CPAH_ASPOZ
ID CPAH_ASPOZ Reviewed; 509 AA.
AC C9K202;
DT 10-OCT-2018, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 1.
DT 03-AUG-2022, entry version 55.
DE RecName: Full=Cytochrome P450 monooxygenase cpaH {ECO:0000303|PubMed:21608094};
DE EC=1.-.-.- {ECO:0000269|PubMed:21608094};
DE AltName: Full=Cyclopiazonic acid biosynthesis cluster protein H {ECO:0000303|PubMed:21608094};
GN Name=cpaH {ECO:0000303|PubMed:21608094};
GN Synonyms=CYP65AC1 {ECO:0000303|PubMed:20358180};
OS Aspergillus oryzae (Yellow koji mold).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=5062;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Seshime Y., Juvvadi P.R., Tokuoka M., Koyama Y., Kitamoto K., Ebizuka Y.,
RA Fujii I.;
RT "Functional expression of the Aspergillus flavus PKS-NRPS hybrid CpaA
RT involved in the biosynthesis of cyclopiazonic acid.";
RL Submitted (AUG-2008) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND IDENTIFICATION.
RX PubMed=20358180; DOI=10.1007/s00203-010-0562-z;
RA Nazmul Hussain Nazir K.H., Ichinose H., Wariishi H.;
RT "Molecular characterization and isolation of cytochrome P450 genes from the
RT filamentous fungus Aspergillus oryzae.";
RL Arch. Microbiol. 192:395-408(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], DISRUPTION PHENOTYPE, FUNCTION, AND
RP PATHWAY.
RC STRAIN=NBRC 4177;
RX PubMed=21608094; DOI=10.1002/cbic.201000672;
RA Kato N., Tokuoka M., Shinohara Y., Kawatani M., Uramoto M., Seshime Y.,
RA Fujii I., Kitamoto K., Takahashi T., Takahashi S., Koyama Y., Osada H.;
RT "Genetic safeguard against mycotoxin cyclopiazonic acid production in
RT Aspergillus oryzae.";
RL ChemBioChem 12:1376-1382(2011).
RN [4]
RP FUNCTION.
RX PubMed=19663400; DOI=10.1021/bi901123r;
RA Liu X., Walsh C.T.;
RT "Cyclopiazonic acid biosynthesis in Aspergillus sp.: characterization of a
RT reductase-like R* domain in cyclopiazonate synthetase that forms and
RT releases cyclo-acetoacetyl-L-tryptophan.";
RL Biochemistry 48:8746-8757(2009).
RN [5]
RP FUNCTION.
RX PubMed=19877600; DOI=10.1021/bi901597j;
RA Liu X., Walsh C.T.;
RT "Characterization of cyclo-acetoacetyl-L-tryptophan
RT dimethylallyltransferase in cyclopiazonic acid biosynthesis: substrate
RT promiscuity and site directed mutagenesis studies.";
RL Biochemistry 48:11032-11044(2009).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of the fungal neurotoxin cyclopiazonic acid
CC (CPA), a nanomolar inhibitor of Ca(2+)-ATPase with a unique pentacyclic
CC indole tetramic acid scaffold (PubMed:21608094). The hybrid two module
CC polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) cpaS
CC incorporates acetyl-CoA, malonyl-CoA, and tryptophan (Trp) and utilizes
CC a C-terminal redox-incompetent reductase domain to make and release the
CC tryptophan tetramic acid, cyclo-acetoacetyl-L-tryptophan (c-AATrp), as
CC the first intermediate in the pathway. CpaS catalyzes a Dieckmann-type
CC cyclization on the N-acetoacetyl-Trp intermediate bound in thioester
CC linkage to the phosphopantetheinyl arm of the T domain to form and
CC release c-AATrp (PubMed:21608094, PubMed:19663400). CpaD than
CC regiospecifically dimethylallylates c-AATrp to form beta-cyclopiazonic
CC acid. CpaD discriminates against free Trp but accepts tryptophan-
CC containing thiohydantoins, diketopiperazines, and linear peptides as
CC substrates for C4-prenylation and also acts as regiospecific O-
CC dimethylallyltransferase (DMAT) on a tyrosine-derived tetramic acid
CC (PubMed:21608094, PubMed:19877600). The beta-cyclopiazonate
CC dehydrogenase cpaO then carries out the dehydrogenation of beta-CPA to
CC yield an unstable enimine product, which is captured by intramolecular
CC cyclization to create the pentacyclic fused scaffold of alpha-
CC cyclopiazonate (PubMed:21608094). Fimally, the cytochrome P450
CC monooxygenase cpaH mediates the conversion of CPA into the less toxic
CC 2-oxocyclopiazonic acid, the end product of the CPA pathway in A.oryza
CC (PubMed:21608094). {ECO:0000269|PubMed:19663400,
CC ECO:0000269|PubMed:19877600, ECO:0000269|PubMed:21608094}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:21608094}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of 2-oxocyclopiazonic
CC acid, but accumulates cyclopiazonic acid (CPA).
CC {ECO:0000269|PubMed:21608094}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AB454443; BAI43483.1; -; Genomic_DNA.
DR EMBL; AB514706; BAJ04383.1; -; mRNA.
DR EMBL; AB506492; BAK26559.1; -; Genomic_DNA.
DR AlphaFoldDB; C9K202; -.
DR SMR; C9K202; -.
DR STRING; 5062.CADAORAP00007923; -.
DR VEuPathDB; FungiDB:AO090026000004; -.
DR OMA; LIWEFDW; -.
DR BioCyc; MetaCyc:MON-18889; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 2: Evidence at transcript level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..509
FT /note="Cytochrome P450 monooxygenase cpaH"
FT /id="PRO_0000445387"
FT TRANSMEM 31..51
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 453
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 15
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 306
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 412
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 509 AA; 58166 MW; A809DF3201520ED4 CRC64;
MSQFAREIVR NAIYNTSSPD ADSVSLRKAT TTILLIGVTY CILVGIYRVT LHPLAKYPGP
KLAAVTRLWH SYHLCTGDIV SVLSRAHEAY GPVLRIAPDE VLFISSRAWD DIYGARPGKP
EMDKDTPLYK GPTAPHSIVT VDGELHRFYR RLLAKGFSDA ALREQEPVIQ RNINLLVEKL
HKEVAAGKTP EMTAWFNYAT FDLIGELAFG ETYGCLENSH YHPWVEMILE VMKLRAMTHA
VGYYPWIFHI LMWFVPKSLR EKFVTHRRYT HDKVQRRMDQ KIHYKDLTTN LVDPQNGLER
YEIDGNCSTL IIAGSETTAT ALSATLYFLT QNENAKRKVI GEIRTTFNNA GDINSISVNQ
LKYLSACMNE ALRIFPPGPA VFPRRVPQGG DFIDGHWIPG GTQVGIAHYC INRSRRNFVD
PDKFIPERWL GDPTYQTDDR HAVQPFSYGP RNCIAHNLAR LEMRLVLARL IWEFDWELAP
GSERWEEEAL VFNVWSTKPL MIKFTPVAR
