4lcm

Simvastatin Synthase (LOVD), from Aspergillus Terreus, LovD9 mutant (simh9014)

spinqualitylabelsall models 4lcm, resolution 3.19Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4lcm is a 4 chain structure with sequence from Aspergillus terreus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.19Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LOVD_ASPTE Monacolin J acid methylbutanoyltransferase; part of the gene cluster that mediates the biosynthesis of lovastatin (also known as mevinolin, mevacor or monacolin K), a hypolipidemic inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in the biosynthesis of lovastatin is the production of dihydromonacolin L acid by the lovastatin nonaketide synthase lovB and the trans-acting enoyl reductase lovC via condensation of one acetyl-CoA unit and 8 malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898, PubMed:22733743). Dihydromonacolin L acid is released from lovB by the thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is oxidized by the dihydromonacolin L monooxygenase lovA twice to form monacolin J acid (PubMed:12929390, PubMed:21495633). The 2-methylbutyrate moiety of lovastatin is synthesized by the lovastatin diketide synthase lovF via condensation of one acetyl-CoA unit and one malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the covalent attachment of this moiety to monacolin J acid is catalyzed by the transesterase lovD to yield lovastatin (PubMed:10334994, PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900). LovD has broad substrate specificity and can also convert monacolin J to simvastatin using alpha-dimethylbutanoyl-S-methyl-3-mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can also catalyze the reverse reaction and function as hydrolase in vitro (PubMed:19875080). LovD has much higher activity with LovF-bound 2-methylbutanoate than with free diketide substrates (PubMed:21069965). Publication Abstract from PubMed Natural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1,000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is to our knowledge the first nonpatent report of the enzyme currently used for the manufacture of simvastatin as well as the intermediate evolved variants. Crystal structures and microsecond-scale molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF. The role of distant mutations and allosteric regulation on LovD active site dynamics.,Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Simvastatin Synthase

Proteopedia Page Contributors and Editors (what is this?)

OCA