ID   LTMP_EPIFI              Reviewed;         498 AA.
AC   Q15FB5;
DT   23-MAY-2018, integrated into UniProtKB/Swiss-Prot.
DT   25-JUL-2006, sequence version 1.
DT   03-AUG-2022, entry version 51.
DE   RecName: Full=Cytochrome P450 monooxygenase ltmP {ECO:0000303|PubMed:16765617};
DE            EC=1.-.-.- {ECO:0000305|PubMed:16765617};
DE   AltName: Full=Lolitrem B biosynthesis cluster 2 protein P {ECO:0000303|PubMed:16765617};
DE   Flags: Precursor;
GN   Name=ltmP {ECO:0000303|PubMed:16765617};
OS   Epichloe festucae var. lolii (Neotyphodium lolii) (Acremonium lolii).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Hypocreomycetidae; Hypocreales; Clavicipitaceae; Epichloe.
OX   NCBI_TaxID=73839;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=Lp19;
RX   PubMed=16765617; DOI=10.1016/j.fgb.2006.04.004;
RA   Young C.A., Felitti S., Shields K., Spangenberg G., Johnson R.D.,
RA   Bryan G.T., Saikia S., Scott B.;
RT   "A complex gene cluster for indole-diterpene biosynthesis in the grass
RT   endophyte Neotyphodium lolii.";
RL   Fungal Genet. Biol. 43:679-693(2006).
RN   [2]
RP   FUNCTION.
RC   STRAIN=Lp19;
RX   PubMed=15991026; DOI=10.1007/s00438-005-1130-0;
RA   Young C.A., Bryant M.K., Christensen M.J., Tapper B.A., Bryan G.T.,
RA   Scott B.;
RT   "Molecular cloning and genetic analysis of a symbiosis-expressed gene
RT   cluster for lolitrem biosynthesis from a mutualistic endophyte of perennial
RT   ryegrass.";
RL   Mol. Genet. Genomics 274:13-29(2005).
RN   [3]
RP   INDUCTION.
RX   PubMed=20519633; DOI=10.1104/pp.110.158451;
RA   Eaton C.J., Cox M.P., Ambrose B., Becker M., Hesse U., Schardl C.L.,
RA   Scott B.;
RT   "Disruption of signaling in a fungal-grass symbiosis leads to
RT   pathogenesis.";
RL   Plant Physiol. 153:1780-1794(2010).
RN   [4]
RP   FUNCTION, AND PATHWAY.
RX   PubMed=22750140; DOI=10.1016/j.febslet.2012.06.035;
RA   Saikia S., Takemoto D., Tapper B.A., Lane G.A., Fraser K., Scott B.;
RT   "Functional analysis of an indole-diterpene gene cluster for lolitrem B
RT   biosynthesis in the grass endosymbiont Epichloe festucae.";
RL   FEBS Lett. 586:2563-2569(2012).
CC   -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene clusters that
CC       mediates the biosynthesis of lolitrems, indole-diterpene mycotoxins
CC       that are potent tremorgens in mammals, and are synthesized by
CC       clavicipitaceous fungal endophytes in association with their grass
CC       hosts (PubMed:16765617, PubMed:22750140). The geranylgeranyl
CC       diphosphate (GGPP) synthase ltmG is proposed to catalyze the first step
CC       in lolitrem biosynthesis (PubMed:16765617, PubMed:15991026). LtmG
CC       catalyzes a series of iterative condensations of isopentenyl
CC       diphosphate (IPP) with dimethylallyl diphosphate (DMAPP), geranyl
CC       diphosphate (GPP), and farnesyl diphosphate (FPP), to form GGPP
CC       (PubMed:16765617, PubMed:15991026). GGPP then condenses with indole-3-
CC       glycerol phosphate to form 3-geranylgeranylindole, an acyclic
CC       intermediate, to be incorporated into paxilline (PubMed:16765617).
