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Showing Protein Dihydromonacolin L monooxygenase LovA (HMDBP13621)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 1 metabolite
Identification
HMDB Protein ID HMDBP13621
Secondary Accession Numbers None
Name Dihydromonacolin L monooxygenase LovA
Synonyms
  1. Dihydromonacolin L hydroxylase
  2. Lovastatin biosynthesis cluster protein A
  3. Monacolin L hydroxylase
Gene Name LOVA
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Dihydromonacolin L monooxygenase; 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).
Pathways
  • lovastatin biosynthesis
Reactions Not Available
GO Classification
Cellular Component
endoplasmic reticulum membrane
integral to membrane
Molecular Function
monooxygenase activity
iron ion binding
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
heme binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues Not Available
Molecular Weight 60578.245
Theoretical pI Not Available
Pfam Domain Function
Signals Not Available
Transmembrane Regions
  • 24-44;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q0C8M4
UniProtKB/Swiss-Prot Entry Name LOVA_ASPTN
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. 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. doi: 10.1126/science.284.5418.1368. [PubMed:10334994 ]
  2. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J: Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957-61. doi: 10.1073/pnas.77.7.3957. [PubMed:6933445 ]
  3. 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. [PubMed:10381407 ]
  4. 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. [PubMed:12929390 ]
  5. 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. doi: 10.1016/j.chembiol.2006.09.008. [PubMed:17113998 ]
  6. 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. doi: 10.1002/bit.22028. [PubMed:18988191 ]
  7. 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. doi: 10.1016/j.chembiol.2009.09.017. [PubMed:19875080 ]
  8. 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. [PubMed:19530726 ]
  9. 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. [PubMed:19900898 ]
  10. 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. [PubMed:21069965 ]
  11. 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. [PubMed:21495633 ]
  12. 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. [PubMed:23653178 ]
  13. Chen MC, Tsai YC, Tseng JH, Liou JJ, Horng S, Wen HC, Fan YC, Zhong WB, Hsu SP: Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer. Int J Mol Sci. 2017 Dec 13;18(12). pii: ijms18122690. doi: 10.3390/ijms18122690. [PubMed:29236027 ]
  14. Zhong WB, Tsai YC, Chin LH, Tseng JH, Tang LW, Horng S, Fan YC, Hsu SP: A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model. Int J Mol Sci. 2018 Jun 22;19(7). pii: ijms19071834. doi: 10.3390/ijms19071834. [PubMed:29932104 ]
  15. 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 Jul 10;109(28):11144-9. doi: 10.1073/pnas.1113029109. Epub 2012 Jun 25. [PubMed:22733743 ]
  16. 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. [PubMed:24727900 ]