Sandbox Reserved 1066: Difference between revisions
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''Mycobacterium tuberculosis'' very-long-chain fatty acyl-CoA synthetase, also known as <scene name='69/694233/General_pic/1'>FadD13</scene>, is unique within its class of FadD proteins in regards to its ability to house lipid substrates longer than itself. These lipid substrates are very-long-chain fatty acids between lengths C22 –C26, which is up to the maximum length tested. <ref name="Our Paper"/> The significance of theses very-long-chain fatty acids lies in their importance to mycolic acid synthesis by ''Mycobacterium tuberculosis'' ''(M. tb)''. Mycolic acids compose part of the cell wall of ''(M. tb)''. FadD13, an activator of mycolic acids, has been identified as key component in the virulence of [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis ''Mycobacterium tuberculosis''], the etiological agent of [https://en.wikipedia.org/wiki/Tuberculosis tuberculosis], and has emerged as possible target for novel therapeutic agents.<ref name="JT">PMID: 20454815</ref> The FadD13 enzyme is the last gene of the ''mymA'' operon. <ref name="residue paper"/> | ''Mycobacterium tuberculosis'' very-long-chain fatty acyl-CoA synthetase, also known as <scene name='69/694233/General_pic/1'>FadD13</scene>, is unique within its class of FadD proteins in regards to its ability to house lipid substrates longer than itself. These lipid substrates are very-long-chain fatty acids between lengths C22 –C26, which is up to the maximum length tested. <ref name="Our Paper"/> The significance of theses very-long-chain fatty acids lies in their importance to mycolic acid synthesis by ''Mycobacterium tuberculosis'' ''(M. tb)''. Mycolic acids compose part of the cell wall of ''(M. tb)''. FadD13, an activator of mycolic acids, has been identified as key component in the virulence of [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis ''Mycobacterium tuberculosis''], the etiological agent of [https://en.wikipedia.org/wiki/Tuberculosis tuberculosis], and has emerged as possible target for novel therapeutic agents.<ref name="JT">PMID: 20454815</ref> The FadD13 enzyme is the last gene of the ''mymA'' operon. <ref name="residue paper"/> | ||
There are four main groups of FadD enzymes categorized on their ability to accommodate different length substrates: short (C2-C4), medium (C4-C12), long (C12-C22), and very long (C22-C26).<ref name="Our Paper"/> Most FadD class proteins exist as integral membrane proteins, involved in both the activation of fatty acids and other hydrophobic substrates in addition to the transport of these lipids into the cell. However, substrates longer than the enzyme itself, like these very-long-chain fatty acids, pose an interesting structural dilemma to the enzyme. FadD13 differs from typical integral membrane fatty acyl-CoA synthetases in that FadD13 exists as a [https://en.wikipedia.org/wiki/Peripheral_membrane_protein peripheral | There are four main groups of FadD enzymes categorized on their ability to accommodate different length substrates: short (C2-C4), medium (C4-C12), long (C12-C22), and very long (C22-C26).<ref name="Our Paper"/> Most FadD class proteins exist as integral membrane proteins, involved in both the activation of fatty acids and other hydrophobic substrates in addition to the transport of these lipids into the cell. However, substrates longer than the enzyme itself, like these very-long-chain fatty acids, pose an interesting structural dilemma to the enzyme. FadD13 differs from typical integral membrane fatty acyl-CoA synthetases in that FadD13 exists as a [https://en.wikipedia.org/wiki/Peripheral_membrane_protein peripheral membrane protein]. This key feature provides a mechanistic basis for FadD13’s activation and transport of fatty acids of length C24-C26 through the two step addition of [http://en.wikipedia.org/wiki/Coenzyme_A Coenzyme A](Figure 1).<ref name="Our Paper">PMID: 22560731</ref> | ||
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== Current Treatment == | == Current Treatment == | ||
Drugs developed thus far that have been shown to inhibit mycolic acid biosynthesis are: [https://en.wikipedia.org/wiki/Isoniazid isoniazid], ethionamide, isoxyl, thiolactomycin, and triclosan. <ref name="Drug Inhibitors"/> Additionally, https://en.wikipedia.org/wiki/Pyrazinamide pyrazinamide] was shown to inhibit fatty acid synthase type I which is involved in providing a precursor necessary for fatty acid elongation to long-chain mycolic acids. <ref name="Drug Inhibitors"/> Treatment for active cases of tuberculosis include the simultaneous therapeutic use of two or more frontline drugs: isoniazid, ethambutol, rifampicin and pyrazinamide. <ref name="molecular studies"/> | Drugs developed thus far that have been shown to inhibit mycolic acid biosynthesis are: [https://en.wikipedia.org/wiki/Isoniazid isoniazid], ethionamide, isoxyl, thiolactomycin, and triclosan. <ref name="Drug Inhibitors"/> Additionally, [https://en.wikipedia.org/wiki/Pyrazinamide pyrazinamide] was shown to inhibit fatty acid synthase type I which is involved in providing a precursor necessary for fatty acid elongation to long-chain mycolic acids. <ref name="Drug Inhibitors"/> Treatment for active cases of tuberculosis include the simultaneous therapeutic use of two or more frontline drugs: isoniazid, ethambutol, rifampicin and pyrazinamide. <ref name="molecular studies"/> | ||
== Future Research == | == Future Research == | ||
