MPAC_PENBR
ID MPAC_PENBR Reviewed; 2448 AA.
AC F1DBA9;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=Non-reducing polyketide synthase mapC {ECO:0000303|PubMed:21398490};
DE EC=2.3.1.- {ECO:0000269|PubMed:21398493};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein C {ECO:0000303|PubMed:21398490};
GN Name=mpaC {ECO:0000303|PubMed:21398490};
OS Penicillium brevicompactum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5074;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=IBT 23078;
RX PubMed=21398490; DOI=10.1128/aem.03015-10;
RA Regueira T.B., Kildegaard K.R., Hansen B.G., Mortensen U.H., Hertweck C.,
RA Nielsen J.;
RT "Molecular basis for mycophenolic acid biosynthesis in Penicillium
RT brevicompactum.";
RL Appl. Environ. Microbiol. 77:3035-3043(2011).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-1643 AND SER-1644, AND
RP PATHWAY.
RX PubMed=21398493; DOI=10.1128/aem.01768-10;
RA Hansen B.G., Salomonsen B., Nielsen M.T., Nielsen J.B., Hansen N.B.,
RA Nielsen K.F., Regueira T.B., Nielsen J., Patil K.R., Mortensen U.H.;
RT "Versatile enzyme expression and characterization system for Aspergillus
RT nidulans, with the Penicillium brevicompactum polyketide synthase gene from
RT the mycophenolic acid gene cluster as a test case.";
RL Appl. Environ. Microbiol. 77:3044-3051(2011).
RN [3]
RP FUNCTION.
RC STRAIN=IBT23078;
RX PubMed=22544261; DOI=10.1128/aem.07955-11;
RA Hansen B.G., Mnich E., Nielsen K.F., Nielsen J.B., Nielsen M.T.,
RA Mortensen U.H., Larsen T.O., Patil K.R.;
RT "Involvement of a natural fusion of a cytochrome p450 and a hydrolase in
RT mycophenolic acid biosynthesis.";
RL Appl. Environ. Microbiol. 78:4908-4913(2012).
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:21398490,
CC PubMed:21398493). MpaC catalyzes the synthesis of 5-methylorsellinic
CC acid (5MOA) via the condensation of 1 acetyl-CoA starter unit with 3
CC malonyl-CoA units and one methylation step (PubMed:21398493). The first
CC step of the pathway is the synthesis of 5-methylorsellinic acid (5MOA)
CC by the cytosolic polyketide synthase mpaC. 5MOA is then converted to
CC the phthalide compound 5,7-dihydroxy-4,6-dimethylphthalide (DHMP) by
CC the endoplasmic reticulum-bound cytochrome P450 monooxygenase mpaDE.
CC MpaDE first catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-
CC (hydroxymethyl)-3-methylbenzoic acid (DHMB). MpaDE then acts as a
CC lactone synthase that catalyzes the ring closure to convert DHMB into
CC DHMP. The next step is the prenylation of DHMP by the Golgi apparatus-
CC associated prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The
CC ER-bound oxygenase mpaB then mediates the oxidative cleavage the C19-
CC C20 double 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:21398490, PubMed:22544261) (Probable).
CC {ECO:0000269|PubMed:21398490, ECO:0000269|PubMed:21398493,
CC ECO:0000305|PubMed:21398490, ECO:0000305|PubMed:22544261}.
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:0000269|PubMed:21398493};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63057;
CC Evidence={ECO:0000269|PubMed:21398493};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:21398490}.
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 (By similarity).
CC {ECO:0000250|UniProtKB:Q5B0D0}.
CC -!- DISRUPTION PHENOTYPE: Loses the ability to produce mycophenolic acid
CC (MPA) and several MPA-related compounds, such as MPA diol lactone, 4-O-
CC mycophenolate, and deacetyl pebrolide (PubMed:21398490).
CC {ECO:0000269|PubMed:21398490}.
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DR EMBL; HQ731031; ADY00130.1; -; Genomic_DNA.
DR AlphaFoldDB; F1DBA9; -.
DR SMR; F1DBA9; -.
DR UniPathway; UPA00213; -.
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:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008236; F:serine-type peptidase activity; 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; IDA:GO_Central.
DR GO; GO:0006508; P:proteolysis; IEA:InterPro.
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; IPR001375; Peptidase_S9.
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; PF00326; Peptidase_S9; 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 1: Evidence at protein level;
KW Cytoplasm; Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..2448
FT /note="Non-reducing polyketide synthase mapC"
FT /id="PRO_0000436572"
FT DOMAIN 1610..1684
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..226
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 330..350
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 359..722
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 885..1188
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1261..1564
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1841..2076
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 524
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 972
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2227
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2385
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2417
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1644
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 1643
FT /note="D->A: Impairs the production of 5-methylorsellinic
FT acid (5-MOA)."
FT /evidence="ECO:0000269|PubMed:21398493"
FT MUTAGEN 1644
FT /note="S->A: Impairs the production of 5-methylorsellinic
FT acid (5-MOA)."
