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PRHL_PENBI
ID   PRHL_PENBI              Reviewed;        2475 AA.
AC   A0A1E1FFN8;
DT   26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT   18-JAN-2017, sequence version 1.
DT   03-AUG-2022, entry version 20.
DE   RecName: Full=Non-reducing polyketide synthase prhL {ECO:0000303|PubMed:27602587};
DE            EC=2.3.1.- {ECO:0000250|UniProtKB:Q5ATJ7};
DE   AltName: Full=Paraherquonin biosynthesis cluster protein L {ECO:0000303|PubMed:27602587};
GN   Name=prhL {ECO:0000303|PubMed:27602587};
OS   Penicillium brasilianum.
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=104259;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC   STRAIN=ATCC 22354 / NBRC 6234 / CBS 338.59 / FRR 3454 / IMI 68220;
RX   PubMed=27602587; DOI=10.1021/jacs.6b08424;
RA   Matsuda Y., Iwabuchi T., Fujimoto T., Awakawa T., Nakashima Y., Mori T.,
RA   Zhang H., Hayashi F., Abe I.;
RT   "Discovery of key dioxygenases that diverged the paraherquonin and
RT   acetoxydehydroaustin pathways in Penicillium brasilianum.";
RL   J. Am. Chem. Soc. 138:12671-12677(2016).
RN   [2]
RP   FUNCTION.
RX   PubMed=28759016; DOI=10.1038/nchembio.2443;
RA   Mori T., Iwabuchi T., Hoshino S., Wang H., Matsuda Y., Abe I.;
RT   "Molecular basis for the unusual ring reconstruction in fungal
RT   meroterpenoid biogenesis.";
RL   Nat. Chem. Biol. 13:1066-1073(2017).
RN   [3]
RP   FUNCTION.
RX   PubMed=29317628; DOI=10.1038/s41467-017-02371-w;
RA   Nakashima Y., Mori T., Nakamura H., Awakawa T., Hoshino S., Senda M.,
RA   Senda T., Abe I.;
RT   "Structure function and engineering of multifunctional non-heme iron
RT   dependent oxygenases in fungal meroterpenoid biosynthesis.";
RL   Nat. Commun. 9:104-104(2018).
CC   -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC       that mediates the biosynthesis of paraherquonin, a meroterpenoid with a
CC       unique, highly congested hexacyclic molecular architecture
CC       (PubMed:27602587). The first step of the pathway is the synthesis of
CC       3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase prhL (By
CC       similarity). Synthesis of DMOA is followed by farnesylation by the
CC       prenyltransferase prhE, methylesterification by the methyl-transferase
CC       prhM, epoxidation of the prenyl chain by the flavin-dependent
CC       monooxygenase prhF, and cyclization of the farnesyl moiety by the
CC       terpene cyclase prhH, to yield the tetracyclic intermediate,
CC       protoaustinoid A (By similarity). The short chain dehydrogenase prhI
CC       then oxidizes the C-3 alcohol group of the terpene cyclase product to
CC       transform protoaustinoid A into protoaustinoid B (PubMed:27602587). The
CC       FAD-binding monooxygenase prhJ catalyzes the oxidation of
CC       protoaustinoid B into preaustinoid A which is further oxidized into
CC       preaustinoid A1 by FAD-binding monooxygenase phrK (PubMed:27602587).
CC       Finally, prhA leads to berkeleydione via the berkeleyone B intermediate
CC       (PubMed:27602587, PubMed:29317628). PrhA is a multifunctional
CC       dioxygenase that first desaturates at C5-C6 to form berkeleyone B,
CC       followed by rearrangement of the A/B-ring to form the cycloheptadiene
CC       moiety in berkeleydione (PubMed:27602587, PubMed:29317628).
CC       Berkeleydione serves as the key intermediate for the biosynthesis of
CC       paraherquonin as well as many other meroterpenoids (Probable). The
CC       cytochrome P450 monooxygenases prhB, prhD, and prhN, as well as the
CC       isomerase prhC, are probably involved in the late stage of
CC       paraherquonin biosynthesis, after the production of berkeleydione
CC       (Probable). Especially prhC might be a multifunctional enzyme that
CC       catalyzes the D-ring expansion via intramolecular methoxy
CC       rearrangement, as well as the hydrolysis of the expanded D-ring
CC       (Probable). {ECO:0000250|UniProtKB:Q5ATJ7, ECO:0000269|PubMed:27602587,
CC       ECO:0000269|PubMed:29317628, ECO:0000305|PubMed:27602587,
CC       ECO:0000305|PubMed:28759016, ECO:0000305|PubMed:29317628}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=acetyl-CoA + 3 malonyl-CoA + 2 S-adenosyl-L-methionine = 3,5-
CC         dimethylorsellinate + 3 CO2 + 4 CoA + 2 S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:49628, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57856,
CC         ChEBI:CHEBI:59789, ChEBI:CHEBI:131856;
CC         Evidence={ECO:0000250|UniProtKB:Q5ATJ7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49629;
CC         Evidence={ECO:0000250|UniProtKB:Q5ATJ7};
CC   -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC       {ECO:0000305|PubMed:27602587}.
