CYPH1_SALMI
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 03-AUG-2022, entry version 31.
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 AlphaFoldDB; S4UX02; -.
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 BINDING 437
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: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
