SWNK_METRA
ID SWNK_METRA Reviewed; 2488 AA.
AC E9F8M3;
DT 30-AUG-2017, integrated into UniProtKB/Swiss-Prot.
DT 05-APR-2011, sequence version 1.
DT 03-AUG-2022, entry version 58.
DE RecName: Full=PKS-NRPS hybrid synthetase swnK {ECO:0000303|PubMed:28381497};
DE EC=2.3.1.- {ECO:0000269|PubMed:32786262};
DE AltName: Full=Swainsonine biosynthesis gene cluster protein K {ECO:0000303|PubMed:28381497};
GN Name=swnK {ECO:0000303|PubMed:28381497}; ORFNames=MAA_08622;
OS Metarhizium robertsii (strain ARSEF 23 / ATCC MYA-3075) (Metarhizium
OS anisopliae (strain ARSEF 23)).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Clavicipitaceae; Metarhizium.
OX NCBI_TaxID=655844;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ARSEF 23 / ATCC MYA-3075;
RX PubMed=21253567; DOI=10.1371/journal.pgen.1001264;
RA Gao Q., Jin K., Ying S.-H., Zhang Y., Xiao G., Shang Y., Duan Z., Hu X.,
RA Xie X.-Q., Zhou G., Peng G., Luo Z., Huang W., Wang B., Fang W., Wang S.,
RA Zhong Y., Ma L.-J., St Leger R.J., Zhao G.-P., Pei Y., Feng M.-G., Xia Y.,
RA Wang C.;
RT "Genome sequencing and comparative transcriptomics of the model
RT entomopathogenic fungi Metarhizium anisopliae and M. acridum.";
RL PLoS Genet. 7:E1001264-E1001264(2011).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=ARSEF 23 / ATCC MYA-3075;
RX PubMed=25368161; DOI=10.1073/pnas.1412662111;
RA Hu X., Xiao G., Zheng P., Shang Y., Su Y., Zhang X., Liu X., Zhan S.,
RA St Leger R.J., Wang C.;
RT "Trajectory and genomic determinants of fungal-pathogen speciation and host
RT adaptation.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:16796-16801(2014).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, DOMAIN, AND PATHWAY.
RX PubMed=28381497; DOI=10.1534/g3.117.041384;
RA Cook D., Donzelli B.G., Creamer R., Baucom D.L., Gardner D.R., Pan J.,
RA Moore N., Jaromczyk J.W., Schardl C.L.;
RT "Swainsonine biosynthesis genes in diverse symbiotic and pathogenic
RT fungi.";
RL G3 (Bethesda) 7:1791-1797(2017).
RN [4]
RP FUNCTION, DOMAIN, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=32786262; DOI=10.1021/acschembio.0c00466;
RA Luo F., Hong S., Chen B., Yin Y., Tang G., Hu F., Zhang H., Wang C.;
RT "Unveiling of Swainsonine Biosynthesis via a Multibranched Pathway in
RT Fungi.";
RL ACS Chem. Biol. 15:2476-2484(2020).
CC -!- FUNCTION: PKS-NRPS hybrid synthetase; part of the gene cluster that
CC mediates the biosynthesis of swainsonine (SW), a cytotoxic fungal
CC alkaloid and a potential cancer therapy drug (PubMed:28381497,
CC PubMed:32786262). Swainsonine production occurs via a multibranched
CC pathway and is dispensable for fungal colonization of plants and
CC infection of insect hosts (PubMed:32786262). The first step of
CC swainsonine biosynthesis is the production of the precursor pipecolic
CC acid (PA) via conversion of L-lysine (Lys) to 1-piperideine-6-
CC carboxylate (P6C) by the aminotransferase swnA, the latter being
CC further reduced to PA by the reductase swnR (PubMed:32786262). PA can
CC be converted from lysine by both the SW biosynthetic cluster and the
CC unclustered genes such as lysine cyclodeaminase (PubMed:32786262). The
CC PKS-NRPS hybrid synthetase swnK uptakes and condensates PA and malonyl-
CC CoA with and without skipping of the ketoreductase (KR) domain in order
CC to produce 3 intermediates, 1-oxoindolizidine, (1S)-1-hydroxyindolizin,
CC and (1R)-1-hydroxyindolizine; with the transisomer (1S)-1-
CC hydroxyindolizin being predominant (PubMed:32786262). The terminal
CC thioester reductase (TE) domain of swnK is involved in reduction of the
CC thioester bond to release the intermediate aldehydes (PubMed:32786262).
CC The oxidoreductase swnN could contribute to the reduction of 1-
CC oxoindolizidine to (1S)-1-hydroxyindolizin and (1R)-1-
CC hydroxyindolizine, contributing to the major route of SW production
CC (Probable). The dioxygenase swnH2 would be responsible for the
CC oxidization of (1R)-1-hydroxyindolizine into (1R,2S)-1,2-
CC dihydroxyindolizine and of (1S)-1-hydroxyindolizin to yield both
CC (1R,2S)-1,2-dihydroxyindolizine and (1S,2S)-1,2-dihydroxyindolizine
CC (PubMed:32786262). The dioxygenase swnH1 then performs the conversion
CC of the 1,2-dihydroxyindolizine epimers to SW (PubMed:32786262).
