CLZ5_COCLU
ID CLZ5_COCLU Reviewed; 286 AA.
AC A0A345BJN5;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2018, sequence version 1.
DT 03-AUG-2022, entry version 10.
DE RecName: Full=NADP-dependent dehydrogenase clz5 {ECO:0000303|PubMed:28605916};
DE EC=1.1.1.- {ECO:0000305|PubMed:28605916};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein clz5 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A biosynthesis cluster protein 5 {ECO:0000303|PubMed:28605916};
GN Name=clz5 {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, AND 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: NADP-dependent dehydrogenase; 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:A0A3G1DJE9, ECO:0000269|PubMed:28605916,
CC ECO:0000305|PubMed:28605916}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:28605916}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P87017}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P87017}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; MF806533; AXF50648.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A345BJN5; -.
DR SMR; A0A345BJN5; -.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 3: Inferred from homology;
KW Cytoplasm; NAD; NADP; Oxidoreductase.
FT CHAIN 1..286
FT /note="NADP-dependent dehydrogenase clz5"
FT /id="PRO_0000452630"
FT ACT_SITE 207
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 44..72
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P16544"
FT BINDING 211
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P16544"
SQ SEQUENCE 286 AA; 30770 MW; B104C093AF6530A2 CRC64;
MAAPNDPELT RRRQRQEDFL RGTSKINFDD HVDHHVLSGK TAIITGGASG LGLGIAKALS
DNGCRVAVLD LSECAEAGTD ESNIESPKLF KCDVSSWESL LAAFQEVMLW SADRLDIVVL
SAGVRSHNIK DLILKRAVGS ASTPVKPPSS VFDVNLLGTY YSAYLALWYF TNLESKSDGL
ESSSWRPQLL FIGSLASYIE QPLSADYCAS KHGVRGLWKS VRSHSASFGG CQTNLLAPTF
IDNRQGSTKS RGDGALISLT TDVKLGEVAD VVAGALRCIC DNNIEG
