MFM4_PHOSM
ID MFM4_PHOSM Reviewed; 496 AA.
AC A0A3G1DJI9;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=Acyltransferase M4 {ECO:0000303|PubMed:27056201};
DE Short=AT M4 {ECO:0000303|PubMed:27056201};
DE EC=2.3.1.- {ECO:0000305|PubMed:27056201};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein M4 {ECO:0000303|PubMed:27056201};
GN Name=M4 {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], AND FUNCTION.
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: Acyltransferase; part of the gene cluster that mediates the
CC biosynthesis of squalestatin S1 (SQS1, also known as zaragozic acid A),
CC a heavily oxidized fungal polyketide that offers potent cholesterol
CC lowering activity by targeting squalene synthase (SS)
CC (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:A0A345BJP2, 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:0000269|PubMed:27056201}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q70PR7}.
CC -!- SIMILARITY: Belongs to the plant acyltransferase family. {ECO:0000305}.
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DR EMBL; KU946987; AMY15061.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJI9; -.
DR SMR; A0A3G1DJI9; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.559.10; -; 2.
DR InterPro; IPR023213; CAT-like_dom_sf.
PE 3: Inferred from homology;
KW Acyltransferase; Transferase.
FT CHAIN 1..496
FT /note="Acyltransferase M4"
FT /id="PRO_0000447834"
FT ACT_SITE 163
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q70PR7"
SQ SEQUENCE 496 AA; 54949 MW; 8C6FEDAD4C3C1327 CRC64;
MPSILTDFNV RPYEDVPAQI IELSVPDAAA PKHCPIQLLY WPVEGKSNFI RGYENLKDGL
SRLLADVPVL VGRLERGSKG DPRYLAVTIS SDASVELEYE DISADDTIAS YDDLVRNGFP
TTGFKDIVSP KMSLGPMVEG SPMMCAKLNL IKGGAILAYG FSHVLADGWA NSELGRLWAL
HAAHVSQGIG FERQKAATPD DEIRRQLSTL PDFDADAPLD AFLQITPSEE ATNFLHKDVL
AAEKAKKKAR EKMMATLLAA GEVPELPRFT FWRFTPEKLK ELKQAATSSD ASKWISTMDA
LAGLFWSRIA RIQGQSSNGH QQSRCIFALD IRRRLQQPVP LAYVGNVFSP VDAICPLDEL
ESDSLGLKAA AQSMRQANKG WTQPRWEAWL NKIMSLPLDQ TLDTSQEFRL QKHNMYFNDY
SAFQLNTASW GAPFGQPART RCLRSGLAGG AAGVWVCPKF PDGSLEVWLT STAAIQKSLF
EDATFNRYAE FVCQYT
