ADRH_PENRW
ID ADRH_PENRW Reviewed; 451 AA.
AC B6HV36;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 1.
DT 03-AUG-2022, entry version 61.
DE RecName: Full=FAD-dependent monooxygenase adrH {ECO:0000303|Ref.2};
DE EC=1.-.-.- {ECO:0000305|Ref.2};
DE AltName: Full=Andrastin A biosynthesis cluster protein H {ECO:0000303|Ref.2};
GN Name=adrH {ECO:0000303|Ref.2}; ORFNames=Pc22g22890;
OS Penicillium rubens (strain ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin
OS 54-1255) (Penicillium chrysogenum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium;
OC Penicillium chrysogenum species complex.
OX NCBI_TaxID=500485;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255;
RX PubMed=18820685; DOI=10.1038/nbt.1498;
RA van den Berg M.A., Albang R., Albermann K., Badger J.H., Daran J.-M.,
RA Driessen A.J.M., Garcia-Estrada C., Fedorova N.D., Harris D.M.,
RA Heijne W.H.M., Joardar V.S., Kiel J.A.K.W., Kovalchuk A., Martin J.F.,
RA Nierman W.C., Nijland J.G., Pronk J.T., Roubos J.A., van der Klei I.J.,
RA van Peij N.N.M.E., Veenhuis M., von Doehren H., Wagner C., Wortman J.R.,
RA Bovenberg R.A.L.;
RT "Genome sequencing and analysis of the filamentous fungus Penicillium
RT chrysogenum.";
RL Nat. Biotechnol. 26:1161-1168(2008).
RN [2]
RP IDENTIFICATION, FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX DOI=10.1016/j.tet.2013.07.029;
RA Matsuda Y., Awakawa T., Abe I.;
RT "Reconstituted biosynthesis of fungal meroterpenoid andrastin A.";
RL Tetrahedron 69:8199-8204(2013).
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 (Ref.2). The
CC first step of the pathway is the synthesis of 3,5-dimethylorsellinic
CC acid (DMOA) by the polyketide synthase adrD via condensation of one
CC acetyl-CoA starter unit with 3 malonyl-CoA units and 2 methylations
CC (Ref.2). DMAO is then converted to farnesyl-DMAO by the
CC prenyltransferase adrG (Ref.2). The methyltransferase adrK catalyzes
CC the methylation of the carboxyl group of farnesyl-DMAO to farnesyl-DMAO
CC methyl ester which is further converted to epoxyfarnesyl-DMAO methyl
CC ester by the FAD-dependent monooxygenase adrH (Ref.2). The terpene
CC cyclase adrI then catalyzes the carbon skeletal rearrangement to
CC generate the andrastin E, the first compound in the pathway having the
CC andrastin scaffold, with the tetracyclic ring system (Ref.2). The post-
CC cyclization tailoring enzymes adrF, adrE, adrJ, and adrA, are involved
CC in the 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 (Ref.2). {ECO:0000269|Ref.2}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000305|Ref.2}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AM920437; CAP99577.1; -; Genomic_DNA.
DR RefSeq; XP_002566183.1; XM_002566137.1.
DR AlphaFoldDB; B6HV36; -.
DR SMR; B6HV36; -.
DR STRING; 1108849.XP_002566183.1; -.
DR EnsemblFungi; CAP99577; CAP99577; PCH_Pc22g22890.
DR GeneID; 8309015; -.
DR KEGG; pcs:Pc22g22890; -.
DR VEuPathDB; FungiDB:PCH_Pc22g22890; -.
DR eggNOG; KOG2614; Eukaryota.
DR HOGENOM; CLU_009665_12_2_1; -.
DR OMA; EHANIEY; -.
DR OrthoDB; 462247at2759; -.
DR BioCyc; PCHR:PC22G22890-MON; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000000724; Contig Pc00c22.
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 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Membrane; Monooxygenase; Oxidoreductase;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..451
FT /note="FAD-dependent monooxygenase adrH"
FT /id="PRO_0000446492"
FT TRANSMEM 426..446
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 221..223
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 288
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 298..302
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 385
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 451 AA; 50721 MW; 983BBA8C9E2A7283 CRC64;
MADSMETHKF KVIIVGGSIA GLTLAHSLSK ANIDHIVIEK RAEIAPQEGA FIGVWPNGAQ
ILDQLGLYQS LEELTAPISR MHLSFPDDYS FSSFLPKTIH ERFKYPIVSL DRQKVLEILF
QNYPDKSNII TNQRVSEVRL LGDSASVVTE DGSVFRGDLI VGADGVHSPL TVEYACVFGI
SRPIPGLRSG EHINHYGDKF CVITFHGKDG RVFWFIIQKL DRVYTYPNAP RYSPNDAADL
CGKMQNVVIW QDITVGDLWK TKVVASMTAL EEGIFETWSL NRIVILGDSV HKMTPNIGQG
ANTAIEDVAV LASLINRMIH ADDLNKPSES CIETMLQEYK SLRYEPAKST YQRSRFGARF
HTRDSWLKAV VGRYVFQYVG GLIENRTIKT LAGGDTIDFL PRPDRLETGR VAQFQKSEES
PQRQWTLLWV SSLALFLFFP WLGSYLHSTI S
