PYR2_ASPFU
ID PYR2_ASPFU Reviewed; 2445 AA.
AC Q4WLD4;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 121.
DE RecName: Full=Non-reducing polyketide synthase pyr2 {ECO:0000303|PubMed:20861902};
DE EC=2.3.1.- {ECO:0000269|PubMed:20861902};
DE AltName: Full=Pyripyropene synthesis protein 2 {ECO:0000303|PubMed:20861902};
GN Name=pyr2 {ECO:0000303|PubMed:20861902}; ORFNames=AFUA_6G13930;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=8534106; DOI=10.1128/aem.61.12.4429-4435.1995;
RA Wang H.J., Gloer J.B., Wicklow D.T., Dowd P.F.;
RT "Aflavinines and other antiinsectan metabolites from the ascostromata of
RT Eupenicillium crustaceum and related species.";
RL Appl. Environ. Microbiol. 61:4429-4435(1995).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=18997389; DOI=10.1038/ja.2008.67;
RA Ohshiro T., Ohte S., Matsuda D., Ohtawa M., Nagamitsu T., Sunazuka T.,
RA Harigaya Y., Rudel L.L., Omura S., Tomoda H.;
RT "Selectivity of pyripyropene derivatives in inhibition toward acyl-
RT CoA:cholesterol acyltransferase 2 isozyme.";
RL J. Antibiot. 61:503-508(2008).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=19571395; DOI=10.1248/bpb.32.1261;
RA Hayashi A., Arai M., Fujita M., Kobayashi M.;
RT "Pyripyropenes, fungal sesquiterpenes conjugated with alpha-pyrone and
RT pyridine moieties, exhibits anti-angiogenic activity against human
RT umbilical vein endothelial cells.";
RL Biol. Pharm. Bull. 32:1261-1265(2009).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20861902; DOI=10.1038/nchem.764;
RA Itoh T., Tokunaga K., Matsuda Y., Fujii I., Abe I., Ebizuka Y., Kushiro T.;
RT "Reconstitution of a fungal meroterpenoid biosynthesis reveals the
RT involvement of a novel family of terpene cyclases.";
RL Nat. Chem. 2:858-864(2010).
RN [6]
RP FUNCTION.
RX PubMed=21224862; DOI=10.1038/ja.2010.162;
RA Hu J., Okawa H., Yamamoto K., Oyama K., Mitomi M., Anzai H.;
RT "Characterization of two cytochrome P450 monooxygenase genes of the
RT pyripyropene biosynthetic gene cluster from Penicillium coprobium.";
RL J. Antibiot. 64:221-227(2011).
RN [7]
RP FUNCTION.
RX PubMed=26019565; DOI=10.1080/13102818.2014.960140;
RA Hu J., Furutani A., Yamamoto K., Oyama K., Mitomi M., Anzai H.;
RT "Characterization of two acetyltransferase genes in the pyripyropene
RT biosynthetic gene cluster from Penicillium coprobium.";
RL Biotechnol. Biotechnol. Equip. 28:818-826(2014).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of pyripyropene A, a specific human
CC acyl-coenzyme A:cholesterol acyltransferase 2 inhibitor
CC (PubMed:20861902). The first step of the pathway is the synthesis of
CC nicotinyl-CoA from nicotinic acid by the nicotinic acid-CoA ligase pyr1
CC (PubMed:20861902). Nicotinyl-CoA is then a substrate of polyketide
CC synthase pyr2 to produce 4-hydroxy-6-(3-pyridinyl)-2H-pyran-2-one
CC (HPPO) which is further prenylated by the polyprenyl transferase pyr6
CC to yield farnesyl-HPPO (PubMed:20861902). The next steps consist of an
CC epoxidation of farnesyl-HPPO to epoxyfarnesyl-HPPO by FAD-dependent
CC monooxygenase pyr5 and a cyclization of the terpenoid portion by the
CC terpene cyclase pyr4 to yield deacetyl-pyripyropene E
CC (PubMed:20861902). The 2 cytochrome P450 monooxygenases pyr3 and pyr9,
CC and the 2 acetyltransferases pyr7 and pyr8 are involved in the
CC conversion of deacetyl-pyripyropene E into pyripyropene A through
CC several cycles of oxidation and acetylation steps (PubMed:20861902).
