MACA_PENTR
ID MACA_PENTR Reviewed; 1783 AA.
AC A0A2P1DP91;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 23-MAY-2018, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=6-methylsalicylic acid synthase {ECO:0000303|PubMed:28926261};
DE Short=6MSAS {ECO:0000303|PubMed:28926261};
DE EC=2.3.1.165 {ECO:0000269|PubMed:28926261};
DE AltName: Full=Macrophorins biosynthesis cluster protein A {ECO:0000303|PubMed:28926261};
DE AltName: Full=Non-reducing polyketide synthase macA {ECO:0000303|PubMed:28926261};
GN Name=macA {ECO:0000303|PubMed:28926261};
OS Penicillium terrestre.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=374132;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RC STRAIN=LM2;
RX PubMed=28926261; DOI=10.1021/acs.orglett.7b02653;
RA Tang M.C., Cui X., He X., Ding Z., Zhu T., Tang Y., Li D.;
RT "Late-stage terpene cyclization by an integral membrane cyclase in the
RT biosynthesis of isoprenoid epoxycyclohexenone natural products.";
RL Org. Lett. 19:5376-5379(2017).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of macrophorins, isoprenoid
CC epoxycyclohexenones containing cyclized drimane moieties
CC (PubMed:28926261). The first step of the pathway is the synthesis of 6-
CC methylsalicylic acid (6-MSA) by the polyketide synthase macA
CC (PubMed:28926261). 6-MSA is then converted to m-cresol by the
CC decarboxylase macB (By similarity). The cytochrome P450 monooxygenase
CC macC then catalyzes the oxidation of m-cresol to toluquinol (By
CC similarity). Epoxidation of toluquinol is then performed by the short
CC chain dehydrogenase macD, with the help of macE, and a further
CC prenylation by macG leads to 7-deacetoxyyanuthone A (By similarity).
CC The next step is the hydroxylation of C-22 of 7-deacetoxyyanuthone A by
CC the cytochrome P450 monooxygenase macH to yield 22-deacetylyanuthone A
CC (By similarity). O-Mevalon transferase macI then attaches mevalon to
CC the hydroxyl group of 22-deacetylyanuthone A to produce yanuthone E (By
CC similarity). The terpene cyclase macJ catalyzes the cyclization of 22-
CC deacetylyanuthone A to macrophorin A (PubMed:28926261). MacJ is also
CC able to catalyze cyclization of yanuthone E and 7-deacetoxyyanuthone A
CC to their corresponding macrophorins (PubMed:28926261). The macJ
CC products can be further modified by macH and macJ, as well as by the
CC FAD-dependent monooxygenase macF, to produce additional macrophorins,
CC including 4'-oxomacrophorin A, 4'-oxomacrophorin D and 4'-
CC oxomacrophorin E (PubMed:28926261). {ECO:0000250|UniProtKB:G3Y419,
CC ECO:0000269|PubMed:28926261}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 H(+) + 3 malonyl-CoA + NADPH = 6-
CC methylsalicylate + 3 CO2 + 4 CoA + H2O + NADP(+);
CC Xref=Rhea:RHEA:12240, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:36658, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=2.3.1.165;
CC Evidence={ECO:0000269|PubMed:28926261};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12241;
CC Evidence={ECO:0000269|PubMed:28926261};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:28926261}.
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: Abolishes completely the production of
CC macrophorin A, 4'-oxomacrophorin A, 4'-oxomacrophorin D and 4'-
CC oxomacrophorin E. {ECO:0000269|PubMed:28926261}.
CC -!- MISCELLANEOUS: The macrophorins cluster contains a single gene
CC insertion (encoding for the terpene cyclase macJ) compared with the
CC yanuthone cluster that produces the linear compound yanuthone.
CC {ECO:0000269|PubMed:28926261}.
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DR EMBL; MF989999; AVK70100.1; -; Genomic_DNA.
DR EMBL; MH388470; QBC75448.1; -; Genomic_DNA.
DR UniPathway; UPA00213; -.
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:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
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; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
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; 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; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 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; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Transferase.
