Sandbox Reserved 1056: Difference between revisions
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==Isocitrate Lyase from ''Mycobacterium Tuberculosis''== | ==Isocitrate Lyase from ''Mycobacterium Tuberculosis''== | ||
<StructureSection load='1F8I' size='340' side='right' caption='Isocitrate Lyase from ''Mycobacterium tuberculosis''' scene=''> | <StructureSection load='1F8I' size='340' side='right' caption='Isocitrate Lyase from ''Mycobacterium tuberculosis''' scene=''> | ||
[[Image: | [[Image:CAC.png|400 px|right|thumb|Figure 1: ICL mediated glyoxylate shunt pathway of the Citric Acid Cycle]] | ||
[http://en.wikipedia.org/wiki/Isocitrate_lyase Isocitrate Lyase] (ICL) is a metabolic enzyme that converts the metabolite isocitrate into glyoxylate and succinate. ICL is a homotetramer with each monomer being composed of 14 alpha helices, 14 beta sheets, and a magnesium ion cofactor. ICL has shown clinical relevance in the disease state [http://en.wikipedia.org/wiki/Tuberculosis Tuberculosis] where it is responsible for the persistence of ''Mycobacterium tuberculosis'' during the chronic stage of infection<ref name="genes">PMID: 18054522</ref> This survival strategy mediated by ICL is characterized by a metabolic shortcut within the [http://en.wikipedia.org/wiki/Citric_acid_cycle Citric Acid Cycle]. ICL creates this shunt pathway by converting isocitrate to succinate and glyoxylate, diverting acetyl-CoA from the beta-oxidation of fatty acids<ref name="ICL">PMID:10932251</ref><ref name="ICL2">PMID: 2696959</ref>. | [http://en.wikipedia.org/wiki/Isocitrate_lyase Isocitrate Lyase] (ICL) is a metabolic enzyme that converts the metabolite isocitrate into glyoxylate and succinate. ICL is a homotetramer with each monomer being composed of 14 alpha helices, 14 beta sheets, and a magnesium ion cofactor. ICL has shown clinical relevance in the disease state [http://en.wikipedia.org/wiki/Tuberculosis Tuberculosis] where it is responsible for the persistence of ''Mycobacterium tuberculosis'' during the chronic stage of infection<ref name="genes">PMID: 18054522</ref> This survival strategy mediated by ICL is characterized by a metabolic shortcut within the [http://en.wikipedia.org/wiki/Citric_acid_cycle Citric Acid Cycle]. ICL creates this shunt pathway by converting isocitrate to succinate and glyoxylate, diverting acetyl-CoA from the beta-oxidation of fatty acids<ref name="ICL">PMID:10932251</ref><ref name="ICL2">PMID: 2696959</ref>. | ||
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==Mechanism== | ==Mechanism== | ||
[[Image: | [[Image:Real_Mechanism.png|400 px|right|thumb|Figure 6: Chemical Mechanism of Isocitrate Lyase]] | ||
Isocitrate lyase catalyzes a reversible aldol condensation, converting isocitrate to glyoxylate and succinate via the breaking of a C-C bond<ref name="claisen"/>. Within the active site of ICL the HIS193 residue deprotonates the <scene name='69/694223/Arginine/1'>Cys191</scene>residue of the active site in order to increase its basicity<ref name="ICL">PMID:10932251</ref><ref name="claisen"/>. The Cys 191 residue then deprotonates the alpha carbon adjacent to one of the carbonyl groups of succinate, thus forming the enolic intermediate<ref name="claisen"/>. The negatively charged alpha carbon atom of the enolic intermediate acts as a nucleophile that attacks the carbonyl carbon of the aldehyde of glyoxylate. The nucleophilic attack will place a negative charge on the oxygen atom oxygen at the former carbonyl oxygen of the aldehyde, which will be stabilized by positive charges of the Mg ion, ARG228 and HIS180<ref name="ICL">PMID:10932251</ref>. The protonation of this species will yield the final product. It is important to note that this reaction is entirely reversible; the breakdown of isocitrate into glyoxylate and succinate occurs using a similar mechanism. | Isocitrate lyase catalyzes a reversible aldol condensation, converting isocitrate to glyoxylate and succinate via the breaking of a C-C bond<ref name="claisen"/>. Within the active site of ICL the HIS193 residue deprotonates the <scene name='69/694223/Arginine/1'>Cys191</scene>residue of the active site in order to increase its basicity<ref name="ICL">PMID:10932251</ref><ref name="claisen"/>. The Cys 191 residue then deprotonates the alpha carbon adjacent to one of the carbonyl groups of succinate, thus forming the enolic intermediate<ref name="claisen"/>. The negatively charged alpha carbon atom of the enolic intermediate acts as a nucleophile that attacks the carbonyl carbon of the aldehyde of glyoxylate. The nucleophilic attack will place a negative charge on the oxygen atom oxygen at the former carbonyl oxygen of the aldehyde, which will be stabilized by positive charges of the Mg ion, ARG228 and HIS180<ref name="ICL">PMID:10932251</ref>. The protonation of this species will yield the final product. It is important to note that this reaction is entirely reversible; the breakdown of isocitrate into glyoxylate and succinate occurs using a similar mechanism. | ||