CC Pyr7 acetylates deacetyl-pyripyropene E to pyripyropene E which is
CC oxidized to 11-deacetyl-pyripyropene O by pyr3, which is in turn
CC acetylated into pyripyropene O by pyr8 (PubMed:21224862,
CC PubMed:26019565). Pyripyropene O is then oxidized to deacetyl-
CC pyripyropene A by pyr9 (PubMed:21224862). Deacetyl-pyripyropene A is
CC finally acetylated to pyripyropene A by pyr8 (PubMed:26019565).
CC {ECO:0000269|PubMed:20861902, ECO:0000305|PubMed:21224862,
CC ECO:0000305|PubMed:26019565}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + 2 malonyl-CoA + nicotinyl-CoA = 4-hydroxy-6-(pyridin-3-
CC yl)-2H-pyran-2-one + 2 CO2 + 3 CoA; Xref=Rhea:RHEA:64336,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:149703, ChEBI:CHEBI:149707;
CC Evidence={ECO:0000269|PubMed:20861902};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64337;
CC Evidence={ECO:0000269|PubMed:20861902};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:20861902}.
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 -!- BIOTECHNOLOGY: Pyripyropene A and its derivatives have very unique
CC characteristics of selectively inhibiting the acyl-coenzyme
CC A:cholesterol acyltransferase 2 (ACAT2) isozyme (PubMed:18997389).
CC Therefore, pyripyropenes are expected to be developed as a new type of
CC anti-atherosclerotic agent (PubMed:18997389). Furthermore,
CC pyripyropenes have been shown to exhibit anti-angiogenic activity
CC against human umbilical vein endothelial cells (PubMed:19571395).
CC Finally, pyripyropene A also exhibits insecticidal properties
CC (PubMed:8534106). {ECO:0000269|PubMed:18997389,
CC ECO:0000269|PubMed:19571395, ECO:0000269|PubMed:8534106}.
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DR EMBL; AAHF01000006; EAL89230.2; -; Genomic_DNA.
DR RefSeq; XP_751268.2; XM_746175.2.
DR AlphaFoldDB; Q4WLD4; -.
DR SMR; Q4WLD4; -.
DR STRING; 746128.CADAFUBP00000081; -.
DR EnsemblFungi; EAL89230; EAL89230; AFUA_6G13930.
DR GeneID; 3508583; -.
DR KEGG; afm:AFUA_6G13930; -.
DR VEuPathDB; FungiDB:Afu6g13930; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR InParanoid; Q4WLD4; -.
DR OMA; GGFEGWW; -.
DR OrthoDB; 19161at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0004312; F:fatty acid synthase activity; IBA:GO_Central.
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; IBA:GO_Central.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0019748; P:secondary metabolic process; NAS:AspGD.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IBA: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; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 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; IPR032821; PKS_assoc.
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; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 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; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 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 Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2445
FT /note="Non-reducing polyketide synthase pyr2"
FT /id="PRO_0000436678"
FT DOMAIN 2356..2431
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 4..384
