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Database: UniProt
Entry: S4UX02
LinkDB: S4UX02
Original site: S4UX02 
ID   CYPH1_SALMI             Reviewed;         495 AA.
AC   S4UX02;
DT   29-OCT-2014, integrated into UniProtKB/Swiss-Prot.
DT   16-OCT-2013, sequence version 1.
DT   29-SEP-2021, entry version 29.
DE   RecName: Full=Ferruginol synthase {ECO:0000303|PubMed:23812755};
DE            EC=1.14.14.175 {ECO:0000269|PubMed:23812755, ECO:0000269|PubMed:24108414, ECO:0000269|PubMed:27703160};
DE   AltName: Full=Cytochrome P450 76AH1 {ECO:0000303|PubMed:23812755};
GN   Name=CYP76AH1 {ECO:0000303|PubMed:23812755};
OS   Salvia miltiorrhiza (Chinese sage).
OC   Eukaryota; Viridiplantae; Streptophyta; Embryophyta; Tracheophyta;
OC   Spermatophyta; Magnoliopsida; eudicotyledons; Gunneridae; Pentapetalae;
OC   asterids; lamiids; Lamiales; Lamiaceae; Nepetoideae; Mentheae; Salviinae;
OC   Salvia; Salvia incertae sedis.
OX   NCBI_TaxID=226208 {ECO:0000312|EMBL:AGN04215.1};
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, FUNCTION, CATALYTIC
RP   ACTIVITY, AND BIOTECHNOLOGY.
RX   PubMed=23812755; DOI=10.1073/pnas.1218061110;
RA   Guo J., Zhou Y.J., Hillwig M.L., Shen Y., Yang L., Wang Y., Zhang X.,
RA   Liu W., Peters R.J., Chen X., Zhao Z.K., Huang L.;
RT   "CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis
RT   and enables heterologous production of ferruginol in yeasts.";
RL   Proc. Natl. Acad. Sci. U.S.A. 110:12108-12113(2013).
RN   [2]
RP   CATALYTIC ACTIVITY.
RX   PubMed=24108414; DOI=10.1039/c3ob41885e;
RA   Zi J., Peters R.J.;
RT   "Characterization of CYP76AH4 clarifies phenolic diterpenoid biosynthesis
RT   in the Lamiaceae.";
RL   Org. Biomol. Chem. 11:7650-7652(2013).
RN   [3]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-301; ASN-303 AND
RP   VAL-479.
RX   PubMed=27703160; DOI=10.1038/ncomms12942;
RA   Scheler U., Brandt W., Porzel A., Rothe K., Manzano D., Bozic D.,
RA   Papaefthimiou D., Balcke G.U., Henning A., Lohse S., Marillonnet S.,
RA   Kanellis A.K., Ferrer A., Tissier A.;
RT   "Elucidation of the biosynthesis of carnosic acid and its reconstitution in
RT   yeast.";
RL   Nat. Commun. 7:12942-12942(2016).
RN   [4]
RP   X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) IN COMPLEX WITH HEME.
RX   PubMed=30837155; DOI=10.1016/j.bbrc.2019.02.103;
RA   Gu M., Wang M., Guo J., Shi C., Deng J., Huang L., Huang L., Chang Z.;
RT   "Crystal structure of CYP76AH1 in 4-PI-bound state from Salvia
RT   miltiorrhiza.";
RL   Biochem. Biophys. Res. Commun. 511:813-819(2019).
CC   -!- FUNCTION: Cytochrome P450 enzyme (CYP) which catalyzes a unique two-
CC       electron oxidation cascade on abieta-8,11,13-triene to produce
CC       ferruginol, an intermediate in tanshinone biosynthesis.
CC       {ECO:0000269|PubMed:23812755, ECO:0000269|PubMed:27703160}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=abieta-8,11,13-triene + O2 + reduced [NADPH--hemoprotein
CC         reductase] = ferruginol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:48080, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:78274,
CC         ChEBI:CHEBI:86062; EC=1.14.14.175;
CC         Evidence={ECO:0000269|PubMed:23812755, ECO:0000269|PubMed:24108414,
CC         ECO:0000269|PubMed:27703160};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48081;
CC         Evidence={ECO:0000269|PubMed:23812755, ECO:0000269|PubMed:24108414,
CC         ECO:0000269|PubMed:27703160};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000269|PubMed:30837155};
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC       Single-pass membrane protein {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Expression is more abundant in the rhizome.
CC       {ECO:0000269|PubMed:23812755}.
