FLVA_ASPFN
ID FLVA_ASPFN Reviewed; 823 AA.
AC B8NHD6;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 03-MAR-2009, sequence version 1.
DT 03-AUG-2022, entry version 54.
DE RecName: Full=Bifunctional enzyme flvA {ECO:0000303|PubMed:31885262};
DE AltName: Full=Flavunoidine biosynthesis cluster protein A {ECO:0000303|PubMed:31885262};
DE Includes:
DE RecName: Full=Pyridoxal 5'-phosphate-dependent lyase {ECO:0000303|PubMed:31885262};
DE Short=PLP-dependent lyase {ECO:0000303|PubMed:31885262};
DE EC=4.4.1.- {ECO:0000305|PubMed:31885262};
DE Includes:
DE RecName: Full=Alpha-ketoglutarate-dependent oxygenase {ECO:0000303|PubMed:31885262};
DE Short=Alpha-KG-dependent oxygenase {ECO:0000303|PubMed:31885262};
DE EC=1.14.11.- {ECO:0000305|PubMed:31885262};
GN Name=flvA {ECO:0000303|PubMed:31885262}; ORFNames=AFLA_135410;
OS Aspergillus flavus (strain ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357
OS / JCM 12722 / SRRC 167).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=332952;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC
RC 167;
RX PubMed=25883274; DOI=10.1128/genomea.00168-15;
RA Nierman W.C., Yu J., Fedorova-Abrams N.D., Losada L., Cleveland T.E.,
RA Bhatnagar D., Bennett J.W., Dean R., Payne G.A.;
RT "Genome sequence of Aspergillus flavus NRRL 3357, a strain that causes
RT aflatoxin contamination of food and feed.";
RL Genome Announc. 3:E0016815-E0016815(2015).
RN [2]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=31885262; DOI=10.1021/jacs.9b13046;
RA Yee D.A., Kakule T.B., Cheng W., Chen M., Chong C.T.Y., Hai Y., Hang L.F.,
RA Hung Y.S., Liu N., Ohashi M., Okorafor I.C., Song Y., Tang M., Zhang Z.,
RA Tang Y.;
RT "Genome mining of alkaloidal terpenoids from a hybrid terpene and
RT nonribosomal peptide biosynthetic pathway.";
RL J. Am. Chem. Soc. 142:710-714(2020).
CC -!- FUNCTION: Bifunctional enzyme; part of the gene cluster that mediates
CC the biosynthesis of flavunoidine, an alkaloidal terpenoid with a
CC tetracyclic cage-like core connected to dimethylcadaverine via a C-N
CC bond and acylated with 5,5-dimethyl-L-pipecolate (PubMed:31885262). The
CC tetracyclic core is synthesized by the terpene cyclase flvE and the
CC cytochrome P450 monooxygenase flvD (PubMed:31885262). The terpene
CC cyclase flvE catalyzes the cyclization of farnesyl pyrophosphate (FPP)
CC to form (1R,4R,5S)-(+)-acoradiene and the cytochrome P450 monooxygenase
CC flvD is then responsible for oxidative conversion of (1R,4R,5S)-(+)-
CC acoradiene into the tetracyclic cage present in the final product
CC flavunoidine (PubMed:31885262). The cytochrome monooxygenase flvC then
CC hydroxylates the C-10 position (PubMed:31885262). The second terpene
CC cyclase flvF is required for attachment of the C-7 axial
CC dimethylcadaverine which is itself produced by the N-methyltransferase
CC flvH and the decarboxylase flvG via methylation of L-lysine to give
CC N,N-dimethyl-L-Lysine, and decarboxylation to afford
CC dimethylcadaverine, respectively (PubMed:31885262). The NRPS flvI
CC acylates the terpenoid core at the hydroxylated C-10 with
CC dimethylpipecolate to yield final flavunoidine (PubMed:31885262). The
CC bifunctional enzyme flvA and the dehydrogenase flvB are responsible for
CC the synthesis of the dimethylpipecolate precursor (PubMed:31885262).
CC The PLP-dependent lyase domain of flvA might use L-O-acetyl-homoserine
CC and alpha-keto-isovalerate to form an intermediary ketone that can
CC cyclize intramolecularly to yield an imine (PubMed:31885262). The imine
CC can be reduced by flvB to yield the 6-carboxylated pipecolate
CC (PubMed:31885262). The C-terminal alpha-KG-dependent oxygenase domain
CC of flvA is then proposed to catalyze the decarboxylation to yield
CC dimethylpipecolate (PubMed:31885262). {ECO:0000269|PubMed:31885262}.
