HKM8_ASPHA
ID HKM8_ASPHA Reviewed; 252 AA.
AC P0DUL6;
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=O-methyltransferase hkm8 {ECO:0000303|PubMed:33242032};
DE EC=2.1.1.- {ECO:0000255|PROSITE-ProRule:PRU01019};
DE AltName: Full=Hancockiamides biosynthesis cluster protein 8 {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: O-methyltransferase; part of the gene cluster that mediates
CC the 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 -!- 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 class I-like SAM-binding methyltransferase
CC superfamily. Cation-dependent O-methyltransferase family.
CC {ECO:0000255|PROSITE-ProRule:PRU01019}.
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DR EMBL; MBFL02000005; KAF7597142.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DUL6; -.
DR SMR; P0DUL6; -.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008171; F:O-methyltransferase activity; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR002935; SAM_O-MeTrfase.
DR Pfam; PF01596; Methyltransf_3; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51682; SAM_OMT_I; 1.
PE 1: Evidence at protein level;
KW Metal-binding; Methyltransferase; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..252
FT /note="O-methyltransferase hkm8"
FT /id="PRO_0000452935"
FT BINDING 73
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 75..76
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 81
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 100
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
SQ SEQUENCE 252 AA; 29031 MW; FEA9D6C1FFC8920C CRC64;
MRDRCMLSFT KEQLTSVGEY CTLHSSPLPK SVEEQCRVTD ERSQDEVVMA PSPAQCAWLM
SFALASRPRR ILELGTFTGV STLAFYEGTR KTKAEIITVD MSEEYLQIAE TAFRRHGATD
RIQTIRGPCL EILPTITGEF DLIYIDAAEE EYEAYTRFVL DHKLLSAEGV MLVDDGTYIR
WFYFFQANWW SVLLEGLVVD RSIVKEFPEE IQEPYLGIAD QMNDFNRYAR SDPRVEVTMI
PLFNGVTQIT WK