CC   -!- BIOTECHNOLOGY: Ferruginol is a widespread diterpenoid metabolite that
CC       serves as a bioactive natural product in its own right, and has been
CC       shown to exhibit a range of activities similar to that of the
CC       tanshinones such as anti-tumor and antibacterial properties. It
CC       therefore contributes to the medicinal effect of danshen.
CC       {ECO:0000303|PubMed:23812755}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family.
CC       {ECO:0000255|RuleBase:RU000461}.
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DR   EMBL; JX422213; AGN04215.1; -; mRNA.
DR   PDB; 5YLW; X-ray; 1.70 A; A=1-495.
DR   PDB; 5YM3; X-ray; 2.60 A; A=1-495.
DR   PDB; 7CB9; X-ray; 1.90 A; A=1-495.
DR   PDBsum; 5YLW; -.
DR   PDBsum; 5YM3; -.
DR   PDBsum; 7CB9; -.
DR   SMR; S4UX02; -.
DR   KEGG; ag:AGN04215; -.
DR   BRENDA; 1.14.14.175; 9850.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0016712; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; IDA:UniProtKB.
DR   GO; GO:0016102; P:diterpenoid biosynthetic process; IDA:UniProtKB.
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   1: Evidence at protein level;
KW   3D-structure; Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding;
KW   Monooxygenase; NADP; Oxidoreductase; Transmembrane; Transmembrane helix.
FT   CHAIN           1..495
FT                   /note="Ferruginol synthase"
FT                   /id="PRO_0000430706"
FT   TOPO_DOM        1
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VWZ7"
FT   TRANSMEM        2..22
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        23..495
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VWZ7"
FT   METAL           437
FT                   /note="Iron (heme axial ligand)"
FT                   /evidence="ECO:0000269|PubMed:30837155,
FT                   ECO:0007744|PDB:5YLW, ECO:0007744|PDB:5YM3"
FT   MUTAGEN         301
FT                   /note="D->E: Acquires ferruginol monooxygenase activity;
FT                   when associated with S-303 and F-479."
FT                   /evidence="ECO:0000269|PubMed:27703160"
FT   MUTAGEN         303
FT                   /note="N->S: Acquires ferruginol monooxygenase activity;
FT                   when associated with E-301 and F-479."
FT                   /evidence="ECO:0000269|PubMed:27703160"
FT   MUTAGEN         479
FT                   /note="V->F: Acquires ferruginol monooxygenase activity;
FT                   when associated with E-301 and S-303."
FT                   /evidence="ECO:0000269|PubMed:27703160"
FT   TURN            36..38
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           41..43
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           48..59
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          61..67
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          70..75
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           78..85
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   TURN            86..92
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           99..108
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   TURN            111..113
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           118..129
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   TURN            130..132
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           134..139
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           141..161
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           167..184
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           194..210
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           215..218
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           220..225
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           230..258
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           268..278
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           285..298
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           300..316
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           318..332
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           340..345
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           347..359
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          375..377
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          380..382
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          387..390
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           392..396
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   TURN            399..401
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          402..404
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           410..413
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          420..423
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           433..435
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           440..457
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          459..463
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   HELIX           468..473
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          478..480
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          482..485
FT                   /evidence="ECO:0007829|PDB:5YLW"
FT   STRAND          488..492
FT                   /evidence="ECO:0007829|PDB:5YLW"
SQ   SEQUENCE   495 AA;  55520 MW;  FB273F43A7D03A30 CRC64;
     MDSFPLLAAL FFIAATITFL SFRRRRNLPP GPFPYPIVGN MLQLGANPHQ VFAKLSKRYG
     PLMSIHLGSL YTVIVSSPEM AKEILHRHGQ VFSGRTIAQA VHACDHDKIS MGFLPVASEW
     RDMRKICKEQ MFSNQSMEAS QGLRRQKLQQ LLDHVQKCSD SGRAVDIREA AFITTLNLMS
     ATLFSSQATE FDSKATMEFK EIIEGVATIV GVPNFADYFP ILRPFDPQGV KRRADVFFGK
     LLAKIEGYLN ERLESKRANP NAPKKDDFLE IVVDIIQANE FKLKTHHFTH LMLDLFVGGS
     DTNTTSIEWA MSELVMNPDK MARLKAELKS VAGDEKIVDE SAMPKLPYLQ AVIKEVMRIH
     PPGPLLLPRK AESDQEVNGY LIPKGTQILI NAYAIGRDPS IWTDPETFDP ERFLDNKIDF
     KGQDYELLPF GSGRRVCPGM PLATRILHMA TATLVHNFDW KLEDDSTAAA DHAGELFGVA
     VRRAVPLRII PIVKS
//
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