PYR4_ASPFU
ID PYR4_ASPFU Reviewed; 241 AA.
AC Q4WLD2;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 25-MAY-2022, entry version 62.
DE RecName: Full=Terpene cyclase pyr4 {ECO:0000303|PubMed:20861902};
DE EC=4.2.3.- {ECO:0000269|PubMed:20861902};
DE AltName: Full=Pyripyropene synthesis protein 4 {ECO:0000303|PubMed:20861902};
GN Name=pyr4 {ECO:0000303|PubMed:20861902}; ORFNames=AFUA_6G13950;
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, CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLU-63 AND ASP-218.
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: Terpene cyclase; part of the gene cluster that mediates the
CC biosynthesis of pyripyropene A, a specific human acyl-coenzyme
CC A:cholesterol acyltransferase 2 inhibitor (PubMed:20861902). The first
CC step of the pathway is the synthesis of nicotinyl-CoA from nicotinic
CC 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=2-oxo-3-[(8S)-epoxy-(2E,6E)-farnesyl]-6-(pyridin-3-yl)-2H-
CC pyran-4-olate + H(+) = deacetylpyripyropene E; Xref=Rhea:RHEA:64348,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:149709, ChEBI:CHEBI:149710;
CC Evidence={ECO:0000269|PubMed:20861902};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64349;
CC Evidence={ECO:0000269|PubMed:20861902};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:20861902}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
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 paxB family. {ECO:0000305}.
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DR EMBL; AAHF01000006; EAL89232.1; -; Genomic_DNA.
DR RefSeq; XP_751270.1; XM_746177.1.
DR AlphaFoldDB; Q4WLD2; -.
DR STRING; 746128.CADAFUBP00000078; -.
DR EnsemblFungi; EAL89232; EAL89232; AFUA_6G13950.
DR GeneID; 3508586; -.
DR KEGG; afm:AFUA_6G13950; -.
DR VEuPathDB; FungiDB:Afu6g13950; -.
DR eggNOG; ENOG502RZAD; Eukaryota.
DR HOGENOM; CLU_087059_3_0_1; -.
DR InParanoid; Q4WLD2; -.
DR OMA; SYAMPLH; -.
DR OrthoDB; 1094347at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000002530; Chromosome 6.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR InterPro; IPR039020; PaxB-like.
DR PANTHER; PTHR42038; PTHR42038; 1.
PE 1: Evidence at protein level;
KW Lyase; Membrane; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..241
FT /note="Terpene cyclase pyr4"
FT /id="PRO_0000436679"
FT TRANSMEM 20..40
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 49..69
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 79..99
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 113..133
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 141..161
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 168..188
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 206..226
FT /note="Helical"
FT /evidence="ECO:0000255"
FT MUTAGEN 63
FT /note="E->A,Q: Completely abolishes the cyclase activity."
FT /evidence="ECO:0000269|PubMed:20861902"
FT MUTAGEN 218
FT /note="D->A,N: Completely abolishes the cyclase activity."
FT /evidence="ECO:0000269|PubMed:20861902"
SQ SEQUENCE 241 AA; 27440 MW; 5A0BBAA914803709 CRC64;
MDGWSDLSSA PPQYREVAGI ADWALLAQGL GWSINYLAMI YHSYKDRTYG MAILPLCCNF
AWEFVYSVIY PSHNSAERAV LTTWMILNLF VMYTAIKFAP NEWQHAPLVR QCLPWIFPVA
IAAFTAGHLA LAATVGVSKA ANWGAFLCFE LLTSGAVCQL MSRGSSRGAS YTIWLSRFLG
SYIGGIFLHV RETHWPQEFG WISHPFVTWH GLMCFSLDIA YVTFLWRIRR QEHRSQRKKA
L
