LOVG_ASPTE
ID LOVG_ASPTE Reviewed; 256 AA.
AC Q9Y7C9;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 25-MAY-2022, entry version 44.
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};
OS Aspergillus terreus.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=33178;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, AND PATHWAY.
RC STRAIN=ATCC 20542 / MF4845;
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 [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, 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 [5]
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 [6]
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 [7]
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 [8]
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 [9]
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 [10]
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 [11]
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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
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; AH007774; AAD34553.1; -; Genomic_DNA.
DR AlphaFoldDB; Q9Y7C9; -.
DR SMR; Q9Y7C9; -.
DR ESTHER; aspte-Q9Y7C9; FSH1.
DR VEuPathDB; FungiDB:ATEG_09962; -.
DR UniPathway; UPA00875; -.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
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.
FT CHAIN 1..256
FT /note="Dihydromonacolin L-[lovastatin nonaketide synthase]
FT thioesterase"
FT /id="PRO_0000449663"
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; 28981 MW; 26DB8A98F81D50C6 CRC64;
MRYQASPALV KAPRALLCIH GAGCSPAIFR VQLSKLRAAL RENFEFVYVT APFPSSAGPG
ILPVFADLGP YYSWFESSSD NNHNGPSVSE RLAAVHDPIR RTIVDWQTQH PHIPIVGAIG
FSEGALVTTL LLWQQQMGHL PWLPRMSVAL LICPWYQDEA SQYMRNEVMK NHDDDNDSKD
TEWQEELVIR IPTLHLQGRD DFALAGSKML VARHFSPREA QVLEFAGQHQ FPNRPRDVLE
VINRFRKLCV TAQTLE
