HIMA_ASPJA
ID HIMA_ASPJA Reviewed; 3970 AA.
AC A0A2Z5TM64;
DT 05-DEC-2018, integrated into UniProtKB/Swiss-Prot.
DT 10-OCT-2018, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=Polyketide synthase-nonribosomal peptide synthetase hybrid himA {ECO:0000303|PubMed:29314577};
DE Short=PKS-NRPS hybrid synthetase himA {ECO:0000303|PubMed:29314577};
DE EC=2.3.1.- {ECO:0000305|PubMed:29314577};
DE EC=6.3.2.- {ECO:0000305|PubMed:29314577};
DE AltName: Full=Himeic acid biosynthesis cluster protein A {ECO:0000303|PubMed:29314577};
GN Name=himA {ECO:0000303|PubMed:29314577};
OS Aspergillus japonicus.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=34381;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], DISRUPTION PHENOTYPE, FUNCTION, AND
RP PATHWAY.
RC STRAIN=MF275;
RX PubMed=29314577; DOI=10.1002/cbic.201700584;
RA Hashimoto M., Kato H., Katsuki A., Tsukamoto S., Fujii I.;
RT "Identification of the biosynthetic gene cluster for himeic acid A: a
RT ubiquitin-activating enzyme (E1) inhibitor in Aspergillus japonicus
RT MF275.";
RL ChemBioChem 19:535-539(2018).
RN [2]
RP FUNCTION.
RX PubMed=29486950; DOI=10.1016/j.bmc.2018.02.034;
RA Katsuki A., Kato H., Tahara Y., Hashimoto M., Fujii I., Tsukamoto S.;
RT "pH-dependent production of himeic acid A and its non-enzymatic conversions
RT to himeic acids B and C.";
RL Bioorg. Med. Chem. 26:1869-1874(2018).
CC -!- FUNCTION: Polyketide synthase-nonribosomal peptide synthetase hybrid;
CC part of the him gene cluster that mediates the biosynthesis of himeic
CC acid A, a ubiquitin-activating enzyme (E1) inhibitor (PubMed:29314577).
CC First, himA, together with the trans-enoyl reductase himH, catalyzes
CC the formation of apolyketide chain, which is then condensed with
CC leucine by the NRPS activity of himA. Dieckmann cyclization and release
CC from himA gives a tetramic acid intermediate as the product of himA
CC PKS-NRPS (PubMed:29314577). HimG then catalyzes alpha-oxidation of the
CC tetramic acid ring, with a subsequent rearrangement to yield apyrone
CC intermediate (Probable). Two terminal methyl groups of polyketide and
CC amide side chains are oxidized to carboxylic acids by himC cytochrome
CC P450 monooxygenase to form himeic acid A (Probable). Himeic acid A is
CC further converted to himeic acids B and C during culture growth. No
CC gene responsible for pyrone to pyridone conversion was found in the him
CC gene cluster and himeic acid A is non-enzymatically converted to himeic
CC acid C by the incorporation of an ammonium nitrogen atom in a pH5
CC buffer, and to himeic acid B at a conversion ratio of 50% during
CC incubation in MeOH for 5 days (PubMed:29486950).
CC {ECO:0000269|PubMed:29314577, ECO:0000269|PubMed:29486950,
CC ECO:0000305|PubMed:29314577}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:29314577}.
CC -!- DOMAIN: The PKS-NRPS himA consists of nine catalytic domains including
CC a ketoacyl synthase domain (KS), an acyl transferase domain (AT), a
CC dehydratase domain (DH), a ketoreductase domaion (KR), an acyl carrier
CC protein (ACP) domains, a condensation (C) domain, an adenylation (A)
CC domain, a thiolation (T) domain, and a releasing or Dieckmann
CC cyclization (R/D) domain. Because himA lacks a designated enoyl
CC reductase (ER) domain, the required ER activity is likely to be
CC provided by the free-standing ER himH. {ECO:0000305|PubMed:29314577}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of himeic
CC acid A. {ECO:0000269|PubMed:29314577}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; LC331673; BBA91557.1; -; Genomic_DNA.
DR SMR; A0A2Z5TM64; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
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; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR013120; Far_NAD-bd.
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; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 2.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
PE 3: Inferred from homology;
KW Ligase; Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Repeat;
KW Transferase.
