ID   MFR3_PHOSM              Reviewed;         465 AA.
AC   A0A3G1DJJ8;
DT   18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT   13-FEB-2019, sequence version 1.
DT   03-AUG-2022, entry version 14.
DE   RecName: Full=Citrate synthase-like protein {ECO:0000303|PubMed:27056201};
DE            EC=2.3.3.- {ECO:0000305|PubMed:27056201};
DE   AltName: Full=Squalestatin S1 biosynthesis cluster protein R3 {ECO:0000303|PubMed:27056201};
GN   Name=R3 {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 INDUCTION.
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).
RN   [2]
RP   FUNCTION.
RX   PubMed=11251290; DOI=10.1016/s1074-5521(00)90064-4;
RA   Nicholson T.P., Rudd B.A., Dawson M., Lazarus C.M., Simpson T.J., Cox R.J.;
RT   "Design and utility of oligonucleotide gene probes for fungal polyketide
RT   synthases.";
RL   Chem. Biol. 8:157-178(2001).
RN   [3]
RP   FUNCTION.
RX   PubMed=15489970; DOI=10.1039/b411973h;
RA   Cox R.J., Glod F., Hurley D., Lazarus C.M., Nicholson T.P., Rudd B.A.,
RA   Simpson T.J., Wilkinson B., Zhang Y.;
RT   "Rapid cloning and expression of a fungal polyketide synthase gene involved
RT   in squalestatin biosynthesis.";
RL   Chem. Commun. (Camb.) 2004:2260-2261(2004).
RN   [4]
RP   FUNCTION.
RX   PubMed=28106181; DOI=10.1039/c6cc10172k;
RA   Liddle E., Scott A., Han L.C., Ivison D., Simpson T.J., Willis C.L.,
RA   Cox R.J.;
RT   "In vitro kinetic study of the squalestatin tetraketide synthase
RT   dehydratase reveals the stereochemical course of a fungal highly reducing
RT   polyketide synthase.";
RL   Chem. Commun. (Camb.) 53:1727-1730(2017).
CC   -!- FUNCTION: Citrate synthase-like protein; part of the gene cluster that
CC       mediates the biosynthesis of squalestatin S1 (SQS1, also known as
CC       zaragozic acid A), a heavily oxidized fungal polyketide that offers
CC       potent cholesterol lowering activity by targeting squalene synthase
CC       (SS) (PubMed:27056201). SQS1 is composed of a 2,8-
CC       dioxobicyclic[3.2.1]octane-3,4,5-tricarboxyclic acid core that is
CC       connected to two lipophilic polyketide arms (PubMed:27056201). These
CC       initial steps feature the priming of an unusual benzoic acid starter
CC       unit onto the highly reducing polyketide synthase pks2, followed by
CC       oxaloacetate extension and product release to generate a tricarboxylic
CC       acid containing product (By similarity). The phenylalanine ammonia
CC       lyase (PAL) M7 and the acyl-CoA ligase M9 are involved in transforming
CC       phenylalanine into benzoyl-CoA (By similarity). The citrate synthase-
CC       like protein R3 is involved in connecting the C-alpha-carbons of the
CC       hexaketide chain and oxaloacetate to afford the tricarboxylic acid unit
CC       (By similarity). The potential hydrolytic enzymes, M8 and M10, are in
CC       close proximity to pks2 and may participate in product release (By
CC       similarity). On the other side, the tetraketide arm is synthesized by a
CC       the squalestatin tetraketide synthase pks1 and enzymatically esterified
CC       to the core in the last biosynthetic step, by the acetyltransferase M4
CC       (PubMed:11251290, PubMed:15489970, PubMed:28106181). The biosynthesis
CC       of the tetraketide must involve 3 rounds of chain extension
CC       (PubMed:11251290, PubMed:15489970, PubMed:28106181). After the first
CC       and second rounds methyl-transfer occurs, and in all rounds of
CC       extension the ketoreductase and dehydratase are active
CC       (PubMed:11251290, PubMed:15489970, PubMed:28106181). The enoyl
CC       reductase and C-MeT of pks1 are not active in the final round of
CC       extension (PubMed:11251290, PubMed:15489970, PubMed:28106181). The
CC       acetyltransferase M4 appears to have a broad substrate selectivity for
CC       its acyl CoA substrate, allowing the in vitro synthesis of novel
CC       squalestatins (Probable). The biosynthesis of SQS1 requires several
CC       oxidative steps likely performed by oxidoreductases M1, R1 and R2
CC       (Probable). Finally, in support of the identification of the cluster as
CC       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 (Probable).
