MFM3_PHOSM
ID MFM3_PHOSM Reviewed; 339 AA.
AC A0A3G1DJE9;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 10.
DE RecName: Full=NADP-dependent dehydrogenase M3 {ECO:0000303|PubMed:27056201};
DE EC=1.1.1.- {ECO:0000305|PubMed:27056201};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein M3 {ECO:0000303|PubMed:27056201};
GN Name=M3 {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: 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: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:A0A345BJN5, 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 -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P87017}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P87017}.
CC -!- INDUCTION: Expression is induced on squalestatin S1-producing YMG
CC medium. {ECO:0000269|PubMed:27056201}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {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; KU946987; AMY15060.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJE9; -.
DR SMR; A0A3G1DJE9; -.
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 2: Evidence at transcript level;
KW Cytoplasm; NAD; NADP; Oxidoreductase.
FT CHAIN 1..339
FT /note="NADP-dependent dehydrogenase M3"
FT /id="PRO_0000447833"
FT ACT_SITE 206
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 210
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P16544"
SQ SEQUENCE 339 AA; 36438 MW; AEBE2CD949937785 CRC64;
MAATNDPELT RRKQRQEDFL RGTSKINFDD HIDHCVLSGK TAIVTGGASG IGHGIAQALS
SNGCKVAVLD LSGPLEAGTD ESNIDSPKLF ECDVSSWESL LAAFQEVLIW SGNSLDIVVL
SAGVRSHNIK DLILERPAGS TSTPVKPPSS VFDVNLLGTY YSAYLALWYF TNLEAKRDEA
EFNWKPQLLF IGSLASYVEQ PLSADYCASK HGVRGLWKSV RSHSALFGDC QTNLLAPTFI
DNRQGSTKSR GDGALISLTN DVKLGEVSDV VAGALRCLCD RNIEGRALCC VKGEQSSPGS
NNFDLCDNLI DFNAGKSVLD SFRNGVVGRL GTQNTTGPQ
