LOVA_ASPTN
ID LOVA_ASPTN Reviewed; 528 AA.
AC Q0C8M4;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 62.
DE RecName: Full=Dihydromonacolin L monooxygenase LovA {ECO:0000303|PubMed:10334994};
DE EC=1.14.14.124 {ECO:0000269|PubMed:21495633};
DE EC=1.14.14.125 {ECO:0000269|PubMed:21495633};
DE AltName: Full=Dihydromonacolin L hydroxylase {ECO:0000303|PubMed:10334994};
DE AltName: Full=Lovastatin biosynthesis cluster protein A {ECO:0000303|PubMed:10334994};
DE AltName: Full=Monacolin L hydroxylase {ECO:0000303|PubMed:10334994};
GN Name=lovA {ECO:0000303|PubMed:10334994}; ORFNames=ATEG_09960;
OS Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=341663;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NIH 2624 / FGSC A1156;
RA Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA Nierman W.C., Milne T., Madden K.;
RT "Annotation of the Aspergillus terreus NIH2624 genome.";
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=6933445; DOI=10.1073/pnas.77.7.3957;
RA Alberts A.W., Chen J., Kuron G., Hunt V., Huff J., Hoffman C., Rothrock J.,
RA Lopez M., Joshua H., Harris E., Patchett A., Monaghan R., Currie S.,
RA Stapley E., Albers-Schonberg G., Hensens O., Hirshfield J., Hoogsteen K.,
RA Liesch J., Springer J.;
RT "Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-
RT coenzyme A reductase and a cholesterol-lowering agent.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:3957-3961(1980).
RN [3]
RP FUNCTION.
RX PubMed=10381407; DOI=10.1016/s1074-5521(99)80061-1;
RA Hendrickson L., Davis C.R., Roach C., Nguyen D.K., Aldrich T., McAda P.C.,
RA Reeves C.D.;
RT "Lovastatin biosynthesis in Aspergillus terreus: characterization of
RT blocked mutants, enzyme activities and a multifunctional polyketide
RT synthase gene.";
RL Chem. Biol. 6:429-439(1999).
RN [4]
RP IDENTIFICATION, AND PATHWAY.
RX PubMed=10334994; DOI=10.1126/science.284.5418.1368;
RA Kennedy J., Auclair K., Kendrew S.G., Park C., Vederas J.C.,
RA Hutchinson C.R.;
RT "Modulation of polyketide synthase activity by accessory proteins during
RT lovastatin biosynthesis.";
RL Science 284:1368-1372(1999).
RN [5]
RP FUNCTION, PATHWAY, AND DISRUPTION PHENOTYPE.
RX PubMed=12929390; DOI=10.1039/b207721c;
RA Sorensen J.L., Auclair K., Kennedy J., Hutchinson C.R., Vederas J.C.;
RT "Transformations of cyclic nonaketides by Aspergillus terreus mutants
RT blocked for lovastatin biosynthesis at the lovA and lovC genes.";
RL Org. Biomol. Chem. 1:50-59(2003).
RN [6]
RP FUNCTION.
RX PubMed=17113998; DOI=10.1016/j.chembiol.2006.09.008;
RA Xie X., Watanabe K., Wojcicki W.A., Wang C.C., Tang Y.;
RT "Biosynthesis of lovastatin analogs with a broadly specific
RT acyltransferase.";
RL Chem. Biol. 13:1161-1169(2006).
RN [7]
RP FUNCTION.
RX PubMed=18988191; DOI=10.1002/bit.22028;
RA Xie X., Pashkov I., Gao X., Guerrero J.L., Yeates T.O., Tang Y.;
RT "Rational improvement of simvastatin synthase solubility in Escherichia
RT coli leads to higher whole-cell biocatalytic activity.";
RL Biotechnol. Bioeng. 102:20-28(2009).
RN [8]
RP FUNCTION.
RX PubMed=19875080; DOI=10.1016/j.chembiol.2009.09.017;
RA Gao X., Xie X., Pashkov I., Sawaya M.R., Laidman J., Zhang W., Cacho R.,
RA Yeates T.O., Tang Y.;
RT "Directed evolution and structural characterization of a simvastatin
RT synthase.";
RL Chem. Biol. 16:1064-1074(2009).
RN [9]
RP FUNCTION.
RX PubMed=19530726; DOI=10.1021/ja903203g;
RA Xie X., Meehan M.J., Xu W., Dorrestein P.C., Tang Y.;
RT "Acyltransferase mediated polyketide release from a fungal megasynthase.";
RL J. Am. Chem. Soc. 131:8388-8389(2009).
RN [10]
RP FUNCTION.
RX PubMed=19900898; DOI=10.1126/science.1175602;
RA Ma S.M., Li J.W., Choi J.W., Zhou H., Lee K.K., Moorthie V.A., Xie X.,
RA Kealey J.T., Da Silva N.A., Vederas J.C., Tang Y.;
RT "Complete reconstitution of a highly reducing iterative polyketide
RT synthase.";
RL Science 326:589-592(2009).
