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