RADH_FLOCH
ID RADH_FLOCH Reviewed; 520 AA.
AC C5H881;
DT 31-JAN-2018, integrated into UniProtKB/Swiss-Prot.
DT 28-JUL-2009, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Non-heme halogenase radH {ECO:0000303|PubMed:19101477};
DE EC=1.14.14.- {ECO:0000305|PubMed:19101477};
DE AltName: Full=Radicicol biosynthesis cluster protein radH {ECO:0000303|PubMed:19101477};
GN Name=radH {ECO:0000303|PubMed:19101477};
OS Floropilus chiversii (Chaetomium chiversii).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Sordariomycetidae; Sordariales; Chaetomiaceae; Floropilus.
OX NCBI_TaxID=2587399;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=CS-36-62;
RX PubMed=19101477; DOI=10.1016/j.chembiol.2008.10.006;
RA Wang S., Xu Y., Maine E.A., Wijeratne E.M., Espinosa-Artiles P.,
RA Gunatilaka A.A., Molnar I.;
RT "Functional characterization of the biosynthesis of radicicol, an Hsp90
RT inhibitor resorcylic acid lactone from Chaetomium chiversii.";
RL Chem. Biol. 15:1328-1338(2008).
CC -!- FUNCTION: Non-heme halogenase; part of the gene cluster that mediates
CC the biosynthesis of radicicol, a resorcylic acid lactone (RAL) that
CC irreversibly inhibits the HSP90 molecular chaperone, an important
CC target for cancer chemotherapy (PubMed:19101477). The cluster encodes
CC only two apparent post-PKS enzymes, a cytochrome P450 monooxygenase
CC (radP) and a non-heme halogenase (radH) that introduce the epoxide and
CC the chlorine, respectively (PubMed:19101477). If this cluster includes
CC all the genes required for radicicol biosynthesis, the remaining
CC structural features of radicicol are presumably generated by the PKSs
CC rads1 and rads2 (PubMed:19101477). The C-2' ketone could arise if the
CC R-PKS rads1 and NR-PKS rads2 each carry out four iterations, in
CC contrast to the five iteration-three iteration split for the
CC hypothemycin PKSs (By similarity). The origin of the cis 5',6' double
CC bond is not known (By similarity). The radicicol R-PKS rads1 ER domain
CC may catalyze either double bond isomerization or reduction in the third
CC iteration (By similarity). {ECO:0000250|UniProtKB:B3FWT7,
CC ECO:0000269|PubMed:19101477}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P95480};
CC Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:P95480};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:19101477}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of radicicol and
CC accumulates 6-dechloro-radicicol, also known as monocillin I
CC (PubMed:19101477). {ECO:0000269|PubMed:19101477}.
CC -!- BIOTECHNOLOGY: Radicicol is an important pharmacophore as an inhibitor
CC of heat shock protein 90 (Hsp90), an ATP-dependent chaperone involved
CC in the post-translational maturation and stabilization of over one
CC hundred proteins, and which activity has been implicated in diverse
CC pathologies ranging from oncology to neurodegenerative and infectious
CC diseases (PubMed:19101477). {ECO:0000305|PubMed:19101477}.
CC -!- SIMILARITY: Belongs to the flavin-dependent halogenase family.
CC {ECO:0000305}.
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DR EMBL; EU980390; ACM42402.1; -; Genomic_DNA.
DR AlphaFoldDB; C5H881; -.
DR SMR; C5H881; -.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR006905; Flavin_halogenase.
DR Pfam; PF04820; Trp_halogenase; 2.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 3: Inferred from homology;
KW FAD; Flavoprotein; Monooxygenase; Oxidoreductase.
FT CHAIN 1..520
FT /note="Non-heme halogenase radH"
FT /id="PRO_0000443045"
FT BINDING 14..17
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P95480"
FT BINDING 37..48
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P95480"
FT BINDING 330..331
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250|UniProtKB:P95480"
SQ SEQUENCE 520 AA; 56453 MW; 420793B520132F47 CRC64;
MSIPKSCEVL VAGGGPAGSY AASALAREGV DVVLLEADKH PRYHIGESML PSIRPLLRFI
DLEETFEKHG FQKKLGAAFK LTAKREGYTD FVAAHGPNGY SWNVVRSESD ELLFKHAAKS
GALTFQGVKV DSLEFEPYDS DFPSGGKVAN PGRPVAARWS AKDGRSGTIS FQYLVDATGR
AGITSTKYLK NRKFNEGLKN LAIWGYYKGA RPWAEGTPRE NQPYFEGMRD GAGWCWTIPL
HNGTVSVGAV LRSDLFFAKK KSLGEDVTNA MIMAECMKLC PTIKELLEPA ELVSDIKQAT
DYSYSASAYA GPYFRIVGDA GCFIDPFFSS GHHLAMAGAL AAAVSIRASM KGDCSEYEAS
NWHARKVDEG YTLFLLVVMA ALKQIRMQEE PVLSDIDDDG FDRAFQFLKP VIQGSGSAEI
VKRFTKKEVS EAIDFAVLAL DNMAGAGEHA NETNGSNGTG ETNGDAKTLE NITVEDEKVL
SGIRILAKVA PSADMKDLEG TAIDGFMPRL EHGHLGLNRV