CC -!- COFACTOR:
CC Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
CC Evidence={ECO:0000250|UniProtKB:P06721};
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q96323};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:31885262}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the trans-sulfuration
CC enzymes family. {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the iron/ascorbate-
CC dependent oxidoreductase family. {ECO:0000305}.
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DR EMBL; EQ963478; EED50778.1; -; Genomic_DNA.
DR RefSeq; XP_002379554.1; XM_002379513.1.
DR STRING; 5059.CADAFLAP00007419; -.
DR EnsemblFungi; EED50778; EED50778; AFLA_135410.
DR VEuPathDB; FungiDB:AFLA_135410; -.
DR eggNOG; KOG1250; Eukaryota.
DR HOGENOM; CLU_335849_0_0_1; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000001875; Unassembled WGS sequence.
DR GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0019346; P:transsulfuration; IEA:InterPro.
DR Gene3D; 3.40.640.10; -; 1.
DR InterPro; IPR018724; 2OG-Fe_dioxygenase.
DR InterPro; IPR000277; Cys/Met-Metab_PyrdxlP-dep_enz.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR PANTHER; PTHR11808; PTHR11808; 1.
DR Pfam; PF10014; 2OG-Fe_Oxy_2; 1.
DR Pfam; PF01053; Cys_Met_Meta_PP; 1.
DR SUPFAM; SSF53383; SSF53383; 1.
PE 1: Evidence at protein level;
KW Dioxygenase; Hydroxylation; Iron; Lyase; Metal-binding;
KW Multifunctional enzyme; Oxidoreductase; Pyridoxal phosphate.
FT CHAIN 1..823
FT /note="Bifunctional enzyme flvA"
FT /id="PRO_0000454477"
FT REGION 56..535
FT /note="Pyridoxal 5'-phosphate-dependent lyase"
FT /evidence="ECO:0000305|PubMed:31885262"
FT REGION 573..823
FT /note="Alpha-ketoglutarate-dependent oxygenase"
FT /evidence="ECO:0000305|PubMed:31885262"
FT BINDING 703
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q96323"
FT BINDING 705
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q96323"
FT MOD_RES 331
FT /note="N6-(pyridoxal phosphate)lysine"
FT /evidence="ECO:0000250|UniProtKB:P06721"
SQ SEQUENCE 823 AA; 94107 MW; 232DB44D5FD23033 CRC64;
MHDVWRTILS RFKQNTNAIK TRFDKYRALC KELGLQRDEW SESIFLDDLE KLLKLTAKFE
MALMPSNGVD THVNGVITKI NGFNNGFDTH INGFDTRING FHTHTNGFDR GLELWQIEER
YRALAQLQST LGSFFERACP GYDQSKIPWF FDPSYYQCQG VNYDRFASPD VRDREQQLLE
TLQLGSNQNP KLLLMSSGMA SFTVIQQYVV QQLNYGDTVV VSPYIYFESF QPMRSQKSLT
VVNAKGFDPE SIIEAAERNN ARAVFLDPMC NTVGLDTIDI RRFAHLVANR GGWADRLVIV
DGTLVSGGMQ LYDWFDGPHC PKVLYYESAH KYIQLGLDLI MCGYVVMPED LVPAIQLIRQ
ITGTVLYSRN ASLLPPIDKT IFNFRMSRLT TNAEKLHRLL DAESRNMAEV TFPHHWRDYR
WRHGGNVVTV RFHGEGLNKR SNLERCCDDI LRAAEEEGVQ MVKGASLGFS TTRIFVADAF
FENTDPFLRI SVGVQSEDIE TVARAVLSGI KRYCMSAVPV NLDVGQRLYD AKFYIAMASM
LEVRARYAKD RVVFMEGEWL VPILKALGAR EEDFDALQQV SHHLGKDPTV DYRTIRNGLF
YFNFENKAIQ RFQKQRFTLT VQENYKRHDS GLPRDFPEVR GDLQYNTVLQ ALMVAKAFIM
NKVDVEPRAH LDYSSPNFLC NVFNIRTFTE KNILGEPTLE GVHADGADHT MTTFLGCTNM
RSDSGITFIH DQKEITGIPA TEAQPSLIKH RFQHRHFLDS LLFADNEAKH SLTSVFQEDV
SKRATRDMLL FLTRKPKLAG HSSGSVDAME PHKTLPMNVP LWL
