MPAC2_PENBR
ID MPAC2_PENBR Reviewed; 2190 AA.
AC A0A0B5KU17;
DT 10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-2015, sequence version 1.
DT 03-AUG-2022, entry version 34.
DE RecName: Full=Non-reducing polyketide synthase mapC' {ECO:0000303|PubMed:25630520};
DE EC=2.3.1.- {ECO:0000269|PubMed:31209052};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein C' {ECO:0000303|PubMed:25630520};
GN Name=mpaC' {ECO:0000303|PubMed:25630520};
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].
RC STRAIN=NRRL864;
RX PubMed=25630520; DOI=10.1002/cbic.201402600;
RA Zhang W., Cao S., Qiu L., Qi F., Li Z., Yang Y., Huang S., Bai F., Liu C.,
RA Wan X., Li S.;
RT "Functional characterization of MpaG', the O-methyltransferase involved in
RT the biosynthesis of mycophenolic acid.";
RL ChemBioChem 16:565-569(2015).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND PATHWAY.
RX PubMed=31209052; DOI=10.1073/pnas.1821932116;
RA Zhang W., Du L., Qu Z., Zhang X., Li F., Li Z., Qi F., Wang X., Jiang Y.,
RA Men P., Sun J., Cao S., Geng C., Qi F., Wan X., Liu C., Li S.;
RT "Compartmentalized biosynthesis of mycophenolic acid.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:13305-13310(2019).
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:31209052). 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 (PubMed:31209052). The first step of the pathway
CC is 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:31209052) (Probable).
CC {ECO:0000269|PubMed:31209052, ECO:0000305|PubMed:31209052}.
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:31209052};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63057;
CC Evidence={ECO:0000269|PubMed:31209052};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:31209052}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:31209052}.
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:0000305}.
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DR EMBL; KM595305; AJG44381.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A0B5KU17; -.
DR SMR; A0A0B5KU17; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0005829; C:cytosol; IDA: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; 3.40.50.1820; -; 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; 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; 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; 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; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 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..2190
FT /note="Non-reducing polyketide synthase mapC'"
FT /id="PRO_0000451891"
FT DOMAIN 1597..1671
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..268
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 404..820
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 893..1190
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1251..1556
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1840..2187
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 566
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 979
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1969
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2127
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2159
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1631
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2190 AA; 238117 MW; 5267A72EFDBB50D1 CRC64;
MNFHKGQPKE DLRVLFGPQC PDITDSITHI RDAISKDPTG LGFLTNILDE LPSLWPTIAG
AWPALKNVEG ENQLLALGRL FEHESEVRVE ASNLMMTPIT VMRHVVDFWN LQDVATHPAF
PSSSLSETEM PRIVDTQGFC VGLLAAIAVA CSRNTQEFQY VASNAIRLSL CIGALVDLDE
ILCGSTTSLA VRWESVEDFN HLEKILNNNT EIPKGYTSCY TDVKSVTITI PNDSAERVKQ
EIHDHGLRTK QLSLRGRFHH EAHREGIQHI MKLCMNDSRF KLPRSDALLT PLRSSQGGEI
FQQEALLHTV ALDSILCAKA NWYDVVSALI NSTEMTVDQS RLLSIGPEEF VPRSARSRSV
ARRELESYGM QGFANESPQP STASLSNSVQ TFDSRPQAAE ASPIAITGMA CRYPNADTLA
QLWELLELGR CTVKSPPESR FHMSDLQREP KGPFWGHFLE RPDVFDHRFF NISAREAESM
DPQQRVALQV AYEAMESAGY LGWQPNRLSQ DIGCYVGVGS EDYTENVASR NANAFSITGT
LQSFIAGRIS HHFGWSGPSI SLDTACSSAA VAIHLACKAL QTNDCKIALA GGVNVLTNPR
VYQNLSAASF LSPSGACKPF DASADGYCRG EGAGLFVLRP LQDAIDNGDP ILGVIAGSAV
NQGSNNSPIT VPDAEAQRSL YNKAMSLAGV SPDEVTYVEA HGTGTQVGDP IELDSLRRTF
GGPHRRNNLH IGSIKGNIGH TETSSGAAGL LKTILMLQQQ RIPRQANFNQ LNPKVKSLTP
DRLVIASEST EWVSTKRVAM VSNYGASGSN AALIVKEHAP IGSEQNGTAP EYIQNKLAYN
LAMKQNRDLP LNLTFSTSSD TTSLGARLEA ISTGASADLI QKRPSNEPPV VLCFGGQNGL
TATISKEVFD ASALLRTHLE DCEEVGRTLG LLSLFPTIFS SAPITNIIHL HFILFSIQYA
SAKAWLDSGL RVSRIVGHSF GQLTALSVAG SLSVRDGIHL VTERARLIES SWGPESGIML
AVEGTEIEVQ QLLDQTVESI EAIENAAART PSASNLRLTR LQNSHAFHSR LVDSIVPGIM
EVAGSLVYQT PIIPIEACSA SGDWSTITAA EIVEHSRMPV YFRRAVERVA EKLQAPAVWL
EAGSASPIIP MVRRVLESSS VANTYHKIDL GGSSGAQNLA NVTSALWAQG VHVQFWPFDR
AQHASFKWMN LPPYQFAQNS HWVDFDPAAF SSAGPSSGKQ SAGQEAGLLC QLSESPDERL
YHVNIQDALY RACTQGHAVL NQTLCPASMY MEMVLRAAAS IFPTGNASEP AMSHIEDLTI
SSPLVLDPQG KVFLRLTRDG AGPTRPWLFS IFSSESNDHT LVHAEGTVCL HQERSRALAR
FQSMDRLLDS ARSKTIEADP ASNGLKGSTV YAALESVTNY GDYFRGVKQV FANGREASGL
VSMMPSTTET NCNPILLDNF LQVAGIHVNC LSDRQSSEVF VCNAIGETFV INSLLKQENG
ASPSTWKVYT SYVRPSKTEI ACDIYVMDCQ TDTLSAAMMG VRFTSVSIRS LTRALAKLNN
NVLETAEAQS VVEAAIPAEQ SVVTATPSAP AADGHAANDL ATVQEMLCEL FGVSVAEVSP
SVSLVDIGVD SLMSTEVLSE IKKRFQVDMS YTTLVDIPNI QGLVEHIFPG HSHAAPSRPV
VEKAPVQSVA PQAVSHVPTP ASNGPPLVSV ARQCFDTTHA AVSHTSDAHW AGFFHTTYPK
QMSLLTAYIL EAFRALGSSL EASEPNEVLT PIAVLPRHEQ LRKHLYKILD SVGLVRQMST
GELTLRQSGF EWVDWTNNET VESNALRVIV ASPTGNSSAA TMSPSKPIKM ETVVWGERDN
LQLRADIYYP ETVDTTRKQR PIALMIHGGG HVMLSRKDIR PAQTQTLLDA GFLPVSIDYR
LCPEVSLAEG PMADARDALS WVRRVLPNIP LLRADIRPDG NQVVAIGWST GGHLAMTLPF
TAPAAGIPAP DAVLAFYCPT NYEDPFWSNP NFPFGQTVAS NEMEYDVWEG LQSMPIAGYN
PALKERPLGG WMSTRDPRSR IALHMNWTGQ TLPVLLKACT IKGNTEKCSP DDLSRPTEED
IQAVSPNYQI RVGRYNTPTF LIHGTSDDLV PCAQTESTHG ALTASGVEAE LRVVQEAAHL
FDLYPASHAG QEAKAAVAEG YEFLRTHVQL