CC       Either ltmG or ltmC could be responsible for this step, as both are
CC       putative prenyl transferases (PubMed:16765617). The FAD-dependent
CC       monooxygenase ltmM then catalyzes the epoxidation of the two terminal
CC       alkenes of the geranylgeranyl moiety, which is subsequently cyclized by
CC       ltmB, to paspaline (PubMed:16765617, PubMed:15991026). The cytochrome
CC       P450 monooxygenases ltmQ and ltmP can sequentially oxidize paspaline to
CC       terpendole E and terpendole F (PubMed:22750140). Alternatively, ltmP
CC       converts paspaline to an intermediate which is oxidized by ltmQ to
CC       terpendole F (PubMed:22750140). LtmF, ltmK, ltmE and ltmJ appear to be
CC       unique to the epichloe endophytes (PubMed:16765617, PubMed:15991026).
CC       The prenyltransferase ltmF is involved in the 27-hydroxyl-O-prenylation
CC       (PubMed:22750140). The cytochrome P450 monooxygenase ltmK is required
CC       for the oxidative acetal ring formation (PubMed:22750140). The multi-
CC       functional prenyltransferase ltmE is required for C20- and C21-
CC       prenylations of the indole ring of paspalanes and acts together with
CC       the cytochrome P450 monooxygenase ltmJ to yield lolitremanes by
CC       multiple oxidations and ring closures (PubMed:22750140). The
CC       stereoisomer pairs of lolitriol and lolitrem N or lolitrem B and
CC       lolitrem F may be attributed to variations in the way in which ring
CC       closure can occur under the action of ltmJ (PubMed:22750140). While the
CC       major product of this pathway is lolitrem B, the prenyl transferases
CC       and cytochrome P450 monooxygenases identified in this pathway have a
CC       remarkable versatility in their regio- and stereo-specificities to
CC       generate a diverse range of metabolites that are products of a
CC       metabolic grid rather than a linear pathway (PubMed:22750140).
CC       {ECO:0000269|PubMed:15991026, ECO:0000269|PubMed:16765617,
CC       ECO:0000269|PubMed:22750140}.
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:22750140}.
CC   -!- INDUCTION: Expression is down-regulated when the stress-activated
CC       mitogen-activated protein kinase (sakA) is deleted (PubMed:20519633).
CC       {ECO:0000269|PubMed:20519633}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; DQ443465; ABF20222.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q15FB5; -.
DR   SMR; Q15FB5; -.
DR   GO; GO:0020037; F:heme binding; IEA:InterPro.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR   GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR   Gene3D; 1.10.630.10; -; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00465; EP450IV.
DR   SUPFAM; SSF48264; SSF48264; 1.
PE   2: Evidence at transcript level;
KW   Glycoprotein; Heme; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Signal.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   CHAIN           22..498
FT                   /note="Cytochrome P450 monooxygenase ltmP"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000444333"
FT   BINDING         435
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:0000250|UniProtKB:P04798"
FT   CARBOHYD        420
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ   SEQUENCE   498 AA;  56978 MW;  C67E0EA824111197 CRC64;
     MLMLHAVPVG ICLLLWYVVY GTKRKECIPT IRRWPRLLPQ FLDRLSYNDH AARLVKHGYE
     KHKNQPFRLL KMDMDLIVIP LQYALELRAV TSDKLDPLTA SFDDNAGKVT RILLGSELHT
     RAIQQRLTPK LPQTLPVLLD ELNHAFGQVL PAGNDGSNAW ISVNPYELVL NLATRATARL
     FVGDLICRNE IFLETTASFS RNTFDTISTS RSFGNLFTHY FARWISTAKE AHGQLQYIQN
     LLGSEVQRRK LNSEEKHDDF LQWCTELAVT EDEARPEALA HRTLGILSMA VIHTTAMALT
     HILFDMISDD SLKESLRREQ QNVLKHGWTE ITQQTMLDMK QLDSLMRESQ RINPVGEFTF
     RRIVRERITL SDGYQLQPGQ QIAIPAKCIN TDSTKLSDAH LFQPFRWLKQ SGTATTSFSN
     SSALNLHFGF GRYACPGRFI ASYMIKAIMS RILLEYDFKL DSEFPSRRPP NIVHGDKILP
     NRNAVVLLRR LEKTVTVC