FT CHAIN 1..1783
FT /note="6-methylsalicylic acid synthase"
FT /id="PRO_0000454084"
FT DOMAIN 1707..1781
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..40
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 45..418
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 587..884
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 942..1215
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1382..1510
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 1..31
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 217
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 673
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1741
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1783 AA; 190836 MW; 722811D28156CF18 CRC64;
MITSTSSTEV LTPANGSDDS KGTTTPATSS GDPEMHDDLL RNDTHDDVAI IGMACRVPGD
VNSPSALWQF LLEKGDASGD MPTWRWDPYR QRHPRNAAVL AETTAKGYFL NDIDQFDAAF
FAISPREAEQ MDPQQRIALE VAWEALENAG ISPSRLAGSN TSVYMGVNSD DYAKLVLEDL
PDVGAHMGVG TAYCGIPSRI SYLLDLMGPS VAMDAACASS LVAVHHARQA IRAGETDLAI
AGGVNALLGP GLTRVLDEAG AISADGKCRS FDDSASGYGR GEGAGVVILK RLDKALTDGD
QVLAVLKGSA VASDGKTLGI MAPNAQAQLL VAQKALKEAK VTSDSINYIE AHATSTSLGD
PTETNALAEV YGVGSGRHPS DPCYIGSIKP NIGHLEAGAG VMGLIKAVLV LRYGEVPPQA
NLQTLNSKIA WKENLLRPAR ELVTLPRGAL SRPLRAAIAS YGYSGTVSHA IIEAFAGQSL
FAERLAQIPD SDAAPALLLL SVPQANRIST TAAGLSRWLR DMDGAVSLAT VASTLSQRRM
HHRFRHAIVA DSVANAIATL DDLAKDVPSR WAISDRIGSE AGKGAVWVFS GHGAQWPDMG
RELFHSSPAF GEVVRNLEPI IQAELGFSAI ETLHAGCPDR TDLIQAMTFL MHLGIAAVLE
AESGPPTAVV GHSLGEAAAA VVSGALTWHE AALVVCRRAR LYREFMGQGA MALVRLSASE
ARARIATHPG ASVAIETSPT ACVVSGTVDA LQRLSEQWLE EGVEVRAVAT DVPFHTPLLE
KLAGPLRGAL KNELHPQVPH RALYSTSLLD PRSDLLRDAE YWVMNMIQPV LLQSTVAALV
DDGFRAFVEV ASHPIITHSI VETISEQTTD RFIATPTMVR KQPALKSILA AVGRLHCFGC
AVKPTDLDPT VPWSSSVPGT IWHHQSFYRA VSGMTAAQLA STHKPAANDL LGTRTALWGT
EEVLYQTRLE EDNRPFPGRH PLHGSEIVPA AVLLRTFLRA LSPRSVEEVS LQVPVVVSPA
REIQIRHNTR NITITSRLEE STSNEHNSWL VNTTATVGAD ATPSVSHVDI AEVAKRLPQK
LSDSFSIDYL ASVGVSAMGF PWRVAHHVAS DNEMLARVHA NPDSLPGMDD LLTSVMDAAT
SIASTLWHSK PRLRMPTAVR RVVAVGVATP QVVYIHCTKA QSSVDEADVI ISSEEGMVLM
EIQGMAFAGV EGESLSRKST SGLVHQISWP PAALAEEPLE FAHIAFLTAD ATKAQVGTYQ
RQIEGRGIST SIHERASDLP LTTHSSMAVV YLPQFTDRIF DTATRSCNDL VTAAQVILSS
SDKPTIRLFA VTSESNLGHS ALTGLGRILH TEHPEIWGSL IDLEDPSVFP LMAMRYVRNA
DVIKIEDGVP RTARLRPLRP APPHSTAGPA TLTFSPASTY LITGGLGSLG ISVAQWMVTQ
GARRILLLSR RSLPPRSIWT ASHKPGTQFI IDSILSLERL GATIHPVAID ISHPSAVTNL
RSALTTLSLP PVAGVVHAAG ILRDQLIEQI TPDAFEAVLA PKIAGALALH TVFPPSSPDL
DFFVLFSSCG QLLGFPGQAS YASGNSFLDA LARSRRKEGD NAISLLWTSW RGMGMGASSN
GALEAELYAR GITDVTPDEA FLAWSSISGT EGADHGVVLR ARPLESGEPL PHAILRDIAP
RKEKAVGEGN GENEEQRKKL SGKELAEYVL VVVKKCVSTT LSIPEDEVDE TVALPEMGMD
SVMTVNFRMS LQQTLTVSVG PTLVWKYPTV HHLVEYFCQV LDE
