulated mechanism of Mycolic acid synthesis as proposed by Wilson et al.<ref name ="Drug Induced Alterations">PMID:10536008</ref>.]] | ||
InhA plays a key role in the synthesis of fatty acids, particularly in ''M. tuberculosis'' which has type one fatty acid synthesis (FASI) and type two fatty acid synthesis (FASII) which together funtion in the synthesis of mycolic acids<ref name ="Function of M Tb">PMID:18552191</ref>. FASI synthesizes C16-18 and C24-26 fatty acids these are then sent to FASII promotes chain extention, forming long-chain meromycolic acids that are 56-64 carbons in length<ref name ="Fatty Acid Synthesis">PMID:18804030</ref>. The final step in FASII is compleated by InhA which reduces 2-trans-enoyl-ACP's with chain lengths over twelve carbons in a NADP dependent manner where the hydride transfer precedes protonation<ref name ="Function of M Tb"/><ref name ="Roles of T158">PMID:10521269</ref>. | InhA plays a key role in the synthesis of fatty acids, particularly in ''M. tuberculosis'' which has type one fatty acid synthesis (FASI) and type two fatty acid synthesis (FASII) which together funtion in the synthesis of mycolic acids<ref name ="Function of M Tb">PMID:18552191</ref>. FASI synthesizes C16-18 and C24-26 fatty acids these are then sent to FASII promotes chain extention, forming long-chain meromycolic acids that are 56-64 carbons in length<ref name ="Fatty Acid Synthesis">PMID:18804030</ref>. The final step in FASII is compleated by InhA which reduces 2-trans-enoyl-ACP's with chain lengths over twelve carbons in a NADP dependent manner where the hydride transfer precedes protonation<ref name ="Function of M Tb"/><ref name ="Roles of T158">PMID:10521269</ref>. | ||
The reaction takes place as follows. Intially NADH binds to the active site mediated by vander wall interactions with phenylalanine 41 (F41) and interations with lysine 165 (K165)<ref name ="Roles of T158"/><ref name ="crystallographic studies"/>. Binding of NADH causes a conformational change in the Aspartate 42 and 43 (E42 and E43) side chains and an over all conformational change in InhA<ref name ="crystallographic studies"/>. In addition tyrosine 158 (Y158) playes an important role in alinging the carbonyl substrate, in fact; rotaion about its C -C bond by 60 brings it into a position where it can hydrogen bond to the carbonyl of the 2-trans enoyl-ACP and provide it with electrophilic stabalization<ref name ="Roles of T158"/>. Inha then reduces the 2-trans double bond of the substrate by forming a enoyl intermediate through the transfer of a hydride ion from NADH to the thrid carbon of the substrate, followed by protonation of the second carbon<ref name ="crystallographic studies"/>. The biniding of both the substrate and the cofactor induces another conformational change in InhA that allows for the release of the meromycolic acid product<ref name ="crystallographic studies"/>. The meromycolic acids undergo Claisen Condensation with a C26 fatty acid followed by reduction to a mature mycolic acid<ref name ="Fatty Acid Synthesis"/><ref name ="crystallographic studies"/>. | |||
=InhA and Thioamide Drugs= | |||
=Protein Superfamilly= | =Protein Superfamilly= | ||
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*[[1i2z]] - EcENR+NAD+imidazole derivative<br /> | *[[1i2z]] - EcENR+NAD+imidazole derivative<br /> | ||
InhA can also be classified into a family of short chain dehydrogenase/reductases (SDR). This family consists of proteins exhibiting a central core with a Rossmann fold that contains a NADH binding site. | InhA can also be classified into a family of short chain dehydrogenase/reductases (SDR). This family consists of proteins exhibiting a central core with a Rossmann fold that contains a NADH binding site. Examples of proteins in this family are listed below. | ||
=Additional Resources= | =Additional Resources= | ||