FT /evidence="ECO:0000269|PubMed:21398493"
SQ SEQUENCE 2448 AA; 266355 MW; C5FB262B654D0886 CRC64;
MNFHKGQPKE DLRVLFGPQC PDITDSITHI RDAISKDPTG LGFLTNILDE LPSLWPTIAG
AWPALKNVEG ESQLLALGRL FEHESEDRVE ASNLMMTPIT VMRHIVDFWN LQDVATHPAF
PSSSLSETEM PRIVDTQGFC VGLLAAIAVA CSRNTQEFQY VASNAIRLSL CVGALVDLDE
ILCGSTTSLA VSAERVKQEI HDHGLRTKQL SLRGRFHHEA HREGIQHIMK LCTNDSRFKL
PRSDALLTPL RSSQGGEIFQ QEALLHTVAL DSILCAKANW YDVVSALINS TEMTVDQSHL
LSIGPEEFVP RSARSRSVAR RELQSYAMQG FSNESPQPST ASLSNSVQTF DSRPQAAEAS
PIAITGMACR YPNADTLAQL WDLLELGRCT VKSPPESRFH MSDLQREPKG PFWGHFLERP
DVFDHRFFNI SAREAESMDP QQRVALQVAY EAMESAGYLG WQPNGLSRDI GCYVGVGSED
YTENVASRNA NAFSITGTLQ SFIAGRISHH FGWSGPSISL DTACSSAAVA IHLACKALQT
NDCKIALAGG VNVLTNPRVY QNLSAASFLS PSGACKPFDA SADGYCRGEG AGLFVLRPLQ
DAIDNGDPIL GVIAGSAVNQ GSNNSPITVP DAEAQRSLYN KAMSLAGVSP DEVTYVEAHG
TGTQVGDPIE LDSLRRTFGG PQRRNSLHIG SIKGNIGHTE TSSGAAGLLK TILMLQQQRI
PRQANFNQLN PKVKSLTPDR LVIASESTEW ASTERVAMVS NYGASGSNAA LIVKEHAPIR
SEQNGTAPEY IQNVPILVSA RSEESLRAYC GALRATLLSH PPSETLVQKL AYNLAMKQNR
DLPLNLTFST SSDATSLSAR LEAISTGASA DLIQKRPSNE PPVVLCFGGQ NGLTATISKE
VFDASALLRT HLEDCEEVGR TLGLPSLFPT IFSSAPITNI IHLHFILFSI QYASAKAWLD
SGLRVSRIVG HSFGQLTALS VAGSLSVRDG IHLVTERARL IESSWGPESG IMLAVEGTDI
EVQQLLDQTG HIADVACYNG PRQQVLAGTA ESIAAIENAA ARTPSASKLR LTRLQNSHAF
HSRLVDSIVP AIMEVAGSLV YQTPIIPIEA CSASGDWSTI TAAEIVEHSR MPVYFRRAVE
RVAEKLQAPA VWLEAGSASP IIPMVRRVLE SSSVANTYHK IDLGGSSGAQ NLANVTSALW
AQGVHVQFWP FDRAQHGSFK WMNLPPYQFA QNSHWVDFDP AAFSSAGPSS GKQSAGQEAG
LLCQLSESPD ERLYHVNIQD ALYRACTQGH AVLNQTLCPA SMYMEMVLRA AASIFPTGNA
SEPAMSHIED LTISSPLVLD PQGDVFLRLT SDGAGPTRPW LFSIFSSESN DHTSVHAEGT
VCLHQERSRA LARFQSMDRL LDSARSKTIE ADPASNGLKG STVYAALESV TNYGDYFRGV
KKVFANGREA SGLVSMMPSA SETNCDPILL DNFLQVAGIH VNCLSDRRSS EVFVCNAIGE
TFVINSLLKQ KNGASPSTWK VYTSYVRPSK TEIACDIYVM DCQTDTLSAA MMGVRFTSVS
IRSLTRALAK LNNNVLETAE AQSVVEPAIP AEKSVVTATP SAPAADGGGA KDLATVQEML
CELFGVSVAE VSPSVSLVDI GVDSLMSTEV LSEIKKRFQV DMSYTTLVDI PNIQGLVEHI
FPGHSHAAPS QPVVETAPVQ SVAPQAVSHV PTPANNGPPL VSVARQCFDT THAAVSHTSD
AHWTGFFHTT YPKQMTLLTA YILEAFRALG SPLEASEPNE VLIPISVLPR HEQLRKHLYK
ILESVGLVRQ MPTGELVRTT TPIPLSQSHD LHTQIRAEYP PYALEHDLLQ ITAPRLADCL
TGKADGVSLI FQDANTRRLV GDVYAQSPVF KSGNLYLARY LLDVVQSFGS SRTIKILEIG
AGTGGTTKNL LEKLSTIPGL STRLEYTFTD ISPSLVAAGR KTFANYNFMR YETLNVENDP
PSALSGQYDI VLSTNCVHAT RNLRESCTNI RKLLRPDGIL CLVELTRDIF WLDLVFGLLE
GWWRFEDGRE HALATEMMWD QTLRQSGFEW VDWTNNETVE SNALRVIVAS PTGNSSTATM
SPSKLTKMET VVWGERDNLQ LRADIYYPET VDTTRKQRPI ALMIHGGGHV MLSRKDIRPA
QTQTLLDAGF LPVSIDYRLC PEVSLAEGPM ADARDALSWV RRVLPNIPLL RADIRPDGNQ
VVAIGWSTGG HLAMTLPFTA PAAGISAPNA VLAFYCPTNY EDPFWSNPNF PFGQTVASNE
MEYDVWEGLQ SMPIAGYNPA LKERPLGGWM STRDPRSRIA LHMNWTGQTL PVLLKACTIK
GNTEKCSPDD LSRPTEEEIQ AVSPNYQIRV GRYNTPTFLI HGTSDDLVPC AQTESTHGAL
TASGVEAELR VVQEAAHLFD LYPASHAGQE AKAAVAEGYE FLRRHVQL
