ID   CLZ11_COCLU             Reviewed;         218 AA.
AC   A0A345BJN2;
DT   02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT   07-NOV-2018, sequence version 1.
DT   25-MAY-2022, entry version 7.
DE   RecName: Full=Probable carboxylesterase clz11 {ECO:0000303|PubMed:28605916};
DE            EC=3.1.1.1 {ECO:0000305};
DE   AltName: Full=Squalestatin S1 biosynthesis cluster protein clz11 {ECO:0000303|PubMed:28605916};
DE   AltName: Full=Zaragozic acid A biosynthesis cluster protein 11 {ECO:0000303|PubMed:28605916};
GN   Name=clz11 {ECO:0000303|PubMed:28605916};
OS   Cochliobolus lunatus (Filamentous fungus) (Curvularia lunata).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC   Pleosporomycetidae; Pleosporales; Pleosporineae; Pleosporaceae; Curvularia.
OX   NCBI_TaxID=5503;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP   PATHWAY.
RC   STRAIN=ATCC 74067;
RX   PubMed=28605916; DOI=10.1021/acs.orglett.7b01534;
RA   Liu N., Hung Y.S., Gao S.S., Hang L., Zou Y., Chooi Y.H., Tang Y.;
RT   "Identification and heterologous production of a benzoyl-primed
RT   tricarboxylic acid polyketide intermediate from the zaragozic acid A
RT   biosynthetic pathway.";
RL   Org. Lett. 19:3560-3563(2017).
CC   -!- FUNCTION: Probable carboxylesterase; 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:28605916). 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:28605916). These
CC       initial steps feature the priming of an unusual benzoic acid starter
CC       unit onto the highly reducing polyketide synthase clz14, followed by
CC       oxaloacetate extension and product release to generate a tricarboxylic
CC       acid containing product (PubMed:28605916). The phenylalanine ammonia
CC       lyase (PAL) clz10 and the acyl-CoA ligase clz12 are involved in
CC       transforming phenylalanine into benzoyl-CoA (PubMed:28605916). The
CC       citrate synthase-like protein clz17 is involved in connecting the C-
CC       alpha-carbons of the hexaketide chain and oxaloacetate to afford the
CC       tricarboxylic acid unit (PubMed:28605916). The potential hydrolytic
CC       enzymes, clz11 and clz13, are in close proximity to pks2 and may
CC       participate in product release (PubMed:28605916). On the other side,
CC       the tetraketide arm is synthesized by a the squalestatin tetraketide
CC       synthase clz2 and enzymatically esterified to the core in the last
CC       biosynthetic step, by the acetyltransferase clz6 (By similarity). The
CC       biosynthesis of the tetraketide must involve 3 rounds of chain
CC       extension (By similarity). After the first and second rounds methyl-
CC       transfer occurs, and in all rounds of extension the ketoreductase and
CC       dehydratase are active (By similarity). The enoyl reductase and C-MeT
CC       of clz2 are not active in the final round of extension (By similarity).
CC       The acetyltransferase clz6 appears to have a broad substrate
CC       selectivity for its acyl CoA substrate, allowing the in vitro synthesis
CC       of novel squalestatins (By similarity). The biosynthesis of SQS1
CC       requires several oxidative steps likely performed by oxidoreductases
CC       clz3, clz15 and clz16 (Probable). Finally, in support of the
CC       identification of the cluster as being responsible for SQS1 production,
CC       the cluster contains a gene encoding a putative squalene synthase (SS)
CC       clz20, suggesting a likely mechanism for self-resistance (Probable).
CC       {ECO:0000250|UniProtKB:A0A3G1DJF0, ECO:0000269|PubMed:28605916,
CC       ECO:0000305|PubMed:28605916}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a carboxylic ester + H2O = a carboxylate + an alcohol + H(+);
CC         Xref=Rhea:RHEA:21164, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:29067, ChEBI:CHEBI:30879, ChEBI:CHEBI:33308; EC=3.1.1.1;
CC         Evidence={ECO:0000305};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:28605916}.
CC   -!- SIMILARITY: Belongs to the 'GDXG' lipolytic enzyme family.
CC       {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; MF806530; AXF50645.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A345BJN2; -.
DR   GO; GO:0080030; F:methyl indole-3-acetate esterase activity; IEA:UniProtKB-EC.
DR   Gene3D; 3.40.50.1820; -; 1.
DR   InterPro; IPR029058; AB_hydrolase.
DR   InterPro; IPR013094; AB_hydrolase_3.
DR   Pfam; PF07859; Abhydrolase_3; 1.
DR   SUPFAM; SSF53474; SSF53474; 1.
PE   1: Evidence at protein level;
KW   Hydrolase.
FT   CHAIN           1..218
FT                   /note="Probable carboxylesterase clz11"
FT                   /id="PRO_0000452634"
FT   MOTIF           7..9
FT                   /note="Involved in the stabilization of the negatively
FT                   charged intermediate by the formation of the oxyanion hole"
FT                   /evidence="ECO:0000250|UniProtKB:Q5NUF3"
FT   ACT_SITE        77
FT                   /evidence="ECO:0000250|UniProtKB:Q5NUF3"
SQ   SEQUENCE   218 AA;  24100 MW;  B6E115F5871BD2ED CRC64;
     MAGDLWLVGD CTNHGGLSDA IIVSPDYRLL PEATGADIFD DVEAFWNWLH TSLPSLAQSY
     SWQAQPDLTR ILCVGQSGGG SMAVHSALLH PEYSIKVIVS LYAPLYHNVP NLTVPRPRRI
     LGTMPPPPRK AEGLIRSYIK QSKGSVRTGG NPFDMWELLL CLLQQGRLIS LMNIKPDSRL
     DTPFLLRQVG KLPPLWLIHG EDDSVVGPST ICVHRVIF