NVFA_ASPN1
ID NVFA_ASPN1 Reviewed; 2255 AA.
AC A0A2I1BSV9;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-FEB-2018, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=Non-reducing polyketide synthase nvfA {ECO:0000303|PubMed:29968715};
DE EC=2.3.1.- {ECO:0000269|PubMed:29968715};
DE AltName: Full=Novofumigatonin biosynthesis cluster protein A {ECO:0000303|PubMed:29968715};
GN Name=nvfA {ECO:0000303|PubMed:29968715}; ORFNames=P174DRAFT_455569;
OS Aspergillus novofumigatus (strain IBT 16806).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1392255;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=IBT 16806;
RX PubMed=29317534; DOI=10.1073/pnas.1715954115;
RA Kjaerboelling I., Vesth T.C., Frisvad J.C., Nybo J.L., Theobald S., Kuo A.,
RA Bowyer P., Matsuda Y., Mondo S., Lyhne E.K., Kogle M.E., Clum A.,
RA Lipzen A., Salamov A., Ngan C.Y., Daum C., Chiniquy J., Barry K.,
RA LaButti K., Haridas S., Simmons B.A., Magnuson J.K., Mortensen U.H.,
RA Larsen T.O., Grigoriev I.V., Baker S.E., Andersen M.R.;
RT "Linking secondary metabolites to gene clusters through genome sequencing
RT of six diverse Aspergillus species.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E753-E761(2018).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=29968715; DOI=10.1038/s41467-018-04983-2;
RA Matsuda Y., Bai T., Phippen C.B.W., Noedvig C.S., Kjaerboelling I.,
RA Vesth T.C., Andersen M.R., Mortensen U.H., Gotfredsen C.H., Abe I.,
RA Larsen T.O.;
RT "Novofumigatonin biosynthesis involves a non-heme iron-dependent
RT endoperoxide isomerase for orthoester formation.";
RL Nat. Commun. 9:2587-2587(2018).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of novofumigatonin, a heavily oxygenated
CC meroterpenoid containing a unique orthoester moiety (PubMed:29968715).
CC The first step of the pathway is the synthesis of 3,5-
CC dimethylorsellinic acid (DMOA) by the polyketide synthase nvfA via
CC condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units
CC and 2 methylations (PubMed:29968715). DMOA is then converted to
CC farnesyl-DMOA by the farnesyltransferase nvfB (PubMed:29968715).
CC Epoxydation by FAD-dependent monooxygenase nvfK, followed by a
CC protonation-initiated cyclization catalyzed by the terpene cyclase nvfL
CC leads to the production of asnavolin H (PubMed:29968715). The short
CC chain dehydrogenase nvfC then as a 3-OH dehydrogenase of asnovolin H to
CC yield chemesin D (PubMed:29968715). There are two branches to
CC synthesize asnovolin A from chemesin D (PubMed:29968715). In one
CC branch, chemesin D undergoes Baeyer-Villiger oxidation by nvfH,
CC methylation by nvfJ, and enoyl reduction by the nvfM D enoylreductase
CC that reduces the double bond between C-5'and C-6', to form respectively
CC asnovolin I, asnovolin K, and asnovolin A (PubMed:29968715). In the
CC other branch, the methylation precedes the Baeyer-Villiger oxidation
CC and the enoyl reduction to yield asnovolin A via the asnovolin J
CC intermediate (PubMed:29968715). Asnovolin A is further converted to
CC fumigatonoid A by the Fe(II)/2-oxoglutarate-dependent dioxygenase nvfI
CC that catalyzes an endoperoxidation reaction (PubMed:29968715). The
CC alpha/beta hydrolase nvfD then acts as an epimerase that converts
CC fumigatonoid A to its C-5' epimer, which then undergoes spontaneous or
CC nvfD-catalyzed lactonization (PubMed:29968715). The following step
CC utilizes the ketoreductase nvfG to produce fumigatonoid B
CC (PubMed:29968715). The dioxygenase nvfE further converts fumigatonoid B
CC into fumigatonoid C (PubMed:29968715). Finally the Fe(II)/2-
CC oxoglutarate-dependent dioxygenase nvfF catalyzes two rounds of
CC oxidation to transform fumigatonoid C into the end product,
CC novofumigatonin A (PubMed:29968715). {ECO:0000269|PubMed:29968715}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 malonyl-CoA + 2 S-adenosyl-L-methionine = 3,5-
CC dimethylorsellinate + 3 CO2 + 4 CoA + 2 S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:49628, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:131856;
CC Evidence={ECO:0000269|PubMed:29968715};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49629;
CC Evidence={ECO:0000269|PubMed:29968715};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:29968715}.
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|PubMed:29968715}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein. {ECO:0000250|UniProtKB:Q5ATJ7}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of
CC novofumigatonin as well as asnovolin A. {ECO:0000269|PubMed:29968715}.
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DR EMBL; MSZS01000014; PKX88487.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A2I1BSV9; -.
DR SMR; A0A2I1BSV9; -.
DR VEuPathDB; FungiDB:P174DRAFT_455569; -.
DR OrthoDB; 93381at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000234474; Unassembled WGS sequence.
