HKM9_ASPHA
ID HKM9_ASPHA Reviewed; 335 AA.
AC P0DUL7;
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=NmrA-like family domain-containing oxidoreductase hkm9 {ECO:0000303|PubMed:33242032};
DE EC=1.-.-.- {ECO:0000305|PubMed:33242032};
DE AltName: Full=Hancockiamides biosynthesis cluster protein 9 {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: NmrA-like family domain-containing oxidoreductase; part of
CC the gene cluster that mediates the biosynthesis of hancockiamides, an
CC unusual new family of N-cinnamoylated piperazines (PubMed:33242032).
CC The NRPS hkm10 and the NmrA-like reductase hkm9 are proposed to convert
CC two molecules of L-Phe to the intermediary piperazine called
CC xenocockiamide A (Probable). Xenocockiamide A is then converted to
CC hancockiamide D via a series of hydroxylations and O-methylations
CC (Probable). The tyrosinase hkm6 may catalyze an aromatic hydroxylation,
CC then the 2-oxoglutarate-dependent Fe(II) dioxygenase hkm4 and the FAD-
CC dependent phenol hydroxylase hkm7 may catalyze consecutive
CC hydroxylations to install 2 more hydroxy groups, and the
CC methyltransferase hkm8 probably catalyzes two methylations using 2
CC molecules of S-adenosyl-L-methionine (SAM) (Probable). The NRPS hkm11
CC activates and transfers trans-cinnamate supplied by the PAL hkm12 to
CC hancockiamide D and produces hancockiamide A (PubMed:33242032). NRPS
CC Hkm11 has the flexibility to tolerate the bulky hancockiamide G as a
CC substrate and the absence of the acetyl-transferase hkm3 opens up the
CC opportunity for hkm11 to introduce a second N-cinnamoyl moiety
CC (PubMed:33242032). The cytochrome P450 monooxygenase hkm5 catalyzes the
CC methylenedioxy bridge formation, converting hancockiamide A into
CC hancockiamide G (PubMed:33242032). Hkm5 can also convert hancockiamide
CC B into hancockiamide C, and hancockiamide D into hancockiamide H
CC (PubMed:33242032). The N-acetyltransferase hkm3 finally transfers an
CC acetyl group to 1-N of piperazine, converting hancockiamide A into
CC hancockiamide B and hancockiamide G into hancockiamide C
CC (PubMed:33242032). {ECO:0000269|PubMed:33242032,
CC 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 NmrA-type oxidoreductase family.
CC {ECO:0000305}.
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DR EMBL; MBFL02000005; KAF7597141.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DUL7; -.
DR SMR; P0DUL7; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR008030; NmrA-like.
DR Pfam; PF05368; NmrA; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW NADP; Oxidoreductase.
FT CHAIN 1..335
FT /note="NmrA-like family domain-containing oxidoreductase
FT hkm9"
FT /id="PRO_0000452936"
FT BINDING 12..17
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 38..42
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 59..60
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 80..82
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 137
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 161..164
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
SQ SEQUENCE 335 AA; 36893 MW; 505432974F6C8ACA CRC64;
MPATTRLITI YGATGNQGGG VARSLLKNPC FQVRALTRNP NSPASQELAG LGAEIRRADG
FDSNSLLAAF EGSWGVFVNI NSDDKAFRPA GPTEYDLGMK IVDMAAQAGV QHFVFSSGPS
STELTNGKIR MKAMEMKNKI ERYARNNTQF QTVSFICAAW YLENFLVKEI APLFGGFPFV
ADAEAFLTFR CPRWGGKEDV PFISISDDYG DIVQGLFLDP HRWNGHVVHG CSDILTFDEL
VTHFQNVTGQ KARFQPLESW ETFDTFGVPE LEDTKLMFGL TQTTGGLYFG PEPSEKNTAA
ALKRATAAAL GLPRDQQTLI TVKGWFQKHF PVTPN