CC   -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC       (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC       repeated decarboxylative condensation to elongate the polyketide
CC       backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC       transfers the extender unit malonyl-CoA; a product template (PT) domain
CC       that controls the immediate cyclization regioselectivity of the
CC       reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC       serves as the tether of the growing and completed polyketide via its
CC       phosphopantetheinyl arm. {ECO:0000305|PubMed:27602587}.
CC   -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC       polyketide synthase is mediated by the thioesterase (TE) domain
CC       localized at the C-terminus of the protein.
CC       {ECO:0000305|PubMed:27602587}.
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DR   EMBL; LC127182; BAV69313.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A1E1FFN8; -.
DR   SMR; A0A1E1FFN8; -.
DR   UniPathway; UPA00213; -.
DR   GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR   GO; GO:0016787; F:hydrolase activity; IEA:InterPro.
DR   GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR   GO; GO:0032259; P:methylation; 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; 1.10.1200.10; -; 1.
DR   Gene3D; 3.10.129.110; -; 1.
DR   Gene3D; 3.40.366.10; -; 2.
DR   Gene3D; 3.40.47.10; -; 1.
DR   Gene3D; 3.40.50.150; -; 1.
DR   Gene3D; 3.40.50.1820; -; 1.
DR   InterPro; IPR029058; AB_hydrolase.
DR   InterPro; IPR013094; AB_hydrolase_3.
DR   InterPro; IPR001227; Ac_transferase_dom_sf.
DR   InterPro; IPR036736; ACP-like_sf.
DR   InterPro; IPR014043; Acyl_transferase.
DR   InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR   InterPro; IPR041068; HTH_51.
DR   InterPro; IPR018201; Ketoacyl_synth_AS.
DR   InterPro; IPR014031; Ketoacyl_synth_C.
DR   InterPro; IPR014030; Ketoacyl_synth_N.
DR   InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR   InterPro; IPR013217; Methyltransf_12.
DR   InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR   InterPro; IPR020807; PKS_dehydratase.
DR   InterPro; IPR042104; PKS_dehydratase_sf.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   InterPro; IPR016039; Thiolase-like.
DR   Pfam; PF07859; Abhydrolase_3; 1.
DR   Pfam; PF00698; Acyl_transf_1; 1.
DR   Pfam; PF18558; HTH_51; 1.
DR   Pfam; PF00109; ketoacyl-synt; 1.
DR   Pfam; PF02801; Ketoacyl-synt_C; 1.
DR   Pfam; PF08242; Methyltransf_12; 1.
DR   Pfam; PF00550; PP-binding; 1.
DR   Pfam; PF14765; PS-DH; 1.
DR   SMART; SM00827; PKS_AT; 1.
DR   SMART; SM00825; PKS_KS; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   SUPFAM; SSF52151; SSF52151; 1.
DR   SUPFAM; SSF53335; SSF53335; 1.
DR   SUPFAM; SSF53474; SSF53474; 1.
DR   SUPFAM; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR   PROSITE; PS50075; CARRIER; 1.
PE   3: Inferred from homology;
KW   Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW   Phosphoprotein; Transferase.
FT   CHAIN           1..2475
FT                   /note="Non-reducing polyketide synthase prhL"
FT                   /id="PRO_0000449176"
FT   DOMAIN          1626..1703
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          14..253
FT                   /note="N-terminal acylcarrier protein transacylase domain
FT                   (SAT)"
FT                   /evidence="ECO:0000255"
FT   REGION          384..747
FT                   /note="Ketosynthase (KS) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          910..1212
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1282..1585
FT                   /note="Product template (PT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1865..2098
