MFM7_PHOSM
ID MFM7_PHOSM Reviewed; 729 AA.
AC A0A3G1DJK5;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 12.
DE RecName: Full=Phenylalanine ammonia-lyase {ECO:0000303|PubMed:27056201};
DE Short=PAL {ECO:0000303|PubMed:27056201};
DE EC=4.3.1.24 {ECO:0000255|RuleBase:RU003955};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein M7 {ECO:0000303|PubMed:27056201};
GN Name=M7 {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: Phenylalanine ammonia-lyase; 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:A0A345BJN1, ECO:0000269|PubMed:11251290,
CC ECO:0000269|PubMed:15489970, ECO:0000269|PubMed:27056201,
CC ECO:0000269|PubMed:28106181, ECO:0000305|PubMed:27056201}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-phenylalanine = (E)-cinnamate + NH4(+);
CC Xref=Rhea:RHEA:21384, ChEBI:CHEBI:15669, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:58095; EC=4.3.1.24;
CC Evidence={ECO:0000255|RuleBase:RU003955};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27056201}.
CC -!- PATHWAY: Phenylpropanoid metabolism; trans-cinnamate biosynthesis;
CC trans-cinnamate from L-phenylalanine: step 1/1.
CC {ECO:0000255|RuleBase:RU003955}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|RuleBase:RU003955}.
CC -!- INDUCTION: Expression is induced on squalestatin S1-producing YMG
CC medium. {ECO:0000269|PubMed:27056201}.
CC -!- PTM: Contains an active site 4-methylidene-imidazol-5-one (MIO), which
CC is formed autocatalytically by cyclization and dehydration of residues
CC Ala-Ser-Gly. {ECO:0000250|UniProtKB:Q68G84}.
CC -!- SIMILARITY: Belongs to the PAL/histidase family. {ECO:0000305}.
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DR EMBL; KU946987; AMY15064.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJK5; -.
DR SMR; A0A3G1DJK5; -.
DR UniPathway; UPA00713; UER00725.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0045548; F:phenylalanine ammonia-lyase activity; IEA:UniProtKB-EC.
DR GO; GO:0009800; P:cinnamic acid biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IEA:UniProtKB-KW.
DR CDD; cd00332; PAL-HAL; 1.
DR Gene3D; 1.10.274.20; -; 1.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR001106; Aromatic_Lyase.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR InterPro; IPR022313; Phe/His_NH3-lyase_AS.
DR InterPro; IPR005922; Phe_NH3-lyase.
DR InterPro; IPR023144; Phe_NH3-lyase_shielding_dom_sf.
DR PANTHER; PTHR10362; PTHR10362; 1.
DR Pfam; PF00221; Lyase_aromatic; 1.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR01226; phe_am_lyase; 1.
DR PROSITE; PS00488; PAL_HISTIDASE; 1.
PE 2: Evidence at transcript level;
KW Cytoplasm; Lyase; Phenylalanine catabolism; Phenylpropanoid metabolism.
FT CHAIN 1..729
FT /note="Phenylalanine ammonia-lyase"
FT /id="PRO_0000447836"
FT ACT_SITE 77
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 342
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 443
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 471
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT MOD_RES 183
FT /note="2,3-didehydroalanine (Ser)"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT CROSSLNK 182..184
FT /note="5-imidazolinone (Ala-Gly)"
FT /evidence="ECO:0000250|UniProtKB:P11544"
SQ SEQUENCE 729 AA; 78702 MW; 5B0E72917E4EAE0A CRC64;
MSSRPLLKLA LSLHDRLDEL CSRGQIALVG YGLDVAAVAA VARHECFPIV DDEEVIARLN
ESTEILERSC RGSTMIYGVH TGFGGSADTR PDDSSGLGRG LMQLLQTGVL VVENLNISGP
STPQIMMPQS MPSSWTKATT AVRINQCVRG HSAIRHQTVK SLLKLVATQI TPIVPLRGSI
SASGDLMPLS YIAGTLEGSP DIYVTKGSGK SAKIISAHEA LGEIGMKPLL LGPREGLGLV
NGTATSAATA SLAVLDAIQL TLLSTGLTCL VSEGMAARVE WLHPFIAETR PHPGQGEVAA
IMRAFLKGSR LVSGLEGEAN AHLHTLNVRP DEGLPQDRYP LRTSPQWLGP QFEDLLLAHS
QITIELNSTS DNPLTNLKTG AMHHGGNFQA TSITSAVEKI RTSLQMVGKL LFSQCTEMIN
HQMNAGLPPN LAADDPSASF CCKGLDINIA AYQSELSYLS NSISNHVQSA EMHNQAVNSL
AFLSTRYTIK AIELLGMMVA GVLYAACQAM DLRVMHATFL DTTTSTLQKA IADLLPNGFK
SDDVEKSLAT AVQGLRNAWW NNAGSDASER CSITAIAFVQ VLCDPSKYHT DTHKEDICLD
LTAKEMRQLQ DDVRLHLSKA YHKHHSAFLE KPTTEEYIGK GSKALYLWTR QDLGIPMNRG
LIDHPSPENL KEPGSVGKRT IGSYVSMIYQ GIQDGRLFKR FATASREVGL GDGGVNGTRK
RAYADYETP