FT CHAIN 1..3970
FT /note="Polyketide synthase-nonribosomal peptide synthetase
FT hybrid himA"
FT /id="PRO_0000445952"
FT DOMAIN 2342..2419
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:29314577"
FT DOMAIN 3496..3574
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:29314577"
FT REGION 11..446
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 561..876
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 949..1253
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 2060..2234
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 2420..2482
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2487..2919
FT /note="Condensation (C) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 2974..3381
FT /note="Adenylation (A) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT REGION 3466..3495
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 3633..3866
FT /note="Reductase (R) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29314577"
FT COMPBIAS 2440..2467
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 3474..3488
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2379
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3534
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3970 AA; 431760 MW; F44F3AE8CF8389F2 CRC64;
MAYIPSSSEP IAIIGSACRF PGHSTSPSRL WELLRNPYDL TKQVPEGRFN VDGFHHPDGE
HHGTTNAPNG YWLEEDPRRF DSTFFNITPK EAEAIDPQGK VLLEAVYEGL ESAGLTLEGC
SGSQVGVYVG TMTADYDILT GKDELTFSQY CATGTSRAII SNRVSYFFHW NGPSMTIDTA
CSSSLVAMHQ AVLGLRSGES TMACVAGANL MLSPEPFICE SSLHMLSPDG KSKMWDQSAD
GYARGEGVGV VFLKTLSRAL ADGDHIECIV RETGVNSDGR TKGITMPSSL AQAALIQDTY
RRSGLDALNP DHRCQYFEAH GTGTQAGDPT EAEAIYKAFF GEDEELQEDG SILVGSIKTI
IGHTEGAAGV AGVLKAALAL KHAQVPPNQH LKSMNPRVVP FTRRLHVPNT LIPWPSVRPG
HPLRASVNSF GFGGTNSHAI LESYVPAIHG GHLAASIEKP IEHPPGFPLV LSANSAEALK
DKVEQYIELL ESEPEIDLQD LAWTLATRRS ELPYRVSFSP VAGRERLLQE MRERLQTTEG
NSSLGVRSKT VNHERGRILG IFTGQGAQWP QMGQQLIQRS PRFKEVIQSL DAVLRSCPDP
PAWSIAHELL APPTSSRLSE AALSQPLCTA VQIALVDILH EAGVELAAAV GHSSGEIAAA
YAAGILTAPD AILIAYYRGF HAGLAQGPEG CRGGMMAVGM GVNEALEFCE QPAFLHHLHI
AASNSPASVT ISGDLEPLKQ AKALLDERGT FARLLKVDTA YHSHHMDRCA APYLQSLQAA
NIAPLSLTRS CVWVSSVYGP SGAPTLRELS GRYWKDNMVQ PVFFTEAVTR ALTEEGPFDM
ALEIGPHPAL QGPAVQTMQE VNGSALPYAG LLHRGRDDLA SVISTMGLIW SLLGSSSIDF
DALSVALGNE RSDCRVVKDL PSYPWDHTHM YHRQPRMAKQ YLNRPARPHE LLGVRTSDDT
ESEWRWRNLL KPSTLPWLKD HRFQDQIIVP AAAYCVMAFE AARALTTKPV KLVEIQNLSI
KRGITMSDDS QGVETIFMLR KEPTVPGEGV ISASFILDFV PGDADAQGTN AVKGMVHLHL
GEPSAETLPR RSLPPPSGLN RVDLDEFYGS IKDIGLGYTG PFRAMTSLQR RLDFATGTLP
KPHPAETSTL PVAPSLLDAC FQAAFAAYAA PGDGSLWTSF LPQEIQNIRF NLDLCPVNPG
PAATVNVDAV ITQFSSASPE SPANFSGDIC VFNANGNMEV QVEGLTVVAL SSTGPANDCE
LFIETVYKPD PYTGIVEART EGINEEYVAL QRACMRIADH FLHPNRTAGK PQQTPEAMQT
GLADSPFRGY LELLISCGRT APSRLPTAIT EILMHFNEQS ALQSHIRASV SQISHRFPQL
