| Structural highlights
Function
[LOVB_ASPTE] Lovastatin nonaketide synthase; 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, PubMed:23023987). 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:23023987, 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).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB-LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB-LovC complex at 3.60 A and the core LovB at 2.91 A resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.
Structural basis for the biosynthesis of lovastatin.,Wang J, Liang J, Chen L, Zhang W, Kong L, Peng C, Su C, Tang Y, Deng Z, Wang Z Nat Commun. 2021 Feb 8;12(1):867. doi: 10.1038/s41467-021-21174-8. PMID:33558520[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science. 1999 May 21;284(5418):1368-72. PMID:10334994
- ↑ Hendrickson L, Davis CR, Roach C, Nguyen DK, Aldrich T, McAda PC, Reeves CD. Lovastatin biosynthesis in Aspergillus terreus: characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene. Chem Biol. 1999 Jul;6(7):429-39. doi: 10.1016/s1074-5521(99)80061-1. PMID:10381407 doi:https://dx.doi.org/10.1016/s1074-5521(99)80061-1
- ↑ Sorensen JL, Auclair K, Kennedy J, Hutchinson CR, Vederas JC. Transformations of cyclic nonaketides by Aspergillus terreus mutants blocked for lovastatin biosynthesis at the lovA and lovC genes. Org Biomol Chem. 2003 Jan 7;1(1):50-9. doi: 10.1039/b207721c. PMID:12929390 doi:https://dx.doi.org/10.1039/b207721c
- ↑ Xie X, Watanabe K, Wojcicki WA, Wang CC, Tang Y. Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem Biol. 2006 Nov;13(11):1161-9. PMID:17113998 doi:10.1016/j.chembiol.2006.09.008
- ↑ Xie X, Pashkov I, Gao X, Guerrero JL, Yeates TO, Tang Y. Rational improvement of simvastatin synthase solubility in Escherichia coli leads to higher whole-cell biocatalytic activity. Biotechnol Bioeng. 2009 Jan 1;102(1):20-8. PMID:18988191 doi:10.1002/bit.22028
- ↑ Xie X, Meehan MJ, Xu W, Dorrestein PC, Tang Y. Acyltransferase mediated polyketide release from a fungal megasynthase. J Am Chem Soc. 2009 Jun 24;131(24):8388-9. doi: 10.1021/ja903203g. PMID:19530726 doi:https://dx.doi.org/10.1021/ja903203g
- ↑ Gao X, Xie X, Pashkov I, Sawaya MR, Laidman J, Zhang W, Cacho R, Yeates TO, Tang Y. Directed evolution and structural characterization of a simvastatin synthase. Chem Biol. 2009 Oct 30;16(10):1064-74. PMID:19875080 doi:10.1016/j.chembiol.2009.09.017
- ↑ Ma SM, Li JW, Choi JW, Zhou H, Lee KK, Moorthie VA, Xie X, Kealey JT, Da Silva NA, Vederas JC, Tang Y. Complete reconstitution of a highly reducing iterative polyketide synthase. Science. 2009 Oct 23;326(5952):589-92. doi: 10.1126/science.1175602. PMID:19900898 doi:https://dx.doi.org/10.1126/science.1175602
- ↑ Meehan MJ, Xie X, Zhao X, Xu W, Tang Y, Dorrestein PC. FT-ICR-MS characterization of intermediates in the biosynthesis of the alpha-methylbutyrate side chain of lovastatin by the 277 kDa polyketide synthase LovF. Biochemistry. 2011 Jan 18;50(2):287-99. doi: 10.1021/bi1014776. Epub 2010 Dec 22. PMID:21069965 doi:https://dx.doi.org/10.1021/bi1014776
- ↑ Barriuso J, Nguyen DT, Li JW, Roberts JN, MacNevin G, Chaytor JL, Marcus SL, Vederas JC, Ro DK. Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin J by a single cytochrome P450 monooxygenase, LovA. J Am Chem Soc. 2011 Jun 1;133(21):8078-81. doi: 10.1021/ja201138v. Epub 2011 Apr , 15. PMID:21495633 doi:https://dx.doi.org/10.1021/ja201138v
- ↑ Ames BD, Nguyen C, Bruegger J, Smith P, Xu W, Ma S, Wong E, Wong S, Xie X, Li JW, Vederas JC, Tang Y, Tsai SC. Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis. Proc Natl Acad Sci U S A. 2012 Jun 25. PMID:22733743 doi:10.1073/pnas.1113029109
- ↑ Boettger D, Bergmann H, Kuehn B, Shelest E, Hertweck C. Evolutionary imprint of catalytic domains in fungal PKS-NRPS hybrids. Chembiochem. 2012 Nov 5;13(16):2363-73. doi: 10.1002/cbic.201200449. Epub 2012, Sep 28. PMID:23023987 doi:https://dx.doi.org/10.1002/cbic.201200449
- ↑ Xu W, Chooi YH, Choi JW, Li S, Vederas JC, Da Silva NA, Tang Y. LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis. Angew Chem Int Ed Engl. 2013 Jun 17;52(25):6472-5. doi: 10.1002/anie.201302406., Epub 2013 May 7. PMID:23653178 doi:https://dx.doi.org/10.1002/anie.201302406
- ↑ Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN. The role of distant mutations and allosteric regulation on LovD active site dynamics. Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900 doi:https://dx.doi.org/10.1038/nchembio.1503
- ↑ Wang J, Liang J, Chen L, Zhang W, Kong L, Peng C, Su C, Tang Y, Deng Z, Wang Z. Structural basis for the biosynthesis of lovastatin. Nat Commun. 2021 Feb 8;12(1):867. doi: 10.1038/s41467-021-21174-8. PMID:33558520 doi:https://dx.doi.org/10.1038/s41467-021-21174-8
|