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:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
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; 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 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 Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2255
FT /note="Non-reducing polyketide synthase nvfA"
FT /id="PRO_0000453076"
FT DOMAIN 1581..1655
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 13..251
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 365..728
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 887..1187
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1232..1535
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1809..2042
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT REGION 2109..2227
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 530
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 974
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2194
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1615
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2255 AA; 246067 MW; 9F857DDE5E3A3E44 CRC64;
MEPSDTERCD VGILFGPQSS DMDEALSCIR SYVLEQPAVR YLVDLVLELP SLWPEIKNAW
PALSQVPGEE QLVALGRFFN GGPFPASDEA MNVITTPVTV IRHIVEFYKV KETMKGFQAR
DVQGFCVGFL AATAVAASCD ETAFRALVSK IIRLAVCIGG LVDLDELAVH RARSMAVRWD
GEEDYDRLEQ VLAAHPEAYI ACVTDANRAT LTVPKSLAPQ MIQDLANHGL SVREIRLCGR
FHHPDHTAAV EQMSRLCERD CRFQLPDASS LSLPLRSNIN GEVIRTGQLH TIALQSILCF
RSQWLITVTA ALASITMTDE SIRLVSIGPH QCVPRMAQSK LIRTVTSSPV DGCYEAINGT
GAAPVRPIAV TGMACRYPQA NSVEELWEML ELGKCAVKPL PNDRLKMVEL LREPKGPYWG
HYLEEPDMFD HRFFGISARE AATMDPQQRL LLQVAYEAME SAGYCGLRSS QIPRDVGCYV
GVGSDDYTDN VGSHHANAYS APGTLQAFNT GRISHYFGWS GPSVVVDTAC SSAAVAIHLA
CQALRTKDCS VAIAGGVNVM TSPKVTQNLA AASFLSPTGA SKAFDADADG YCRGEGAGLV
VLRPLEDAIS DVDPILAVIT GTAVNQGSNC SPITVPVSES QMSLYGKSLA ASGIAPEDVT
YVEAHGTGTQ VGDPIEFDSI RRMFGGRHRS EELYVGSIKD NIGHTETSSG VAGLVKTILM
MQKGRIPKQA NFSRLNPKIP APEGDRIVIP KQSTDWKSAR RVAMVTNYGA AGSNAAIVLR
QHTITTNTGS SWLSDVPVFV AAKSPESLRS YCYKMQAFLR QTAGLLGCTM RDITYNLAIK
QNRDLDFLVS FPTPSQDPMT LLSQLESVAA GVTDLQQRPA QAPSVILCFG GQNGNTAHIS
QDLFAGCHLL QAHLADCEKI CQSMGLPSLF PTIFQEEPIH DLVNLHCILF AIQYASAMCW
IHSGLQVKRM LGHSFGQLTA LCVAGGLTLI DAIRLVSERA RLIETSWAGD HGVMLSVDAS
EAEVRALVNR AGDTVDLACY NGARSYVLAG DEISIQVVEK LADGMRIKRL PNTHAFHSRL
VDSIVPGLRK LAQSLKYHPT TIPVEACSED GSAWTCVTPD QIVAHSRMPV HFDSAVQRAA
NHVQGPVVWL EAGSASPIVS MVRRVVEESS SSRAHLYQAS DLKSPQAQAN LAKATSGLWA
NGIPTSHWTE YDPLAFLPAS APIAEASSEP MGLVQVLEKR PSECLFSVNT KDPLYRTCTQ
GHAVVEQNLC PASLYLEMVV SAAGCLSSAG LITAMPHLQE LSISAPLVLE PDGDVLLRLS
QSPAEKTAWT FSLFTQAGQK APVSHATGRI SLHPFDSTST ILSRFRSLDR LMNPSRPDSI
ASLPSSSGLK GSAVYQAFRR VVNYADYYRG VESVFCVSTE ATGRVFVPLS LSRESACDPI
LIDNFVQVAG VHVNCLADVP EDEVYVCSAV GEAFIGEVFM KRDPAAPQPW RVYSNYDRLS
KGQVACDVFV MDQKSGQLAI AILAATFTSV SIRALTRTLA KLNNHQPSML ATNEPSAGHK
EVNSILNVVD RPPPTAATVD TNKFPAIQAM LSDLLGVGLD ELSPYSSLMA IGVDSLMSTE
VLTEIKKRFG VNITSAELGE IPDIQCLVQA IFPGASVAQK QATTSKMPPL SDLAESVFNG
PAPPDALMLA QKAYDLFGTT QANTDYSQIT KWAGFCESVF PKQMALVTAY VVEAFRALGY
PLELLHAGQA VPLIPVLPQH ESVRNQLYEV LKFSKLICRK DDGMFRTAEA VPSDTSLLLH
EDIIKEYPHH ASEHTLLRTT GSRLAECLSG SADPLALLFQ NADARRVMED VYTNAPMFKS
ATMHLAQYLQ DLVILLRSRR DIKILEIGAG TGGTTKYLVS QLAAVPGLRF EYTFTDISTS
LVTLAKKKFN GYSCIQYATL NIEQDPPDDL LGQYDIVLST NCIHATRNIA HSCDNIRKLL
RPDGILCLIE LTRNLFWFDL VFGLLEGWWL FNDGRNHALA TEQFWNESLR QAGYNWVNWS
CNDSRESEIL RLIVASPTLP HGASQILFRS PLVTEETVKY DEKDGVQLLA DIYYPSEVDD
AHRRRPIALL IHGGGHVMLS RKDIRSQQIK MLLNSGFLPV SIDYRLCPET SLTEGPMRDV
RDALVWTRRT LPRLSLKRPD IRPNGDQVVA VGWSTGGHLA MTLSWTASLC GVRAPEAILS
FYCPTDYSDP FWSQPNFPYG RDIAPQMKCT IFGMQ