CC {ECO:0000269|PubMed:28381497, ECO:0000269|PubMed:32786262,
CC ECO:0000305|PubMed:32786262}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4 H(+) + L-pipecolate + malonyl-CoA + 2 NADPH = (8aS)-
CC octahydroindolizin-1-one + CO2 + CoA + 2 H2O + 2 NADP(+);
CC Xref=Rhea:RHEA:65392, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:61185,
CC ChEBI:CHEBI:167645; Evidence={ECO:0000269|PubMed:32786262};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:65393;
CC Evidence={ECO:0000269|PubMed:32786262};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5 H(+) + L-pipecolate + malonyl-CoA + 3 NADPH = (1R,8aS)-
CC octahydroindolizin-1-ol + CO2 + CoA + 2 H2O + 3 NADP(+);
CC Xref=Rhea:RHEA:67128, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:61185,
CC ChEBI:CHEBI:167675; Evidence={ECO:0000269|PubMed:32786262};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67129;
CC Evidence={ECO:0000269|PubMed:32786262};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5 H(+) + L-pipecolate + malonyl-CoA + 3 NADPH = (1S,8aS)-
CC octahydroindolizin-1-ol + CO2 + CoA + 2 H2O + 3 NADP(+);
CC Xref=Rhea:RHEA:67132, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:61185,
CC ChEBI:CHEBI:167676; Evidence={ECO:0000269|PubMed:32786262};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67133;
CC Evidence={ECO:0000269|PubMed:32786262};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:32786262}.
CC -!- DOMAIN: The architecture of swnK is the following one: adenylation (A),
CC phosphopantetheine-binding/thiolation (T), beta-ketoacyl synthase (KS),
CC malonyl-CoA:ACP transacylase (MAT), ketoreductase (KR) domain, and
CC thioester reductase (TE) domains. The presence and positions in swnK of
CC the 2 reductase domains, ketoeductase and thioester reductase, suggests
CC that the intermediate released from this enzyme has a hydroxyl group.
CC {ECO:0000305|PubMed:28381497, ECO:0000305|PubMed:32786262}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of swainsonine but does
CC not affect virulence. {ECO:0000269|PubMed:28381497,
CC ECO:0000269|PubMed:32786262}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; ADNJ02000001; EFY95969.1; -; Genomic_DNA.
DR RefSeq; XP_007824811.1; XM_007826620.1.
DR AlphaFoldDB; E9F8M3; -.
DR SMR; E9F8M3; -.
DR EnsemblFungi; EFY95969; EFY95969; MAA_08622.
DR GeneID; 19262908; -.
DR KEGG; maj:MAA_08622; -.
DR HOGENOM; CLU_000022_1_1_1; -.
DR Proteomes; UP000002498; Unassembled WGS sequence.
DR GO; GO:0016746; F:acyltransferase activity; IEA:InterPro.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
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; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR013120; Far_NAD-bd.
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; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR010080; Thioester_reductase-like_dom.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF13193; AMP-binding_C; 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 SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF51735; SSF51735; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR TIGRFAMs; TIGR01746; Thioester-redct; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Methyltransferase; Multifunctional enzyme; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2488
FT /note="PKS-NRPS hybrid synthetase swnK"
FT /id="PRO_0000441177"
FT DOMAIN 523..598
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2002..2077