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 547..881
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 985..1487
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1751..2150
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 177
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 642
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2391
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2445 AA; 265821 MW; CB7B31811FC52DAB CRC64;
MKENEPVAII GTGCRFPGGA SSPAKLWELL RNPREIARKI PANRFNIDAF YHPDGDHHGT
TNVQESYFLD EDVRAFDAAF FNISPTEAAA MDPQQRLLLE TVYESLDAAG LRMDALQGSM
TGVFCGALRN DYSQIQTMDP QALPAYMVTG NSPSIMANRI SYYFDWRGPS MTVDTGCSSS
LLAVHLGVEA LQNDDCSLAV AVGSNLILSP NAYIADSKTR MLSPTGRSRM WDSQADGYAR
GEGVASVVLK RLRDAIVDGD PIECVIRASG ANSDGRTMGI TMPNAQAQQA LILQTYARAG
LSPQERPTDR CQYFEAHGTG TQAGDPQEAA AIHASFFGPK SVADPLDRLF VGSIKTVVGH
TEATAGLAGL IKASLSLQHG MIVPNLLMQQ LNPKIEAFAA HLCVPTECVP WPAVPEGCPR
RASVNSFGFG GANVHVVLES YTARQITPSH NLPSSLPFVF SAASERTLTS VLESYATFLR
EHAAVSLPSL AVSMWTRRSA HRHRLTLIAR SVEELQDHID KELSRRATGT PSSIVSRPSS
RPRRVLGVFT GQGVQWPQMG LDLIEASPQI QQWMADLQEA LDQLPLEYRP EFSLLRELSR
PASSSRVHEG LLSLPLRTAL QIVQVNILRA VGIEFSMVVG HSSGEIVAAY AAGVLTAADA
IRIAYLRGRA IHESRDSAGR MMAVNLTWQQ AQAVCAAEPF SGRISVAAAN SPSSVTLSGD
AEGLRDLEWL LKSLGFTPRM LQVDTAYHSP YMKPCADPYR RAMQACPVAV APSAARWYSS
VYPGEVMTGQ DQAQRTGEYW VENMLRPVQF AQALEAAVRE TGAPDVIVEV GPHPTLRGPV
LQTLSKVHSA HSTIPYLALA ERGKPGLDCW AMALGLAWAH LGPSVVRLDG YVSLLDPGQS
HVPLTSLPPY PFDRSQTYWA QSRISLNYNH CITPPNALLG VLSPETGPGE FRWRNYLRPE
ELPWLADRRV GSRSVFPETG YISMALEAAR MMVETQGLRL LSVKDFTVHT PLPIQNDAIG
TEILVTVNDI FSHDGVISAL FRCEAAVSDE FVKCATAKMI MHPGDPDRAL LPTQGQRALA
VGPVDINGFY NSLRCVDYHC TGPFAGLTGL HRGCDLATGT VHVPSRDPDG PIILHPATLE
LAIQAMIAAL GAPDEGLLTG ALLSKTVDNI WVNPALCVSE KEMTVVGYLT DVDGDHIRGD
VDIFTRNGQK AVQMEGVCLV YQPSGIAPTD RQVLSQTEWG PLEPSLKTAS RSLPANVLEL
YSLRDELALL YIKQASDGLT DSGRNELDCD GTRLLAQMNQ CIANAREGRQ LAGSPERLDK
SIEAFAARVG PSIDDSGLRA IAAVGQQRPH VLRESGHQRV VTWPHFDEGN EYLKQDVQVS
HLVDNLISVV SQTCFRFPQM DILQIGTLGG SVHSVLREMG RSFRSFTYAA PSQPTDGPGL
ERPGEVQHRT FDVDRNPLEQ GYQDHAYDMV LFTTARFPLE VAVAHIRRLL KPRGFLVLMV
RTNPNITHLN LLFGHPARCT ETCSGEQVIT KEHWIELLST NGFRVESLDA PPEMAGHQGF
SLLLCRASGE YKEPSPRGDL LLVGGGDKNA DCVISELAEL VQGRFDQVLR SPSLDLMEIT
VRSELTALIL VDDQDLTEAS LSALRRLITT SKRALWVTCA KSDQPNGGLT RGLLRSIMAS
EQLSCQLQLL HITDPVGVSV EILATALERL VQASAAQECP DSCGLDNIEP EVEYDGSMFL
IPRQYHNNST GLRHLGRRQT VTGYVDLSQG VVQVLPPTTD ATCERFRLLS VAQPPLTSDD
GSTIHLRVRY SSLAAVRVAG AMFLRLVIGR EVSSNNRMIA LSSHIASQVI VPESWACSLP
DTVSEAQEQA FLHVTAAALL AGYLFDQLPP FGTFVVHGAD RVFQSIVHQI PTWRNVKVIF
STSTNNLDKD GAMLYLHEHS TARQLSQVLP SDVSAVAVLD RRGQGIYDRM LSLLPDNATR
IQIDDLYRAS ASTMTPNGRV SLLVVRAFIT ACLVAYTSCE AVSLTSMDLV PTATVAEYPP
THCHQGIIDW NPSIPVRAEI PTASSQVQLS PKKTYILVGI ASELARMACL WLAAHGARWI
LLTSSKPEPD AWWVEELSSR GTRIAFSTMN LIDGVSVTSL HHSIAHPFPP AVGGVLIQPG
PLPDCSLSQL TAEVLQSRLH PVLKELQLLD ELHETQPLDF WVLIGSISGT LGHADQALTA
AMSERMATLV RQRRSRGRPA SLVHLGEISG IDIPADGARP WWGPTAVTQR DIDEVLSEAV
LCGGPNSFAR SAEFIVGLRH QSLQTGRMAG PVPKLWPFYS YTATASQGQK PPSLPERRQS
AKDLVAAATS REEKAEAIAA CLMEKIRARL KLNADAPLSS DTLISELGVD SLVAVELRRW
FAKQLAVDMS IVLILSGASV GELANAAASK LCNGNSELCT SSNLV
