ADRH_PENRO
ID ADRH_PENRO Reviewed; 476 AA.
AC A0A1Y0BRF9;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2017, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=FAD-dependent monooxygenase adrH {ECO:0000303|PubMed:28529508};
DE EC=1.-.-.- {ECO:0000305|PubMed:28529508};
DE AltName: Full=Andrastin A biosynthesis cluster protein H {ECO:0000303|PubMed:28529508};
GN Name=adrH {ECO:0000303|PubMed:28529508};
OS Penicillium roqueforti.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5082;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, FUNCTION, AND DISRUPTION
RP PHENOTYPE.
RC STRAIN=CECT 2905;
RX PubMed=28529508; DOI=10.3389/fmicb.2017.00813;
RA Rojas-Aedo J.F., Gil-Duran C., Del-Cid A., Valdes N., Alamos P., Vaca I.,
RA Garcia-Rico R.O., Levican G., Tello M., Chavez R.;
RT "The biosynthetic gene cluster for andrastin A in Penicillium roqueforti.";
RL Front. Microbiol. 8:813-813(2017).
CC -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of andrastins, meroterpenoid compounds that
CC exhibit inhibitory activity against ras farnesyltransferase, suggesting
CC that they could be promising leads for antitumor agents
CC (PubMed:28529508). The first step of the pathway is the synthesis of
CC 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase adrD via
CC condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units
CC and 2 methylations (By similarity). DMAO is then converted to farnesyl-
CC DMAO by the prenyltransferase adrG (By similarity). The
CC methyltransferase adrK catalyzes the methylation of the carboxyl group
CC of farnesyl-DMAO to farnesyl-DMAO methyl ester which is further
CC converted to epoxyfarnesyl-DMAO methyl ester by the FAD-dependent
CC monooxygenase adrH (By similarity). The terpene cyclase adrI then
CC catalyzes the carbon skeletal rearrangement to generate the andrastin
CC E, the first compound in the pathway having the andrastin scaffold,
CC with the tetracyclic ring system (By similarity). The post-cyclization
CC tailoring enzymes adrF, adrE, adrJ, and adrA, are involved in the
CC conversion of andrastin E into andrastin A. The short chain
CC dehydrogenase adrF is responsible for the oxidation of the C-3 a
CC hydroxyl group of andrastin E to yield the corresponding ketone,
CC andrastin D. The ketoreductase adrE stereoselectively reduces the
CC carbonyl moiety to reverse the stereochemistry of the C-3 position to
CC yield andrastin F. The acetyltransferase adrJ is the acetyltransferase
CC that attaches the acetyl group to the C-3 hydroxyl group of andrastin F
CC to yield andrastin C. Finally, the cytochrome P450 monooxygenase adrA
CC catalyzes two sequential oxidation reactions of the C-23 methyl group,
CC to generate the corresponding alcohol andrastin B, and aldehyde
CC andrastin A (By similarity). {ECO:0000250|UniProtKB:B6HV36,
CC ECO:0000269|PubMed:28529508}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:28529508}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Drastically reduces the production of andrastin
CC A. {ECO:0000269|PubMed:28529508}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; KY349137; ART41213.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A1Y0BRF9; -.
DR SMR; A0A1Y0BRF9; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; 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; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 2.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 3: Inferred from homology;
KW FAD; Flavoprotein; Glycoprotein; Membrane; Monooxygenase; Oxidoreductase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..476
FT /note="FAD-dependent monooxygenase adrH"
FT /id="PRO_0000446493"
FT TRANSMEM 449..471
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 39..40
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 135
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 245..247
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 312
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 322..326
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 409
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 476 AA; 53750 MW; 013D19B267928A5A CRC64;
MEEGMEAPKF KVIIVGGSIA GLTLAHSLSQ ANIDHVVLEK RASIAPQEGA FIGVWPNGAQ
ILDQLGLYHS LEKLTAPLSR MHLSFPDGYS FSSLLPKTIH EIFKYPIVSL DRQKVLEILF
QNYPNKEKII TNQRVSEVRL LGDSASVVTE DGSVFQGDLI VGADGVHSRI RSEMWRLADE
LHPGMITPQE RQTLTVEYAC VFGISRAIPG LRSGEHINHY GDKFCVITFH GKDGRVFWFI
IQKLDRVYTY PNAPRYSPND AAELCDKIQD VIIWRDITVG DLWKTKLVSS MTALEEGLFE
TWSLNRIVIL GDSVHKMTPN IGQGANTAIE DVAVLASLIN RVVHADALHK PSESCIETML
QKYKTLRYER AKSTYERSRF GARFHTRDNW LKALVGRYVF QYVGGLIENR TSKTLAGGNV
IDFLPRPHRL ETGCVTRLPK GQGRPQQQWT LLWVSSLVLF LFLPWLRSYL PSATFW