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 33..422
FT /note="Adenylation (A) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28381497"
FT REGION 619..1042
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28381497"
FT REGION 1149..1471
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28381497"
FT REGION 1723..1901
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28381497"
FT REGION 2084..2103
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2136..2364
FT /note="Thioester reductase (TE) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28381497"
FT MOD_RES 558
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2037
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2488 AA; 266926 MW; DDF4F5C120420CF9 CRC64;
MSGISDHDYQ VLVNEFNATE DISLLGSRLD QLFEQVADRF PDNTAVIHNE SEVTFKQLNS
SANILARCLA KRGLQQGDVV GLAVSRSIDL IAAMLAVLKL GAAYVPIDPS FPAERINQMV
EDAGLRLILL SGRPTKGLGR WASLCLSVSE ARDGSVTDGT NLETEIQTRD LAYVIYTSGS
TGRPKGVEIS HGAAANFLSS LRKHEPGCSE RDRLLAITTI SFDMSALELL LPLVSGSAMI
VANTSAVKDP RELISLMARH KVTILQATPA TWTMLLESGW KGNPRLSKVI CGGEPLSRQL
ADRLLAAADS VWNVYGPSET TYGSVGRVGQ GDIVVGNPVA NGRIYVLDDN MSPVPIGSEG
EVYIGGGSVS NGYRNKAELT RSRFLVNPFH GGVFFRTGDL ARFIAPGKLQ VVGRIDGVVK
IRGHRIDVGD IEAVLVDHAN VSEAVVVSRD DRLVAYCVLH APCHDAASLD GILRPWVAER
LPAYMLPTFF VQMDALPLSP SEKVNRKALP DPIEAMQHQT MIQPTSELEQ RIQAIWSDIL
GHDRFGIEDN FFRIGGDSVR IIRMQAALEK QLHRPVPTPK LFEHYTIKAL AAYLAGTGRE
NNNESQAVSQ TFAGSHEDIA IVSMACRLPG GVATPEALWQ LLQSGGDTII DVPKDRWDAD
KLYNADANID GTSYCRRGGF LDAIYSYDAS FFGISPREAQ AMDPTHNLML ELCWEGFERS
GYTRDQLSGS ATGVFLGVSN NATTNGTPPD LKGYSITGSA SATMCGRLSH TLGLRGPSLA
VDTACSSSLV ATHLACNALR QGECSMALAG GVSLLTTPGI HIEFSKLGGL SADGRCRAFS
DDTDGTGFSE GAAIIVLKRL SDARRDGDDI HAVLRGTAVM HGGSSAGLTA PSGPGQVALL
RNALARAALE PGDIDYVEAH GTATKLGDPI EATALAEVFG TERSGSDPLR IGSAKSNLGH
TQAAAGVVGL LKVVLSMNHD TLPRTLHVRE PMAAVDWKRT NMELVLQNRP WLPNNNRLRR
AGVSAFGIGG TNAHVIVEES PPPAVEETGN ITLPSLPATL PFVLSGQGDS ALRAQAEKLR
LHIESGAGKD SPLRDVAYSL ATCRSHLHRR LVVMAGDKAE TLEKLASVSS GPTQPLSVNE
VGSPTVAMLF TGQGSQLPGM GKDLYAVYPV FRDALDEIAA KFTDLERPLL DIMWAESGSE
NAALLSRTDF AQPALFALEV SLWKLWQSWG VKPDFLLGHS VGELAAAHAA GVLDLSDACR
LVMMRGRLMQ AIPRQGKMAS VEASSAEVSA AIQELGQHDK VEIAGYNTPL QTVISGHEEA
VEATSVYMSK LGRKTKLLDT SHAFHSFHMN GMLDDLRALA QNIRFSPPKM RIISSMTGRL
AGAGELERPE YWAQQARNAV RFSDAFQTLA GQGANVFLEL GPSAMLCGLG AACLADPGQV
GAALWLPSLK PNMNGPLVIQ SSLSELHVRH VPVDWAAYFK PFDCKRVMLP TYAFQREDFR
PANKASWFDV ASLSTGTNDA APRVQDMMFE INWRRVETKS IQPRGAWGLL CPSGETAWTT
EAQRALLATG IQLVAVSKPH EADQLDGLLS LWDSDADTVQ MAHGVTALAL AQLQEAIRTG
LGAPIVWVTR HAVGAGADDR PVNIGAGPLW GLMRAARSEH PELRLRLIDV DEETDRASLS
QAIMLADQTE IAVRREQLLM PHMERAGLAA PLPVGQPFVR TDGAVLVTGG LGDLGSRVAR
RLATAHGVCD LVLVSRQGTN SPGADALVAE LAELGAKATI VGCDLADLDS LGSVMQLFTP
DRPLRGVVHA AGVVDSGTLS SLTPRKCAAV FAPKVDGLWN LHQLTKHMDL DLFMMFSSIS
GIIGLPGLGN YAAANSFIDS LAHLRRAQGL PASSVAYGTW AGDGMATTLV PTTRAHLSQL
GLGFLPPEAG LEIFEHAVYQ GRALTVAAVL DLQRLRAYYE EQGGVPPLLN SMLGGTKVQK
PADEVVNLRD LLADAAPEQH SSIVLHMVQA TIAKALGYTR AEDVDASRPM QELGIDSLTA
ILTRNHLATL TGMALPPNIA LLYPNLKSLS EFLLCRLMDD VESSTSSPSD TDGATPSTPT
SAASCVDMAD IRRGVLDSTF QFNNPVSPGV PGTVFVTGAT GFVGTFMIHE FLQRRISVYC
LVRASGSQEA QQRMITTLKQ YGLWRPEHEP LLVSVAGDLS QPLLGLGEVV FDDLASRVDA
ILHSGALVDW MRPLDDYIGP NVLGTHEVLR LASCGRAKAI HFISTISTLP IHAGYGLAEH
DGEYGYGTSK YLAEKMVVAA RFRGAKASSY RLPFVAASAA SGRFRLDRGD FLNNLVTGSL
DLGAFPLINA DLSSVLPVDY LCGTIAAIMT EDQERVGEDY DFVNPQALTF KHFFEMMCSV
SGGKEMVSFG EWHRRALEYA AAHPTSSLAR IATVLDGYND KTVGSLVSGS PVGKHVLGLD
AYRAPPLDEE YVRRYVHCIE AARAKMRT
