Sandbox Reserved 316: Difference between revisions

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OCA, Eric Ginter

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-{{STRUCTURE_3hle |  PDB=3hle  |  SCENE=  }}
 ==Introduction==
-[[Image:svs.jpg|200px|left|thumb|]]'''Simvastatin synthase''' (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis<ref name="paper4">PMID:
+[[Image:svs.jpg|300px|left|thumb|]]'''Simvastatin synthase''' (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis<ref name="paper4">PMID:
-17113998</ref>. Pictured here is the D5 mutant (Figure 1).
+17113998</ref>. Pictured here is the generated double mutant C40A/C60N (G0), from wild type LovD (Figure 1).
+This enzyme is isolated from the natural product biosynthetic pathways of [http://en.wikipedia.org/wiki/Aspergillus_terreus ''Aspergillus terreus''], specifically the polyketide biosynthetic pathway. Simvastatin Synthase  converts the inactive monacolin J acid (MJA) by dimethylbutyryl chloride to yield the protected form of simvastatin (Figure 2), which subsequently undergoes lactonization to yield [http://en.wikipedia.org/wiki/Simvastatin ''simvastatin'']<ref name="paper5">PMID:19875080</ref>.
-This enzyme is isolated from the natural product biosynthetic pathways of ''Aspergillus terreus''. Simvastatin Synthase  converts the inactive monacolin J acid (<scene name='Sandbox_Reserved_316/Blah/2'>MJA</scene>) by dimethylbutyryl chloride to yield the protected form of simvastatin (Figure 2), which subsequently undergoes lactonization to yield simvastatin<ref name="paper5">PMID:19875080</ref>.
+[[Image:Sim_mja.jpg]]
-[[Image:Sim_mja.jpg]]
 LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester<ref name="paper1">PMID:17277201</ref>.
 ==Exploring the structure==
-LovD is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis<ref name="paper2">PMID:10334994</ref>.
+{{STRUCTURE_3hle |  PDB=3hle  |  SCENE=Sandbox_Reserved_316/Default/1}}
-LovD has of two domains. The <scene name='Sandbox_Reserved_316/First_domain_1/1'>first domain</scene>, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face<ref name="paper1">PMID:17277201</ref>. The <scene name='Sandbox_Reserved_316/Second_domain_1/1'>second domain</scene> is smaller, consists of residues 93–203 and is primarily α-helical<ref name="paper1">PMID:17277201</ref>.
+<scene name='Sandbox_Reserved_316/Default/1'>LovD</scene> is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis<ref name="paper2">PMID:10334994</ref>.
+LovD has of two domains. The <scene name='Sandbox_Reserved_316/Firsstdomain/1'>first domain</scene>, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face<ref name="paper1">PMID:17277201</ref>. The
+<scene name='Sandbox_Reserved_316/Seconddomainn/1'>second domain</scene> is smaller, consists of residues 93–203 and is primarily α-helical<ref name="paper1">PMID:17277201</ref>.
-At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. In LovD, these loops give the impression of a ringshaped ridge or baseball catcher’s mitt over the active site with fingers composed of <scene name='Sandbox_Reserved_316/5_loops/1'>five loops</scene>: residues 114–125, 147–173, 243–258, 321–327, and 388–391<ref name="paper1">PMID:17277201</ref>.
+At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. Upon ligand binding LovD undergoes a conformational change analogous to the closing of a catcher's mitt by these loops. This ringshaped ridge over the active site with fingers is composed of <scene name='Sandbox_Reserved_316/5_loops/2'>five loops</scene>: residues 114–125, 147–173, 243–258, 321–327, and 388–391<ref name="paper1">PMID:17277201</ref>.
-LovD has <scene name='Sandbox_Reserved_316/Cysteines/1'>nine cysteines</scene> at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395<ref name="paper3">PMID:18988191</ref>.
+LovD has <scene name='Sandbox_Reserved_316/Cysteines/2'>nine cysteines</scene> at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395<ref name="paper3">PMID:18988191</ref>.
-==Significance==
+==Additional Information==
+<Structure load='1CI8' size='300' frame='true' align='right' caption='' scene='Sandbox_Reserved_316/Estb/1'/>
 As simvastatin is an active pharmaceutical ingredient in the cholesterol-lowering drug Zocor®, its efficient synthesis from lovastatin, via LovD is intensely pursued <ref name="paper4">PMID:19875080</ref>.
+The protein-protein interaction between LovD and the acyl carrier protein domain of LovF facilitates the highly efficient tailoring reaction during LVA biosynthesis <ref name="paper4">PMID:
+17113998</ref>. The α-''S''-methylbutyrate side chain is synthesized by the lovastatin diketide synthase (LDKS) LovF and then transferred by LovD regioselectively to the C8 hydroxyl of <scene name='Sandbox_Reserved_316/Blah/3'>MJA</scene><ref name="paper3">PMID:18988191</ref>.
+Among enzymes that of known structures, <scene name='Sandbox_Reserved_316/Estb/1'>EstB</scene> (cephalosporin esterase), is homologous to LovD: 26% sequence identity <ref name="paper6">PMID:
+11847270</ref>.
 ==References==
 <references/>