MFL1_PHOSM
ID MFL1_PHOSM Reviewed; 1327 AA.
AC A0A3G1DJF1;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 25-MAY-2022, entry version 8.
DE RecName: Full=Squalestatin S1 biosynthesis cluster protein L1 {ECO:0000303|PubMed:27056201};
DE Flags: Precursor;
GN Name=L1 {ECO:0000303|PubMed:27056201};
OS Phoma sp. (strain ATCC 20986 / MF5453).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Didymellaceae; Phoma.
OX NCBI_TaxID=1828523;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RX PubMed=27056201; DOI=10.1039/c6cc02130a;
RA Bonsch B., Belt V., Bartel C., Duensing N., Koziol M., Lazarus C.M.,
RA Bailey A.M., Simpson T.J., Cox R.J.;
RT "Identification of genes encoding squalestatin S1 biosynthesis and in vitro
RT production of new squalestatin analogues.";
RL Chem. Commun. (Camb.) 52:6777-6780(2016).
CC -!- FUNCTION: Part of the gene cluster that mediates the biosynthesis of
CC squalestatin S1 (SQS1, also known as zaragozic acid A), a lead compound
CC for the treatment of hyper-cholesterolemia by targeting squalene
CC synthase (SS) (PubMed:27056201). Both phenylalanine and benzoic acid
CC are known precursors of SQS1 and so it is unsurprising that the cluster
CC also contains genes potentially involved in benzoate production:
CC phenyl-alanine ammonia lysase (PAL) M7, which catalyzes the first step
CC in the degradation of phenylalanine, and the NADP-dependent
CC dehydrogenase M3 (PubMed:27056201). The cluster contains two PKS
CC encoding genes. The tetraketide synthase is responsible for the
CC biosynthesis of the tetraketide sidechain of SQS1 (By similarity). The
CC biosynthesis must involve 3 rounds of chain extension. After the first
CC and second rounds methyl-transfer occurs, and in all rounds of
CC extension the ketoreductase and dehydratase areactive. The enoyl
CC reductase and C-MeT are not active in the final round of extension (By
CC similarity). The other PKS is therefore likely to encode squalestatin
CC hexaketide synthase (SQHKS) (PubMed:27056201). The hexaketide main
CC chain is initiated by benzoate which is an unusual starter unit for a
CC highly reducing polyketide synthase (PubMed:27056201). The cluster also
CC contains a gene encoding a citrate synthase-like protein R3 presumably
CC involved in linking the hexaketide to the oxaloacetate moiety
CC (Probable). Formation of the tetraketide CoA may be catalyzed by the M9
CC CoA ligase, but the mechanism of release of the tetraketide and the
CC hexaketide from their respective PKS remains unknown, although the
CC cluster encodes a potential esterase (M8) and a possible hydrolase
CC (M10) which could be involved in these processes (Probable). Two
CC acyltransferases (AT), M4 and R4, are also encoded in the cluster. M4
CC is responsible for loading of the tetraketide sidechain from CoA onto
CC the squalestatin core as the final step of biosynthesis
CC (PubMed:27056201). M4 appears to have a broad substrate selectivity for
CC its acyl CoA substrate, allowing the in vitro synthesis of novel
CC squalestatins (PubMed:27056201). The biosynthesis of SQS1 requires
CC several oxidative steps likely performed by oxidoreductases M1, R1 and
CC R2 (Probable). Finally, in support of the identification of the cluster
CC as being responsible for SQS1 production, the cluster contains a gene
CC encoding a putative squalene synthase (SS) R6, suggesting a likely
CC mechanism for self-resistance (PubMed:27056201). The function of
CC protein L1 in the biosynthesis of squalestatin S1 has still to be
CC determined (Probable). {ECO:0000250|UniProtKB:Q86ZD9,
CC ECO:0000269|PubMed:27056201, ECO:0000305|PubMed:27056201}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27056201}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
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DR EMBL; KU946987; AMY15056.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJF1; -.
DR SMR; A0A3G1DJF1; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR Gene3D; 2.120.10.80; -; 1.
DR InterPro; IPR011043; Gal_Oxase/kelch_b-propeller.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR SUPFAM; SSF50965; SSF50965; 1.
