HKM6_ASPHA
ID HKM6_ASPHA Reviewed; 286 AA.
AC P0DUQ0;
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=Oxidase hkm6 {ECO:0000303|PubMed:33242032};
DE EC=1.14.-.- {ECO:0000305|PubMed:33242032};
DE AltName: Full=Hancockiamides biosynthesis cluster protein 6 {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: Oxidase; part of the gene cluster that mediates the
CC biosynthesis of hancockiamides, an unusual new family of N-
CC 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 -!- COFACTOR:
CC Name=Cu(2+); Xref=ChEBI:CHEBI:29036;
CC Evidence={ECO:0000250|UniProtKB:Q9ZP19};
CC Note=Binds 2 copper ions per subunit. {ECO:0000250|UniProtKB:Q9ZP19};
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 tyrosinase family. {ECO:0000305}.
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DR EMBL; MBFL02000005; KAF7597144.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DUQ0; -.
DR SMR; P0DUQ0; -.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR Gene3D; 1.10.1280.10; -; 1.
DR InterPro; IPR008922; Di-copper_centre_dom_sf.
DR InterPro; IPR002227; Tyrosinase_Cu-bd.
DR Pfam; PF00264; Tyrosinase; 1.
DR PRINTS; PR00092; TYROSINASE.
DR SUPFAM; SSF48056; SSF48056; 1.
DR PROSITE; PS00497; TYROSINASE_1; 1.
DR PROSITE; PS00498; TYROSINASE_2; 1.
PE 1: Evidence at protein level;
KW Copper; Metal-binding; Monooxygenase; Oxidoreductase.
FT CHAIN 1..286
FT /note="Oxidase hkm6"
FT /id="PRO_0000452933"
FT BINDING 16
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="A"
FT /evidence="ECO:0000250|UniProtKB:Q9ZP19"
FT BINDING 25
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="A"
FT /evidence="ECO:0000250|UniProtKB:Q9ZP19"
FT BINDING 215
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="B"
FT /evidence="ECO:0000250|UniProtKB:Q9ZP19"
SQ SEQUENCE 286 AA; 32205 MW; 98BAFF5CB047E98F CRC64;
MDDFSATHIN YTLSIHLSGI FFAWHRHFVW LWERTLREEC GYNGYQPYWD WALSANNISA
SPIFDGSPTS LSGNGDPINQ EPFLQLEPTN ITIPTGTGGG CVTNGPFANM TLNLPDLSMA
GDEEFPSNAF DYKPHCFTRN LNSHMSSAFT SQADVDRLLN SPSITDLQAN IDFSAWPELR
EARILGPHAA AHMSLGRTMD DFWTAPQDPS FMLHHAQVDR IWSLWQARGP ESRRWALNGT
STINNRPTSP EVTLDTELVW GSLSESKTMR EVMSTEAYHF CYEYGA
