ID PYR1_ASPFU Reviewed; 581 AA.
AC Q4WLD5;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 27-MAR-2024, entry version 80.
DE RecName: Full=Nicotinic acid-CoA ligase pyr1 {ECO:0000303|PubMed:20861902};
DE EC=6.2.1.- {ECO:0000269|PubMed:20861902};
DE AltName: Full=Pyripyropene synthesis protein 1 {ECO:0000303|PubMed:20861902};
GN Name=pyr1 {ECO:0000303|PubMed:20861902}; ORFNames=AFUA_6G13920;
OS Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 /
OS Af293) (Neosartorya fumigata).
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 / CBS 101355 / FGSC A1100 / Af293;
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: Nicotinic acid-CoA ligase; part of the gene cluster that
CC mediates the biosynthesis of pyripyropene A, a specific human acyl-
CC coenzyme A:cholesterol acyltransferase 2 inhibitor (PubMed:20861902).
CC The first step of the pathway is the synthesis of nicotinyl-CoA from
CC nicotinic acid by the nicotinic acid-CoA ligase pyr1 (PubMed:20861902).
CC Nicotinyl-CoA is then a substrate of polyketide synthase pyr2 to
CC produce 4-hydroxy-6-(3-pyridinyl)-2H-pyran-2-one (HPPO) which is
CC further prenylated by the polyprenyl transferase pyr6 to yield
CC 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=ATP + CoA + nicotinate = AMP + diphosphate + nicotinyl-CoA;
CC Xref=Rhea:RHEA:64332, ChEBI:CHEBI:30616, ChEBI:CHEBI:32544,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57287, ChEBI:CHEBI:149703,
CC ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:20861902};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64333;
CC Evidence={ECO:0000269|PubMed:20861902};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:20861902}.
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}.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC {ECO:0000305}.
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DR EMBL; AAHF01000006; EAL89229.1; -; Genomic_DNA.
DR RefSeq; XP_751267.1; XM_746174.1.
DR AlphaFoldDB; Q4WLD5; -.
DR SMR; Q4WLD5; -.
DR STRING; 330879.Q4WLD5; -.
DR EnsemblFungi; EAL89229; EAL89229; AFUA_6G13920.
DR GeneID; 3508582; -.
DR KEGG; afm:AFUA_6G13920; -.
DR VEuPathDB; FungiDB:Afu6g13920; -.
DR eggNOG; KOG1176; Eukaryota.
DR HOGENOM; CLU_000022_59_2_1; -.
DR InParanoid; Q4WLD5; -.
DR OMA; THHTIIS; -.
DR OrthoDB; 2282191at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016405; F:CoA-ligase activity; IBA:GO_Central.
DR GO; GO:0019748; P:secondary metabolic process; IBA:GO_Central.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR CDD; cd05911; Firefly_Luc_like; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.40.50.12780; N-terminal domain of ligase-like; 1.
DR InterPro; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig_com.
DR InterPro; IPR042099; ANL_N_sf.
DR PANTHER; PTHR24096:SF317; ADENYLATE-FORMING ENZYME AFEA; 1.
DR PANTHER; PTHR24096; LONG-CHAIN-FATTY-ACID--COA LIGASE; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF13193; AMP-binding_C; 1.
DR SUPFAM; SSF56801; Acetyl-CoA synthetase-like; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Ligase; Nucleotide-binding; Reference proteome.
FT CHAIN 1..581
FT /note="Nicotinic acid-CoA ligase pyr1"
FT /id="PRO_0000436771"
FT REGION 477..555
FT /note="AMP-binding"
FT /evidence="ECO:0000255"
FT BINDING 204..215
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000255"
SQ SEQUENCE 581 AA; 63501 MW; 3D2B04C925922F36 CRC64;
MEPHGETDLV SFAFSSPTPF DPTRPIYLDA QNPSRAFNAR QFRLLVRSLI AGLRALGLKP
GHCVLVQLEN TVIHSALFFA IVGAGGVYMG CDVGSPAHEL THLLRLAEPQ LVITAPGALS
TLEVCSTQGE SFSGQVLLVD ELSIDNIVQF AHRAAAAGAE AQTEGLVDQT AGPCIRLESL
LQHGESDWLR FEDREQSKRT PAAMFLTSGT SGLPKAAIST HHTIISHHLS VHYRVPYPVV
RLMALPMYHS FGDFWTNIFP IRYGEPLYVL PRFDISTFLD AVRQHHISET YMVPAMVQIL
SQSSLPVAES LASLRYVGIS GAPIDGFSIQ RFQRLLSPDA VAGNLWGMTE VGVVFQNRYR
VPLQFGSVGT LLHGYELRFV DPATGEDVAG TPDSPGELYV RGPGLLLGYK WRTDDKDEQG
WFRTGDMVYA RDGNYYIIGR TKDLIKVRGQ VPDSLNSWTS HSTNRLCDSR YSVAPAEIEG
ILLKDPGVKD AAVIGVMLPD GSSEVPRAYV VRAGISPEST ADQLTDLVQT QLASYKALDG
GVVFVDEIPR TGIGKPHRAR LSQLDREREK LASILGVSVP A
//