CC       {ECO:0000250|UniProtKB:A0A345BJN4, ECO:0000269|PubMed:11251290,
CC       ECO:0000269|PubMed:15489970, ECO:0000269|PubMed:27056201,
CC       ECO:0000269|PubMed:28106181, ECO:0000305|PubMed:27056201}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000305|PubMed:27056201}.
CC   -!- INDUCTION: Expression is induced on squalestatin S1-producing YMG
CC       medium. {ECO:0000269|PubMed:27056201}.
CC   -!- SIMILARITY: Belongs to the citrate synthase family. {ECO:0000305}.
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DR   EMBL; KU946987; AMY15071.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A3G1DJJ8; -.
DR   SMR; A0A3G1DJJ8; -.
DR   GO; GO:0046912; F:acyltransferase activity, acyl groups converted into alkyl on transfer; IEA:InterPro.
DR   Gene3D; 1.10.230.10; -; 1.
DR   Gene3D; 1.10.580.10; -; 1.
DR   InterPro; IPR016142; Citrate_synth-like_lrg_a-sub.
DR   InterPro; IPR016143; Citrate_synth-like_sm_a-sub.
DR   InterPro; IPR002020; Citrate_synthase.
DR   InterPro; IPR019810; Citrate_synthase_AS.
DR   InterPro; IPR024176; Citrate_synthase_bac-typ.
DR   InterPro; IPR036969; Citrate_synthase_sf.
DR   PANTHER; PTHR11739; PTHR11739; 1.
DR   Pfam; PF00285; Citrate_synt; 1.
DR   PIRSF; PIRSF001369; Citrate_synth; 1.
DR   PRINTS; PR00143; CITRTSNTHASE.
DR   SUPFAM; SSF48256; SSF48256; 1.
DR   PROSITE; PS00480; CITRATE_SYNTHASE; 1.
PE   2: Evidence at transcript level;
KW   Transferase.
FT   CHAIN           1..465
FT                   /note="Citrate synthase-like protein"
FT                   /id="PRO_0000447841"
FT   REGION          13..40
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        17..38
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        357
FT                   /evidence="ECO:0000255|PIRSR:PIRSR001369-1"
FT   ACT_SITE        413
FT                   /evidence="ECO:0000255|PIRSR:PIRSR001369-1"
SQ   SEQUENCE   465 AA;  52029 MW;  8E02F98E479DF046 CRC64;
     MAIVNGAVGK PQHISDMVDS TKMNGNQSQD TAGRADTPVS NGGQDYLHVF DSRTCNIHHI
     PVSDGFVRGS DLSTIAAPLK GSSGRMQKLA VLDPGFQHTA CKESSITFID GEKGELRYRG
     VRIEDLFHDH DFDSTLHLLV WGRLPTKEEK IKFERRMFEV ASPPQEVCDV IRKLPKNMDF
     ISMFLTGLST YMGTDEEMTR SRHQAVMTYH KNLQTTDDAI IRCFSYVSAT LATVYCHVKG
     VELHHPQEGL TLVENFLHMI GMEDPDKKIS RTIDRLSINM ADHELSCSTA AFLHVASSLT
     DPMTCLLTAI SAASGPLHGG ALEVCYQGLE LIGSVDNVPA YIAAVKAKKF RLFGYGHRVY
     KIQDPRAALT KELMEEHREA IDANPLLQIA VEIDRQANTD PYFVERKLKL NADFYGCFIY
     IALGIPRDMI PGLLTISRMG GLMAHWREAM NNPIKIWRPM QKFKL