LOVC_ASPTE
ID LOVC_ASPTE Reviewed; 363 AA.
AC Q9Y7D0;
DT 03-SEP-2014, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 85.
DE RecName: Full=Lovastatin nonaketide synthase, enoyl reductase component lovC {ECO:0000303|PubMed:10334994};
DE EC=2.3.1.161 {ECO:0000269|PubMed:10334994};
DE AltName: Full=Lovastatin biosynthesis cluster protein C {ECO:0000303|PubMed:10334994};
DE AltName: Full=Trans-enoyl reductase lovC {ECO:0000303|PubMed:10334994};
GN Name=lovC {ECO:0000303|PubMed:10334994};
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], PATHWAY, DISRUPTION PHENOTYPE, FUNCTION,
RP AND CATALYTIC ACTIVITY.
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.
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 PATHWAY.
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.
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 [13]
RP FUNCTION.
RC STRAIN=ATCC 20542 / MF4845;
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 [14]
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 [15]
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).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.74 ANGSTROMS) IN COMPLEX WITH NADP, FUNCTION,
RP INTERACTION WITH LOVB, SUBUNIT, AND MUTAGENESIS OF LYS-54; SER-138; THR-139
RP AND ASN-263.
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).
CC -!- FUNCTION: Trans-enoyl reductase; part of the gene cluster that mediates
CC the 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 -!- CATALYTIC ACTIVITY:
CC Reaction=19 H(+) + holo-[lovastatin nonaketide synthase] + 9 malonyl-
CC CoA + 11 NADPH + S-adenosyl-L-methionine = 9 CO2 + 9 CoA +
CC dihydromonacolin L-[lovastatin nonaketide synthase] + 6 H2O + 11
CC NADP(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:18565, Rhea:RHEA-
CC COMP:10042, Rhea:RHEA-COMP:10043, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:59789, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:79032; EC=2.3.1.161;
CC Evidence={ECO:0000269|PubMed:10334994};
CC -!- PATHWAY: Polyketide biosynthesis; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:19900898}.
CC -!- SUBUNIT: Monomer. Interacts with LovB. {ECO:0000269|PubMed:22733743}.
CC -!- DISRUPTION PHENOTYPE: Loss of lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994}.
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 zinc-containing alcohol dehydrogenase
CC family. {ECO:0000305}.
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DR EMBL; AF141925; AAD34554.1; -; Genomic_DNA.
DR PDB; 3B6Z; X-ray; 1.88 A; A=1-363.
DR PDB; 3B70; X-ray; 1.89 A; A=1-363.
DR PDB; 3GQV; X-ray; 1.74 A; A=1-363.
DR PDB; 7CPY; EM; 3.60 A; C/D=1-363.
DR PDBsum; 3B6Z; -.
DR PDBsum; 3B70; -.
DR PDBsum; 3GQV; -.
DR PDBsum; 7CPY; -.
DR AlphaFoldDB; Q9Y7D0; -.
DR SMR; Q9Y7D0; -.
DR DIP; DIP-60050N; -.
DR IntAct; Q9Y7D0; 1.
DR KEGG; ag:AAD34554; -.
DR VEuPathDB; FungiDB:ATEG_09963; -.
DR BioCyc; MetaCyc:MON-18781; -.
DR UniPathway; UPA00875; -.
DR EvolutionaryTrace; Q9Y7D0; -.
DR GO; GO:0050637; F:lovastatin nonaketide synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0030639; P:polyketide biosynthetic process; IDA:UniProtKB.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020843; PKS_ER.
DR Pfam; PF08240; ADH_N; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW 3D-structure; NADP; Nucleotide-binding; Oxidoreductase; Transferase.
FT CHAIN 1..363
FT /note="Lovastatin nonaketide synthase, enoyl reductase
FT component lovC"
FT /id="PRO_0000430267"
FT BINDING 51..54
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 135..142
FT /ligand="substrate"
FT /evidence="ECO:0000255"
FT BINDING 174..177
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 197..200
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 215
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 262..263
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 280
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT BINDING 282..286
FT /ligand="substrate"
FT /evidence="ECO:0000255"
FT BINDING 351..352
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:22733743"
FT MUTAGEN 54
FT /note="K->S: Reduces catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:22733743"
FT MUTAGEN 138
FT /note="S->M: Reduces catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:22733743"
FT MUTAGEN 139
FT /note="T->V: Reduces catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:22733743"
FT MUTAGEN 263
FT /note="N->S: Reduces catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:22733743"
FT STRAND 12..17
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 23..29
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 38..47
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 50..53
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 57..59
FT /evidence="ECO:0007829|PDB:3B6Z"
FT STRAND 68..77
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 89..93
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 127..131
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 134..147
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 167..172
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 176..187
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 191..196
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 198..200
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 201..206
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 210..214
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 220..227
FT /evidence="ECO:0007829|PDB:3GQV"
FT TURN 228..230
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 234..239
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 242..251
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 257..263
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 275..279
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 282..286
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 289..291
FT /evidence="ECO:0007829|PDB:3B70"
FT TURN 294..296
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 302..320
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 329..334
FT /evidence="ECO:0007829|PDB:3GQV"
FT HELIX 336..347
FT /evidence="ECO:0007829|PDB:3GQV"
FT STRAND 355..360
FT /evidence="ECO:0007829|PDB:3GQV"
SQ SEQUENCE 363 AA; 39511 MW; FDB9524DDB255713 CRC64;
MGDQPFIPPP QQTALTVNDH DEVTVWNAAP CPMLPRDQVY VRVEAVAINP SDTKMRGQFA
TPWAFLGTDY AGTVVAVGSD VTHIQVGDRV YGAQNEMCPR TPDQGAFSQY TVTRGRVWAK
IPKGLSFEQA AALPAGISTA GLAMKLLGLP LPSPSADQPP THSKPVYVLV YGGSTATATV
TMQMLRLSGY IPIATCSPHN FDLAKSRGAE EVFDYRAPNL AQTIRTYTKN NLRYALDCIT
NVESTTFCFA AIGRAGGHYV SLNPFPEHAA TRKMVTTDWT LGPTIFGEGS TWPAPYGRPG
SEEERQFGED LWRIAGQLVE DGRLVHHPLR VVQGGFDHIK QGMELVRKGE LSGEKLVVRL
EGP
