HKM7_ASPHA
ID HKM7_ASPHA Reviewed; 532 AA.
AC P0DUL5;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 02-JUN-2021, sequence version 1.
DT 03-AUG-2022, entry version 5.
DE RecName: Full=FAD-dependent monooxygenase hkm7 {ECO:0000303|PubMed:33242032};
DE EC=1.-.-.- {ECO:0000305|PubMed:33242032};
DE AltName: Full=Hancockiamides biosynthesis cluster protein 7 {ECO:0000303|PubMed:33242032};
OS Aspergillus hancockii.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1873369;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FRR 3425 / CBS 142004 / DTO 360-G7;
RA Gilchrist C.L.M., Chooi Y.H.;
RL Submitted (APR-2019) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, PATHWAY, AND BIOTECHNOLOGY.
RX PubMed=33242032; DOI=10.1039/d0ob02243h;
RA Li H., Lacey A.E., Shu S., Kalaitzis J.A., Vuong D., Crombie A., Hu J.,
RA Gilchrist C.L.M., Lacey E., Piggott A.M., Chooi Y.H.;
RT "Hancockiamides: phenylpropanoid piperazines from Aspergillus hancockii are
RT biosynthesised by a versatile dual single-module NRPS pathway.";
RL Org. Biomol. Chem. 19:587-595(2021).
CC -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of hancockiamides, an unusual new family of
CC N-cinnamoylated piperazines (PubMed:33242032). The NRPS hkm10 and the
CC NmrA-like reductase hkm9 are proposed to convert two molecules of L-Phe
CC to the intermediary piperazine called xenocockiamide A (Probable).
CC Xenocockiamide A is then converted to hancockiamide D via a series of
CC hydroxylations and O-methylations (Probable). The tyrosinase hkm6 may
CC catalyze an aromatic hydroxylation, then the 2-oxoglutarate-dependent
CC Fe(II) dioxygenase hkm4 and the FAD-dependent phenol hydroxylase hkm7
CC may catalyze consecutive hydroxylations to install 2 more hydroxy
CC groups, and the methyltransferase hkm8 probably catalyzes two
CC methylations using 2 molecules of S-adenosyl-L-methionine (SAM)
CC (Probable). The NRPS hkm11 activates and transfers trans-cinnamate
CC supplied by the PAL hkm12 to hancockiamide D and produces hancockiamide
CC A (PubMed:33242032). NRPS Hkm11 has the flexibility to tolerate the
CC bulky hancockiamide G as a substrate and the absence of the acetyl-
CC transferase hkm3 opens up the opportunity for hkm11 to introduce a
CC second N-cinnamoyl moiety (PubMed:33242032). The cytochrome P450
CC monooxygenase hkm5 catalyzes the methylenedioxy bridge formation,
CC converting hancockiamide A into hancockiamide G (PubMed:33242032). Hkm5
CC can also convert hancockiamide B into hancockiamide C, and
CC hancockiamide D into hancockiamide H (PubMed:33242032). The N-
CC acetyltransferase hkm3 finally transfers an acetyl group to 1-N of
CC piperazine, converting hancockiamide A into hancockiamide B and
CC hancockiamide G into hancockiamide C (PubMed:33242032).
CC {ECO:0000269|PubMed:33242032, ECO:0000305|PubMed:33242032}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:33242032}.
CC -!- BIOTECHNOLOGY: Hancockiamide D displays potent cytotoxic activity
CC against murine myeloma NS-1 cells, suggesting a potential antitumour
CC application (PubMed:33242032). More interestingly, hancockiamide C, the
CC likely end metabolite of the hkm pathway, shows potent Arabidopsis
CC thaliana seed anti-germination activity, but is inactive against the
CC monocot Eragrostis tef seed, suggesting that it could be a herbicidal
CC lead targeting monocots (PubMed:33242032). The herbicidal activity of
CC hancockiamide C could be due to its phenylpropanoid-like structural
CC features, which may act on the plant lignan pathways, and hence
CC warrants further investigations (PubMed:33242032).
CC {ECO:0000269|PubMed:33242032}.
CC -!- SIMILARITY: Belongs to the PheA/TfdB FAD monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; MBFL02000005; KAF7597143.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DUL5; -.
DR SMR; P0DUL5; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.40.30.20; -; 1.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR012941; Phe_hydrox_C_dim_dom.
DR InterPro; IPR038220; PHOX_C_sf.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR Pfam; PF07976; Phe_hydrox_dim; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR SUPFAM; SSF52833; SSF52833; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Monooxygenase; Oxidoreductase.
FT CHAIN 1..532
FT /note="FAD-dependent monooxygenase hkm7"
FT /id="PRO_0000452934"
FT BINDING 191..193
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
FT BINDING 261
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
SQ SEQUENCE 532 AA; 59262 MW; B73D4246B6F0FE28 CRC64;
MEIFESFGIE GEVTKQWEPA TDEILWCRNE SGTLSRMERF RNEPPVGVKW THGTLQQGRV
EEIMKKRITE ISGVEVEYST ELSDLTINTR ESSNSKASAC SVTIRSVADD QEAHRSSETI
RARYIIGADG GRSSIRDLMG VAMEGTKGTA IWGVMDILGG SDFPDFGATS VVRSDSDGAV
DFVRREEGLT RIYVELNKCA AGWEALERDT ITPELILEKC RYIIRPYKLE VDYVEWWSSF
TVWQRLSKSM IVHDRVFLVG DAVHTHSPLC GMGMNTGIQD SFNLGWKLAG VVQGQLNYDI
LQTYETERRP VAEALLDTDR TVLDLFHAPL GPEAEALLAK VPALQVYLGG RGICYHESVL
TCRLAQTLGD LTAGECLPDV TVFDYATGRP SSTHSWIKGN GGWAIIVWAG DVSRPSQMNL
VQSLSRDMIE LRDSLGKSGS MIDFFLIHCS AWPSVELADF PPLFFPTTKT IGRPNGRIFV
DEKAVYDGLH ISRAEGGVAI VRPDKHIAWA GGLQEVDSLQ RYLRQVFRPQ PE
