MPAC_PENRF
ID MPAC_PENRF Reviewed; 2477 AA.
AC W6QL47;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 44.
DE RecName: Full=Non-reducing polyketide synthase mapC {ECO:0000303|PubMed:26751579};
DE EC=2.3.1.- {ECO:0000250|UniProtKB:A0A0B5KU17};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein C {ECO:0000303|PubMed:26751579};
GN Name=mpaC {ECO:0000303|PubMed:26751579}; ORFNames=PROQFM164_S05g000559;
OS Penicillium roqueforti (strain FM164).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=1365484;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FM164;
RX PubMed=24407037; DOI=10.1038/ncomms3876;
RA Cheeseman K., Ropars J., Renault P., Dupont J., Gouzy J., Branca A.,
RA Abraham A.L., Ceppi M., Conseiller E., Debuchy R., Malagnac F., Goarin A.,
RA Silar P., Lacoste S., Sallet E., Bensimon A., Giraud T., Brygoo Y.;
RT "Multiple recent horizontal transfers of a large genomic region in cheese
RT making fungi.";
RL Nat. Commun. 5:2876-2876(2014).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=26751579; DOI=10.1371/journal.pone.0147047;
RA Del-Cid A., Gil-Duran C., Vaca I., Rojas-Aedo J.F., Garcia-Rico R.O.,
RA Levican G., Chavez R.;
RT "Identification and functional analysis of the mycophenolic acid gene
RT cluster of Penicillium roqueforti.";
RL PLoS ONE 11:E0147047-E0147047(2016).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of mycophenolic acid (MPA), the first
CC isolated antibiotic natural product in the world obtained from a
CC culture of Penicillium brevicompactum in 1893 (PubMed:26751579). MpaC
CC catalyzes the synthesis of 5-methylorsellinic acid (5MOA) via the
CC condensation of 1 acetyl-CoA starter unit with 3 malonyl-CoA units and
CC one methylation step (By similarity). The first step of the pathway is
CC the synthesis of 5-methylorsellinic acid (5MOA) by the cytosolic
CC polyketide synthase mpaC. 5MOA is then converted to the phthalide
CC compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) by the endoplasmic
CC reticulum-bound cytochrome P450 monooxygenase mpaDE. MpaDE first
CC catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-
CC methylbenzoic acid (DHMB). MpaDE then acts as a lactone synthase that
CC catalyzes the ring closure to convert DHMB into DHMP. The next step is
CC the prenylation of DHMP by the Golgi apparatus-associated
CC prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The ER-bound
CC oxygenase mpaB then mediates the oxidative cleavage the C19-C20 double
CC bond in FDHMP to yield FDHMP-3C via a mycophenolic aldehyde
CC intermediate. The O-methyltransferase mpaG catalyzes the methylation of
CC FDHMP-3C to yield MFDHMP-3C. After the cytosolic methylation of FDHMP-
CC 3C, MFDHMP-3C enters into peroxisomes probably via free diffusion due
CC to its low molecular weight. Upon a peroxisomal CoA ligation reaction,
CC catalyzed by a beta-oxidation component enzyme acyl-CoA ligase ACL891,
CC MFDHMP-3C-CoA would then be restricted to peroxisomes for the following
CC beta-oxidation pathway steps. The peroxisomal beta-oxidation machinery
CC than converts MFDHMP-3C-CoA into MPA_CoA, via a beta-oxidation chain-
CC shortening process. Finally mpaH acts as a peroxisomal acyl-CoA
CC hydrolase with high substrate specificity toward MPA-CoA to release the
CC final product MPA (PubMed:26751579) (Probable).
CC {ECO:0000250|UniProtKB:A0A0B5KU17, ECO:0000269|PubMed:26751579,
CC ECO:0000305|PubMed:26751579}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + H(+) + 3 malonyl-CoA + S-adenosyl-L-methionine =
CC 5-methylorsellinate + 3 CO2 + 4 CoA + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:63056, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:146172;
CC Evidence={ECO:0000250|UniProtKB:A0A0B5KU17};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63057;
CC Evidence={ECO:0000250|UniProtKB:A0A0B5KU17};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:26751579}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:A0A0B5KU17}.
CC -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm. {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DISRUPTION PHENOTYPE: Results in dramatic reduction in MPA production.
CC {ECO:0000269|PubMed:26751579}.
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DR EMBL; HG792019; CDM36726.1; -; Genomic_DNA.
DR AlphaFoldDB; W6QL47; -.
DR SMR; W6QL47; -.
DR EnsemblFungi; CDM36726; CDM36726; PROQFM164_S05g000559.
DR OrthoDB; 93381at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000030686; Unassembled WGS sequence.