RN [11]
RP FUNCTION.
RX PubMed=21069965; DOI=10.1021/bi1014776;
RA Meehan M.J., Xie X., Zhao X., Xu W., Tang Y., Dorrestein P.C.;
RT "FT-ICR-MS characterization of intermediates in the biosynthesis of the
RT alpha-methylbutyrate side chain of lovastatin by the 277 kDa polyketide
RT synthase LovF.";
RL Biochemistry 50:287-299(2011).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=21495633; DOI=10.1021/ja201138v;
RA Barriuso J., Nguyen D.T., Li J.W., Roberts J.N., MacNevin G., Chaytor J.L.,
RA Marcus S.L., Vederas J.C., Ro D.K.;
RT "Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin
RT J by a single cytochrome P450 monooxygenase, LovA.";
RL J. Am. Chem. Soc. 133:8078-8081(2011).
RN [13]
RP FUNCTION.
RX PubMed=22733743; DOI=10.1073/pnas.1113029109;
RA Ames B.D., Nguyen C., Bruegger J., Smith P., Xu W., Ma S., Wong E.,
RA Wong S., Xie X., Li J.W., Vederas J.C., Tang Y., Tsai S.C.;
RT "Crystal structure and biochemical studies of the trans-acting polyketide
RT enoyl reductase LovC from lovastatin biosynthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11144-11149(2012).
RN [14]
RP FUNCTION.
RX PubMed=23653178; DOI=10.1002/anie.201302406;
RA Xu W., Chooi Y.H., Choi J.W., Li S., Vederas J.C., Da Silva N.A., Tang Y.;
RT "LovG: the thioesterase required for dihydromonacolin L release and
RT lovastatin nonaketide synthase turnover in lovastatin biosynthesis.";
RL Angew. Chem. Int. Ed. Engl. 52:6472-6475(2013).
RN [15]
RP FUNCTION.
RX PubMed=24727900; DOI=10.1038/nchembio.1503;
RA Jimenez-Oses G., Osuna S., Gao X., Sawaya M.R., Gilson L., Collier S.J.,
RA Huisman G.W., Yeates T.O., Tang Y., Houk K.N.;
RT "The role of distant mutations and allosteric regulation on LovD active
RT site dynamics.";
RL Nat. Chem. Biol. 10:431-436(2014).
RN [16]
RP BIOTECHNOLOGY.
RX PubMed=29236027; DOI=10.3390/ijms18122690;
RA Chen M.C., Tsai Y.C., Tseng J.H., Liou J.J., Horng S., Wen H.C., Fan Y.C.,
RA Zhong W.B., Hsu S.P.;
RT "Simvastatin inhibits cell proliferation and migration in human anaplastic
RT thyroid cancer.";
RL Int. J. Mol. Sci. 18:0-0(2017).
RN [17]
RP BIOTECHNOLOGY.
RX PubMed=29932104; DOI=10.3390/ijms19071834;
RA Zhong W.B., Tsai Y.C., Chin L.H., Tseng J.H., Tang L.W., Horng S.,
RA Fan Y.C., Hsu S.P.;
RT "A synergistic anti-cancer effect of troglitazone and lovastatin in a human
RT anaplastic thyroid cancer cell line and in a mouse xenograft model.";
RL Int. J. Mol. Sci. 19:0-0(2018).
CC -!- FUNCTION: Dihydromonacolin L monooxygenase; part of the gene cluster
CC that mediates the biosynthesis of lovastatin (also known as mevinolin,
CC mevacor or monacolin K), a hypolipidemic inhibitor of (3S)-
CC hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)
CC (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in
CC the biosynthesis of lovastatin is the production of dihydromonacolin L
CC acid by the lovastatin nonaketide synthase lovB and the trans-acting
CC enoyl reductase lovC via condensation of one acetyl-CoA unit and 8
CC malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898,
CC PubMed:22733743). Dihydromonacolin L acid is released from lovB by the
CC thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is
CC oxidized by the dihydromonacolin L monooxygenase lovA twice to form
CC monacolin J acid (PubMed:12929390, PubMed:21495633). The 2-
CC methylbutyrate moiety of lovastatin is synthesized by the lovastatin
CC diketide synthase lovF via condensation of one acetyl-CoA unit and one
CC malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the
CC covalent attachment of this moiety to monacolin J acid is catalyzed by
CC the transesterase lovD to yield lovastatin (PubMed:10334994,
CC PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900).
CC LovD has broad substrate specificity and can also convert monacolin J
CC to simvastatin using alpha-dimethylbutanoyl-S-methyl-3-
CC mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can
CC also catalyze the reverse reaction and function as hydrolase in vitro
CC (PubMed:19875080). LovD has much higher activity with LovF-bound 2-
CC methylbutanoate than with free diketide substrates (PubMed:21069965).
