Sandbox Reserved 321: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 26: | Line 26: | ||
==Substructure 1 of | ==Substructure 1 of InhA== | ||
<scene name='Sandbox_Reserved_321/Substructure_1/1'>Substructure 1</scene> consists of 6 parallel β strands and 4 α helices interwoven together to form a core α/β structure that contains the n-terminal domain<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>. | <scene name='Sandbox_Reserved_321/Substructure_1/1'>Substructure 1</scene> consists of 6 parallel β strands and 4 α helices interwoven together to form a core α/β structure that contains the n-terminal domain<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>. | ||
| Line 33: | Line 33: | ||
==Substructure 2 of | ==Substructure 2 of 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"/>. | <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"/>. | ||
| Line 44: | Line 44: | ||
=Function in | =InhA's Function in the Mycolic Acid Pathway= | ||
[[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>.]] | ||
| Line 51: | Line 51: | ||
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 | 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 <scene name='Sandbox_Reserved_321/Lys165/1'>(K165)</scene><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 Cα-Cβ 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"/>. | ||
| Line 59: | Line 59: | ||
=Protein Superfamilly= | =Protein Superfamilly= | ||
InhA | 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. | ||
InhA can be further claasified into the acyl carrier protein family. These proteins generally all function in the transport of substrates in a myrid of pathways, such as: the sysnthesis of polyketides and fatty acids<ref name ="Acyl Carrier Proteins">PMID:17012233</ref>. Some examples of such proteins are listed below with links to their cooresponding proteopedia page. | |||
*[[3oic]] - FabL | *[[3oic]] - FabL | ||
| Line 78: | Line 80: | ||
*[[1i2z]] - EcENR+NAD+imidazole derivative<br /> | *[[1i2z]] - EcENR+NAD+imidazole derivative<br /> | ||