DR GO; GO:0005829; C:cytosol; ISS:GO_Central.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016787; F:hydrolase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0140722; P:mycophenolic acid biosynthetic process; IMP:GO_Central.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR013094; AB_hydrolase_3.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR041068; HTH_51.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF07859; Abhydrolase_3; 1.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF18558; HTH_51; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 3: Inferred from homology;
KW Cytoplasm; Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..2477
FT /note="Non-reducing polyketide synthase mapC"
FT /id="PRO_0000449215"
FT DOMAIN 1651..1725
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..269
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 403..766
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 930..1233
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1307..1611
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1882..2117
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 568
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1017
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2267
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2421
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1685
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2477 AA; 270657 MW; 343AEB311C95F943 CRC64;
MSLNTEHSKG DLRLLFGPQC SEIEDSIAHI RDAVYKDSAG LGFLSDILDE LPSLWPVITS
AWPALRKVQG EKQLAALGRR FENGSPDSEA EPSSLIMTPV TVMKHLVDFW NLQNVATHPA
FPSSPLSRTT APRIIDSQGF CVGILAAIAV ACSQDTREFQ SLASNAIRLA VCIGALVDFD
EIVSGKAKSI AVRWETPADH DYLEQTLTKS PNVYISCYTD VNSVTITIPG DTAQRVKFKQ
ELSGRGLHTK PIPLQGRFHH QQTHREGIQH IMNLCVKDPR FQLPHSNALI LPLRSSHNGQ
VLINAAMLHT VALESILSVK ADWWGTVSAL LNSADMEVDE SRLLSIGQEE FVPRSARGRL
VARSNLDVYG AGVFANGNTS ARSAVSLQNG TNTLNGSPQA AEMPPIAITG MACRYSNADT
TSELWDLLEL GVCTVEKAPG NRFRMPDLQR EPKGPFWGHF LDRPDAFDHR FFNISAREAE
SMDPQQRVLL QVAYEAMESA GYCGWQHTEL SDEIGCYVGV GSEDYTENVA SRNANAFSAT
GTLQSFIAGR ISHHFGWSGP SITLDTACSS AAVAIHMACK ALQTKECSIA VAGGVNILTN
PRVYQNLAAA SFLSSTGACK SFDVSADGYC RGEGAGLVVL RPLQDAIDNG DPILGVIAGS
VVNQGSNRSP ITVPDAESQR SLYRKALSLA GVAPDEVTYV EAHGTGTQVG DPIELESLRK
AFGNPLRSQS LHVGSIKGNI GHTETSSGVA GLLKTILMLQ KQRIPKQANF RQLNPKVMPP
LENDRLVIPV ESTKWASARR VAMVSNYGAS GSNAALIVRD HTPSLSGQGK AMAEYIRDMP
ILISARSEES IRAYCGALRT TLLRHPYSNT VVRELAYNVA MKQNRTLPFT LTFSTSSDPT
SLSTRLEAIA AGKSADIIQK RESNEPPIVL CFGGQNGVTS SISQELYDSC VLLQTHLMAC
EQAGQKLGLP SLFPTIFTSD PIVNTVYLHF MLFSIQYASA RAWIDSGLRV DRIVGHSFGQ
LTALSVAGSL SVQEGIRLVT ERARLIQSNW GPESGVMLAV EGTQAEVQRV LEQTGHRAEI
ACYNGPQQQV LAGTGECIRA VEDALATNPL TSNVRVRRLE NSHAFHSRLV DSIVPGLTEL
AESFVYQAPA IPIEACSATG DWSIVTPAKI VEHSRMPVHF QRAVERIAQK LQVPAVWLEA
GSASPIIPMV RRVLEKSSAT HTYHRVNLDG SDGSGNLATV TSALWGQGVH VQFWPFHHSQ
RGTFGWMNLP PYQFAKNRHW VDFDPTAFSF SGSSAEPQCG SQERAGLLRK LSDGPEEYLF
AVNTQDVLYR SCTKGHAVLD QTLCPASMYM EMVLRAATSV FTLGESSTLT MSHIEDLVIS
SPLVLDPQGS VFVRLIPEAV ASSQTWSFSI FSSSGTGNES SIHATGSVSL CNERSRALSH
FQSMNRLMDP ARARGIEDHL ASNGLKGSTV YSALEQVTNY ADYFRGVRQV FANGREAAGL
VSMAPSATET TCNPILLDNF LQVAGIHVNC LSGREAEEVF VCNAIGETYV SDSLFKKEDG
AIPLSWKVYT NYVRPSKNEI VCDIYVMNSQ GDGLTAAIMG VRFMSVSIRS LTRALAKLNN
NFPDVPQLPP TIQPAIVTAD YDEASDNVNV DSDLVAVQEM LCELFGVSVE EVSPSVSLID
IGVDSLISTE VLSEIKRRFH KDISYSTLVD IPNIQGLTEH IFPGHSHLAP SQIVIKPVRQ
QTVIPQTVTS LPVPANAGPS LVSVAHQCFY ETHAAVSHTH NADWAGFFNA IYPQQMTLIT
AYILEAFRAL GSPLESSQAD EVLPIISVLP RHEQLKKHLY TILESVNLVR QTPTGQLVRT
ATPISPLSSH ALHAQIRDEH PPYALEHDLL QITGSRLAEC LTGQADGVSL IFQDSQTRRL
VGDVYTDSPV FKSGNLYLAQ YLTDVIQTLG NGRQVKILEI GAGTGGTTKN LLEQLSALPG
MATRMEYTFT DISPSLVAAA RKKFSKYDFV RYETINVESS PPSLLHGQYD IVLSTNCVHA
TRNLVESCSN IRKLLRPDGI LCLVELTRDI FWLDLVFGLL EGWWRFEDGR KHALATEDLW
DQTLRQSGFE WVGWTNNEAV ESNALRVIVA SPTKAPSALE ICSKPANMET VVWGERNGLQ
LLADIFYPDV VDTTQKRRAC ALMVHGGGHV MLSRKDIRPA QTQTLLDAGF LPISVDYRLC
PEVSLSEGPM ADVRDALGWV RRILPNIPLL RPDIRPDGNQ VVAIGWSTGG HLAMTLAFTA
PAVGIAAPEA ILAFYCPTDY EDPFWSRPNF PFGQTVASND IEYDVWEGVQ SAPIKGYNPA
FKERPLGGWM STSDPRSRIA LHMNWTGQTL PVLLGGMHKE FRIPDELPRP TDEEIQAVSP
NYQIRIGRYR TPTFMVHGTS DDLVPCAQTE STYNALTQNG IEADIRVVQG AIEVLLYLQH
PERARKWICS GSLTLEI