FT                   /note="Methyltransferase (CMeT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          2127..2475
FT                   /note="Thioesterase (TE) domain"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        549
FT                   /note="For beta-ketoacyl synthase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        997
FT                   /note="For acyl/malonyl transferase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        2250
FT                   /note="For thioesterase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT   ACT_SITE        2412
FT                   /note="For thioesterase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT   MOD_RES         1663
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   2475 AA;  269599 MW;  1642A842F0C3576B CRC64;
     MGSLGDLPLN RISVLFGSKY SEIDRSALHI RRYLSTHRAA TWLEGAVEDL PSVWQDVTKV
     WPAGEGIHGE ARLQQLSAFL RGEGLPSNME DPMNYLLMPI TVLRHLVDFH EFKEAGVNCD
     IKSMQGFCAG YLAAVAACWE KDQSEFSKVV ATMVRTAIFI GAAVDLDELA TQRATSIAVR
     WKTAEAYKPF AATLGRYPGA YMACITDESS VTVTVWEDQA AALVQELERN GLLVKDTRLR
     GRFHHADHLS AAQDILKLCQ QDSRFQLPDT CPAEELPRSN ADGDLPTLKS LLSAAIQSIL
     ITQADWNLTV SNTLNSLDSS DAKCILSIGA GQFLPRQARS QILNITDSSR GDNLVNGDHD
     SMTITNGASF VADSINGTAP VPTSIPIAVT GLACRYPQAD CVEELWKILE QGLCTVSRMP
     ESRLKPDRLQ RKPDGPFWGN FISRPDAFDH RFFKISAREA ESMDPQQRLL LQVAYEAMES
     AGYCGLRATN LPEDVGCYVG VGTEDYSENV GSRNATAFSA TGTLQAFNSG RVSHHFGWTG
     PSVTVDTACS SAAVAIHLAC QALQTSDCSV AVAGGVNVMT DPRWSQNLAA ASFLSPTGAS
     KAFDANANGY CRGEGAGLVI LRPLEAALRD GDPIHAVITG TSVNQGANCS PITVPDSNSQ
     RSLYMKALSL SGLKPEVVSY VEAHGTGTQV GDPIEFESIR KTFAVPSRTE RLYVGSIKDN
     IGHTETSSGV AGLLKTILML QKGKIPKQAN FTQLNPKITV NQEDKMSIPT SSILWKTQKR
     VAMVTNYGAA GSNAAIVLKE PISTPRALCS DEKERLPSVV PFFVAAQTDE SLRAYCQTLK
     ASLLNGAHLE SIAVQDLAFN LARKQNRSME FSVSFTNSSS LTELHDRLDD VISGRMNIEK
     KTHTSNPVVL CFGGQTGNKA SISESLVASS ALLRLHLDEC ESACKALGLP SLFPAIFDSS
     PNNDIVNLHC VLFSIQYATA KAWIDSGLKV DRMIGHSFGQ LTAVCVAGGL SLIDTMQLIS
     TRAHLIRSEW TSEIGVMLSL KGEKNAVREL LDSVPESADL ACVNGADSFV AAGSEVAIHE
     IQKNAAERGI KSQRLDNTHA FHSRLVDPIL PGLAKVASTL NYKPLRIPVE ACSESEDDWL
     LPTWEKIVQH SRKPVYFHQA VHRTISRIQG PAIWLEAGTM SPIIGMVRRA VDTPSSVQGH
     VFCPMDLSGP QAESNLAKIT SSLWSNGVPV QFWPFHSSQR GYQWINLPPY QFAKTSHWIE
     YDPTAFSYQI SKHEEPLTEG LKLVQLLKNE GKVSLFRIND NDPMFRMCTA GHAVVEQNLC
     PASLYFELVA RAATTTLPKG TDPTMYHLAD LNISAPLVLD MPGSVLLELT QRDSTPGQWA
     FVLFTREDTL QSVTHATGTI SLSPGANNTG ISSRFSSLKR LLNPAHWDSI ATSPSSSGLK
     RSTVYQAFRR AVTYAEYYRG VESVYALGHE ATGRVNLPSS PTKNSPCDPI LIDNFIQVAG
     IHVNCLSETH DDEVFVCSSV GDVIIGESFV KRDPSVATPW VVYSNYEQES RKKALCDVFV
     VDEATGSLAL CVLAATFTSV SIQSLRRTLT RLTNKGVSPV PVDIAVAAEV APAVPAASLI
     TATRASSNGD DLRTVQAMLS ELLGIPASEI PASASLADVG VDSLMNTEVL SEIKNRFQVV
     ITKSELTAIE DVGALVQRIF PGRSTVHIET HAQPAVGITA INGGSKPSSR GSVPASRVGD
     DLSGFADKAG ELFTASRKSN EHSKATQFLG FCDTVFPQQM ELVTAYVVEA FKALGVDLQS
     LNAGQPIPSV DILPQHSQVM NQLYAVLEYS GLIERSGTSF CRGHCEVNQN ATPVLHQRIL
     NDHPHHTSEH KLLHTTGPRL ADCLTGAADP LSLLFQDAQA RALMQDVYSN APMFKSATMH
     LAQYLKNLLS QVNSPRPIKI LEIGAGTGGT TDYLLKQLSS VAGLCFEYTF TDISPSLVTL
     ARKRFKTFNS IHYQTLDIEK GPTSEMLGQY DIIVSSNCIH ATRSLSTSCS NIQKLLRPQG
     ILCLIELTRN LFWFDLVFGL LEGWWLFNDG RSHALAHESF WDRTLRSSGF NWVDWTDNQS
     EESNILRLIV ASPTRPALSL EATMESSDIH EETVVYGRKD DLDLLADIYY PQILDSDGKS
     RPVALLIHGG GHIMLSRKDV RHTQVQLLID MGFLPVSIDY RLCPEVSLLE GPMADACEAL
     AWAQSTLPQL NLQRPDIRPD GNNVVAVGWS SGGHLAMTLA WTAPARGLRA PSAVLSFYCA
     TDYTDPFWTK PNFPYQGDVS IEDVPTQSPF LGLNDRAITS YNPAPSKRAL GGWMSPSDPR
     SMIALHMNWT GQTLSVLFNG HKYKSLVAIA GGDDNVILPK PTLSEIQKAC PLSHVCAGRY
     KSPTFIIHGT LDDLIPVEQS QRTHDQMLAN GVESELRVVA DAPHLFDMSP NLKNNKDAFR
     AVADGYEFLR SHVRL
 
 
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