RVLEITLGEL QKYVTDAVVA GLAAPFHSYS HLFETTEKDA PSLLSAQTSI QDSRFRLLAF
DKTALLSEQF PDETFDLVIL SDGNRKNATL TSQLDGVHQL LAPGGYVFCV HSTGIPLQDR
LLNPQKHHQS LSLQTLLRAT PRVQGDFDLI SSWTSPLRTI ALSIRQSMSA DVRHLIMPLT
ATDVSYMSDT VLLIGGETGE TAQLSYQLAA ILRDKSLEVV TAPRLEDVVS TSMGTVKAVI
VLSDLDKPVL SSVNSSEFTA LKQILVPNMS VLWLTSGFRD DQPYHYGTVG LFRSIRTETP
QLKLQILDVA HISGAETVIA ECFLRLITYL DSESTPLWTS EPELVWDGQH LLIPRVLPID
DLNRRYNSTR RVVHNYQNAS LQVVQVVARW NGDRYTHHAV EATPSKASAP ADEHFVNLRV
LYSSAWAIEI KKGFHAFVSV ATDSASRHLL ALSPTNSSLI TIPATHVHAL PATGLDLSAL
LNRIVATLLA QSLLRQASPG GLLVHEADSF FADTLQRLND EVRLLCFSTT DLALDDNRFI
RLHPLSTKDA TKAAVPSSRI SSVADFSLGL TPTALVGLKS STCMLIKAMD SLVKTEASIL
DNGNALSTAQ DALLVVRWVV ETALEELGST RKPHTTTRVS DVLDKGLQPL GAVLDWTENV
HVPLRVNRFD PGSQMRGNKT YVMIGLTGEL GQSLCQFMVS HGARHLVVAS RNPDKSPAWK
TDLEKQGATI QVLSVDVTNV DAVRQLRVDL ETSMPPVGGI VNGAMVLSDG LFADMPVESL
QKALAPKVLG SQNLHDVFSD VDLDFFVMFS SLTGVPGNQG QSNYTAANMF MAGLAAQRRK
AGQAASVLDI GMVSGIGYIN RTDGAKIYAN LKRQGYMPIS ERDIHGMFIE AIHCGRPTST
TGAQLTTGLQ RFGVEGEEPL YWHTDPRFSH HRVLRNAVHK STVSSSVESL KSRISEVQSQ
TAIAAILTES FASHVEAMLH LDPGSLDKET AIINLGVDSL MAVEIRSWFL AEVEKDMPVL
KVLGGSSVAT LAEEVAKELF EDRSTSAPPP MDLDKNSFDL GSVHGSSTDP SSNSDSKSGF
DGFSSDDSSD IANDDSDPTA QCDQIEPMSL SQARMWLPYL MLQDKTAYNC TTSYRLIGQL
DIPRFERALR SLLQSHQAFR TLFYTDHETG EAMQAIVPTS STFSLRKVGS ANDSSDVKVE
HDRVAQHVYE LERGDSFIAT LVTHRPDYHT VIFGYHHIIL DGVSWQIFLQ ELDRFYADPQ
RRPSLGVDFL DFSTRQHHDL TSIPSLSKRQ FWKMTFASGS LPESLPLFPF AKAPARMPLT
QYRVTEYFVE LDRSLAAKIR SASTTNQTTA FHFYLSVFSV MMYRMLGVTD LCIGMTDANR
NDQAFLETIG LLLDMLPLRF RLDKTPSDES AFADHLRATR DIVYSALGNS GVPLETILQD
IGAESSATEL PLFQAVVNYR MGAIKHKSIG DLGLEYLSYE DAGHPFDFIL TIDEDEGRAG
LTLSMQDYLY DRAGANIFLD SYIHLLEFFA TTPTERVATP PAFAPALERT AIELGTGPRL
SDPWEEPTLV HRIDHMAAKY PSDVALGDER GSLSYKAMSD RVNAIATQLL AVGAQVSTRV
AVFGTPSTDN ICSLLAILRI GAIYVPCDVR SADERLRTIL TESEATVVIV NRETSSRFAK
FHPDTVQAVI QLATVPIQSS PVHNAATAAG LAFIMFTSGS TGTPKGIQLT HANFLTHVQA
ASAYMQLGRE VVLQQSAASY DASLAQIFYA LANGGRLVVA DNLRDTVALA SILEKEAVTF
TLMAPSEYLL LMEYTGDILA RCSEWKVAMC GGEAFPPRLK GDFGRLGHGE LSVYNAYGPT
EIAVASNIGE VAIPRKEAAG ESNDGDESHV PIGSALPEYN VYLVNEDIEP VPLGCPGQIA
VAGPAVSAGY LKNEPLTSDK FPLVGERFHP EKSTRVYLTG DLARMLSNGS MVYLGRIESD
TQIKLRGIRV ELGDIANAIL KTSRGVIANA AVGVRNPGPD QFLVAYVVLS GEKGTKRPAN
VRQYLDQLLV DLPLPQAMKP AVAVDVGSSL PMTSSGKLDM RALNARPLPA SGDEDGDEDT
ETETGADADA DAGADTTLSD IHSKLREIWN RALGGHTSIP ITPSSNFFAV GGSSLSLLKM
QALVQREFDL RIALPELFRT STFGAIAERI LRGVSAGFTE EEVEDTVPSS SPVDIIDWKK
ETALSETLRS LASSSQSDTR SPPMRRRPLT VILTGATGFL GRAIARALQA RDDVLHIHCI
AVRNPHSSAA LELERTCDKV ILHAGDLALP FLGMMEEEAR LVFEEADVIV HNGADVSFLK
SYQTLRGPNL RATQTLVEMT AHRQVPFHFV STAGVATTLS EGSSPVIDEI SLANHPPPTS
RTGDAVLIDG YVASKWASET FLEHVHAQLA LPVRIYRPSS ITGADAPALD VMHNVLNLSR
RMRALPDLGT WTGYFDFIRV ETVAEEIAAG VTASPTPTAT TPTPSGVEFI HLSGEKLIPV
AEARKHLERE TGYAFRTLEM AEWCREAAGY GLPALVAGYL ESLEGQALSF PRLRSRIAEW
GGGGREVVAV
