LOVG_ASPTN
ID LOVG_ASPTN Reviewed; 256 AA.
AC Q0C8M2;
DT 03-SEP-2014, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Dihydromonacolin L-[lovastatin nonaketide synthase] thioesterase {ECO:0000305};
DE EC=3.1.2.31 {ECO:0000269|PubMed:23653178};
DE AltName: Full=Esterase lovG {ECO:0000303|PubMed:23653178};
DE AltName: Full=Lovastatin biosynthesis cluster protein G {ECO:0000303|PubMed:23653178};
GN Name=lovG {ECO:0000303|PubMed:23653178}; ORFNames=ATEG_09962;
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 FUNCTION.
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, AND BIOTECHNOLOGY.
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, AND BIOTECHNOLOGY.
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 IDENTIFICATION, FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND DISRUPTION
RP PHENOTYPE.
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: Esterase; part of the gene cluster that mediates the
CC biosynthesis of lovastatin (also known as mevinolin, mevacor or
CC monacolin K), a hypolipidemic inhibitor of (3S)-hydroxymethylglutaryl-
CC coenzyme A (HMG-CoA) reductase (HMGR) (PubMed:10334994,
CC PubMed:12929390, PubMed:21495633). The first step in the biosynthesis
CC of lovastatin is the production of dihydromonacolin L acid by the
CC lovastatin nonaketide synthase lovB and the trans-acting enoyl
CC reductase lovC via condensation of one acetyl-CoA unit and 8 malonyl-
CC 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 -!- FUNCTION: Esterase that catalyzes the release of covalently bound
CC dihydromonacolin L from LovB during lovastatin biosynthesis.
CC {ECO:0000269|PubMed:23653178}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dihydromonacolin L-[lovastatin nonaketide synthase] + H2O =
CC dihydromonacolin L carboxylate + H(+) + holo-[lovastatin nonaketide
CC synthase]; Xref=Rhea:RHEA:11592, Rhea:RHEA-COMP:10042, Rhea:RHEA-
CC COMP:10043, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:79031, ChEBI:CHEBI:79032; EC=3.1.2.31;
CC Evidence={ECO:0000269|PubMed:23653178};
CC -!- PATHWAY: Polyketide biosynthesis; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:23653178}.
CC -!- DISRUPTION PHENOTYPE: Strongly reduced lovastatin biosynthesis. Low
CC levels of lovastatin are released due to complementation by other
CC esterases. {ECO:0000269|PubMed:23653178}.
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 LovG family. {ECO:0000305}.
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DR EMBL; CH476609; EAU29411.1; -; Genomic_DNA.
DR RefSeq; XP_001209264.1; XM_001209264.1.
DR AlphaFoldDB; Q0C8M2; -.
DR SMR; Q0C8M2; -.
DR ESTHER; asptn-LOVG; FSH1.
DR EnsemblFungi; EAU29411; EAU29411; ATEG_09962.
DR GeneID; 4319608; -.
DR KEGG; ag:EAU29411; -.
DR VEuPathDB; FungiDB:ATEG_09962; -.
DR eggNOG; KOG2551; Eukaryota.
DR HOGENOM; CLU_051938_0_2_1; -.
DR OMA; SGNIFRM; -.
DR OrthoDB; 1190789at2759; -.
DR BioCyc; MetaCyc:MON-18783; -.
DR UniPathway; UPA00875; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016788; F:hydrolase activity, acting on ester bonds; IDA:UniProtKB.
DR GO; GO:0030639; P:polyketide biosynthetic process; IMP:UniProtKB.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR005645; FSH_dom.
DR Pfam; PF03959; FSH1; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Hydrolase; Reference proteome.
FT CHAIN 1..256
FT /note="Dihydromonacolin L-[lovastatin nonaketide synthase]
FT thioesterase"
FT /id="PRO_0000430266"
FT ACT_SITE 122
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
FT ACT_SITE 201
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
FT ACT_SITE 229
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P38777"
SQ SEQUENCE 256 AA; 28932 MW; C84064BFEE774F21 CRC64;
MRYQASPALA KAPRALLCIH GAGCSPAIFR VQLSKLRAAL REDFEFVYVT APFPSSAGPG
ILPVFADLGP YYSWFESSSG NNNNGPSVGE RLAAVHDPIR RTIVDWQTQH PHIPIVGAIG
FSEGALVTTL LLWQQQMGRL PWLPRMSVAM LICPWYQDEA SQYMRNEVME NHDDDHDSKD
TEWQEELVIR IPTLHLQGRD DFALAGSKML VARHFSPREA QVLEFAGQHQ FPNRPRDVLE
VINRFRKLCV TVQTLE