PE 3: Inferred from homology;
KW Glycoprotein; Kelch repeat; Membrane; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT CHAIN 31..1327
FT /note="Squalestatin S1 biosynthesis cluster protein L1"
FT /id="PRO_5018033050"
FT TRANSMEM 1170..1190
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REPEAT 595..641
FT /note="Kelch 1"
FT /evidence="ECO:0000255"
FT REPEAT 699..754
FT /note="Kelch 2"
FT /evidence="ECO:0000255"
FT REPEAT 945..993
FT /note="Kelch 3"
FT /evidence="ECO:0000255"
FT REPEAT 994..1040
FT /note="Kelch 4"
FT /evidence="ECO:0000255"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 90
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 105
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 132
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 170
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 217
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 224
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 235
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 318
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 342
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 452
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 475
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 601
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 639
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 648
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 691
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 835
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 852
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 877
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 931
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1000
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1006
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1126
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1327 AA; 141145 MW; 3F6EE429322554D0 CRC64;
MRESFASLLA TGAGKLALSL LFAATPFTSA YTFNQVPSPN LDISNLGRIA FAGDFDSISL
YEYEGQTQET PSRNGTLLSR YPNGVFASIN TTDADIKAMC NLRINDTERI VFAGNFTGVG
NMPTPGGIAL LNTTDGRVRA LDGLDGTVNT LYCDKSGGQV YVGGLFNGLN SSNAIIWKDG
WQELDFNGFN GAVHSIAQAA GGNIIFGGEF TGIGRGNASV ASENATQIIP ISSANISAQT
NSGLPGFTDP KVIACKSDYS SGGAGQTWLL ANNAPGFWKA DFGFGFEPTR LKMYNTDFEG
RGTKTFRFTA LPDGGIMNMS YVDPSNGRTA YCDARCPLPQ GNKTAQDFTF VNVVGMNSFR
VDISEWYGSG AGLNGIQLFQ DAMFSYAVND FNEAQNCGAS GTLSKASSTG NWQVSPSHNS
NSQYLTTVLQ GDPIRPDAAS VTFSPDIKQS GNYSVTIYTP GCQGDGTCGS RGRVNVTATI
GQGQSEEAIL WQTNNFDKYD EVYNGYIDAA GGFQPSVILR PASGQGPGPL TVVAQRVRFT
LLKATSGNIN GLFEYKPGEK LDENNLADSV INAAGASLDP RGKALITSVS SSGQNLYVAG
NFSNNDGRNN IFSFKQGASD PTALPNRGLN RQVMTLYQND SMLYVGGNFT NTGEGNVQGL
NGVAALVNDK WQPLGAGVNG VVLYLVPFSL NVTANQPEQV LAVSGFFDSV NEFNGNPSTN
VQDFAVWVPS RSNWLHNLDF FTLAMSGRLM TFADVPGGER WFGGSVSSGS LLASGTAELN
NGDDALSLEA FPVNLQAQQS GEAGVPSRKR AILEGQDMST TGVRTGKFHT EGNNNMTILA
GHFSTTGTDQ QNITNLVIVD GGDSDKITGF SDELDANSTF TALAVTSNNI LFAGGMVTGR
LDNSRVAGLV TYDLTAKRFT PVQPPPLQGP NITVNAIAPR PNSNDVFVAG QFLTAGSLGC
AAVCIWNTER NQWNSPGNSL SGVVSSLTWI SDTQMYISGN LTSGDNVTTI LSFNPSNNQF
TAIPGAINLP GPVNALTIAN EDGSQFWAAG QGSDGTAYLQ RYNGEQQWMP VDSALFGPGT
DIRGIQVIQV SENHESSDLI SDNEDLLLMG QIQIPNFGTV SAALFNGTNL VPFLLATKGA
DGQTTDGSLS SIFVEFPAFF SQQNGKHLAL WAIVLIGLAI ALVLTFLLVV AGILLEWYRN
KAKGYSPAPQ SYPDRMGNVG RLPPEQLFGT LSVPRSRPTN YLFTCTALCI GMDVPTIHRR
CNPVAHHKQL PAWTEQVRTE QTTETRPAIN EDGCGTSIGG LLFRLPFSRA RRISGDDVFD
TILACSS