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407,
CC ECO:0000269|PubMed:12929390, ECO:0000269|PubMed:17113998,
CC ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19530726,
CC ECO:0000269|PubMed:19875080, ECO:0000269|PubMed:19900898,
CC ECO:0000269|PubMed:21069965, ECO:0000269|PubMed:21495633,
CC ECO:0000269|PubMed:22733743, ECO:0000269|PubMed:23653178,
CC ECO:0000269|PubMed:24727900}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dihydromonacolin L carboxylate + O2 + reduced [NADPH--
CC hemoprotein reductase] = H(+) + 2 H2O + monacolin L carboxylate +
CC oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:42368,
CC Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:79031, ChEBI:CHEBI:79044;
CC EC=1.14.14.124; Evidence={ECO:0000269|PubMed:21495633};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=monacolin L carboxylate + O2 + reduced [NADPH--hemoprotein
CC reductase] = H(+) + H2O + monacolin J carboxylate + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:29599, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:79035, ChEBI:CHEBI:79044; EC=1.14.14.125;
CC Evidence={ECO:0000269|PubMed:21495633};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC Note=Binds 1 heme group per subunit. {ECO:0000250|UniProtKB:P04798};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=6.2 uM for monacolin L acid {ECO:0000269|PubMed:21495633};
CC -!- PATHWAY: Polyketide biosynthesis; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:12929390}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305|PubMed:21495633}; Single-
CC pass membrane protein {ECO:0000305|PubMed:21495633}. Endoplasmic
CC reticulum membrane {ECO:0000305|PubMed:21495633}; Single-pass type II
CC membrane protein {ECO:0000305|PubMed:21495633}.
CC -!- DISRUPTION PHENOTYPE: Loss of lovastatin biosynthesis. Accelerates
CC degradation of lovastatin precursors. {ECO:0000269|PubMed:12929390}.
CC -!- BIOTECHNOLOGY: Lovastatin acts as a hypolipidemic agent that works as
CC inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
CC (HMGR) which reduces HMG-CoA to mevalonate and is the key step in
CC cholesterol biosynthesis (PubMed:6933445). Lovastatin, simvastatin and
CC related compounds are widely used to treat hypercholesteremia and
CC reduce the risk of cardiovascular disease (PubMed:6933445).
CC Furthermore, statins such as lovastatin were found to be anticancer
CC agents (PubMed:29236027, PubMed:29932104).
CC {ECO:0000269|PubMed:29236027, ECO:0000269|PubMed:29932104,
CC ECO:0000269|PubMed:6933445}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; CH476609; EAU29409.1; -; Genomic_DNA.
DR RefSeq; XP_001209262.1; XM_001209262.1.
DR AlphaFoldDB; Q0C8M4; -.
DR SMR; Q0C8M4; -.
DR STRING; 33178.CADATEAP00000506; -.
DR EnsemblFungi; EAU29409; EAU29409; ATEG_09960.
DR GeneID; 4319545; -.
DR VEuPathDB; FungiDB:ATEG_09960; -.
DR eggNOG; KOG0157; Eukaryota.
DR HOGENOM; CLU_022195_0_3_1; -.
DR OMA; VICEQAT; -.
DR OrthoDB; 572303at2759; -.
DR UniPathway; UPA00875; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Heme; Iron; Membrane; Metal-binding;
KW Monooxygenase; Oxidoreductase; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..528
FT /note="Dihydromonacolin L monooxygenase LovA"
FT /id="PRO_0000430274"
FT TOPO_DOM 1..23
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 24..44
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 45..528
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT BINDING 465
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 399
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 528 AA; 60579 MW; B89A58A01837881A CRC64;
MTVDALTQPH HLLSLAWNDT QQHGSWFAPL VTTSAGLLCL LLYLCSSGRR SELPVFNPKT
WWELTTMRAK RDFDANAPSW IESWFSQNDK PIRFIVDSGY CTILPSSMAD EFRKMKELCM
YKFLGTDFHS HLPGFDGFKE VTRDAHLITK VVMNQFQTQA PKYVKPLANE ASGIITDIFG
DSNEWHTVPV YNQCLDLVTR TVTFIMVGSK LAHNEEWLDI AKHHAVTMAI QARQLRLWPV
ILRPLVHWLE PQGAKLRAQV RRARQLLDPI IQERRAERDS CLAKGIEPPR YVDSIQWFED
TAKGKWYDAA GAQLAMDFAG IYGTSDLLIG GLVDIVRHPH LLEPLRDEIR TVIGQGGWTP
ASLYKLKLLD SCLKESQRVK PVECATMRSY ALQDVTFSNG TFIPKGELVA VAADRMSNPE
VWPEPAKYDP YRYMRLREDP AKAFSAQLEN TNGDHIGFGW HPRACPGRFF ASKEIKMMLA
YLLIRYDWKV VPNEPLQYYR HSFSVRIHPT TKLMMRRRDE DIRLPGSL
