HKM11_ASPHA
ID HKM11_ASPHA Reviewed; 1305 AA.
AC P0DUL9;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 02-JUN-2021, sequence version 1.
DT 25-MAY-2022, entry version 4.
DE RecName: Full=Nonribosomal peptide synthetase hkm11 {ECO:0000303|PubMed:33242032};
DE EC=6.3.2.- {ECO:0000269|PubMed:33242032};
DE AltName: Full=Hancockiamides biosynthesis cluster protein 11 {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, DOMAIN, CATALYTIC ACTIVITY, 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: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of hancockiamides, an unusual new family
CC of N-cinnamoylated piperazines (PubMed:33242032). The NRPS hkm10 and
CC the NmrA-like reductase hkm9 are proposed to convert two molecules of
CC L-Phe to the intermediary piperazine called xenocockiamide A
CC (Probable). Xenocockiamide A is then converted to hancockiamide D via a
CC series of hydroxylations and O-methylations (Probable). The tyrosinase
CC hkm6 may catalyze an aromatic hydroxylation, then the 2-oxoglutarate-
CC dependent Fe(II) dioxygenase hkm4 and the FAD-dependent phenol
CC hydroxylase hkm7 may catalyze consecutive hydroxylations to install 2
CC more hydroxy groups, and the methyltransferase hkm8 probably catalyzes
CC two 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:0000269|PubMed:33242032}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC epimerase (E) domains (responsible for l- to d- amino acid conversion)
CC are present within the NRP synthetase. Hkm11 has the following
CC architecture: A-T-C. {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 NRP synthetase family. {ECO:0000305}.
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DR EMBL; MBFL02000005; KAF7597139.1; -; Genomic_DNA.
DR AlphaFoldDB; P0DUL9; -.
DR SMR; P0DUL9; -.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 1.
DR Pfam; PF00550; PP-binding; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein.
FT CHAIN 1..1305
FT /note="Nonribosomal peptide synthetase hkm11"
FT /id="PRO_0000452938"
FT DOMAIN 788..864
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:33242032"
FT REGION 278..672
FT /note="Adenylation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:33242032"
FT REGION 926..1166
FT /note="Condensation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:33242032"
FT MOD_RES 825
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1305 AA; 144312 MW; 89CF989DB3B010E7 CRC64;
MTVPATTKDP RDSLLDSPLV HFPSLPRDSY LPHPTEHTVV SIDDEEILPS TRSSLHDVLQ
VAWSLVLADQ TSSPEVVFGM AYDGRTTDDG EQAIMPFRLR LRAEDSVQEA LAAAAAVTLQ
MRQWEHMGLR RFSTMSPQNV VLCQFRNLFV IDHKDPTEDC VERSCTSYSK GYALTVLCEI
VDQVIHVHAM FDPLVLPPGQ LRLILHQFGD ILKTCLRGPP GRVKDLQQIG PDGLNYIYEW
NRGGERDEGI VCVHQLIEDR FKQAPFAAAV CAWDGALTYG ELDRWAKRIA AQLVEAGVKP
GSFVGIYMQK SVLAVVAMVA IVKAGAAFIF LPPFLPTVRL QLMCQRTPVE LVLSVATLLR
SASDLSVPVQ VLDYRAKDEE ETAATSGGSE IAQPNHPLYA IFTSGSTGEP KGVVVDRASF
GPGVREYCRR AQLGPNSRLF QSVSYAFIVS IFEQLISLAL GACICVPSEE QLQNDMEGAM
CRYQATWGCM TPSVARTLKP ERLSCLKTLA LTGEPVNQSD MEQWKDHVNL YTLYGQSETG
STLLINSITG SLADSRGLGR PSTGACWIVD PEDPTTLRPL GAEGELLIET TALARGYMNN
LEESARTFIE MPKWLKQLRP QGHRSRCLLT GDIVRYYDTD GTIRLLSRKG TGAKIRGQRV
ELGEIEHHLR PKFPDARHIL VDVVCPAKAG TGHSILVAFV HGPWKDTEKT GELATATSEF
RQQARRVIAE LRQVLPSFMV PSAIVPLADV PTTATGKVHR KSLRERMSAL TVAEILAYNQ
EDRSAYRAPT TEQEALLLSI CAELLYLPAS SISLDNSFFQ VGGDSLNARQ LAAKVRSHGF
SLLATDIFEA STLASLASRM RQYNQTDSEV STAPEGDPFE GLKQELLGEL PSSLVKENVE
DVYPASDMQA RAIRTHMLDY FPFEIKGQLD RHQLQHACET LIRRTPVMRS VFINFRGKML
QVTLRSVAIP YKELTIPTGE DPLSWARLHI AEDKKKTAAF DRPTIRFTLC RQSLQHHIFI
VRLPHAIYDG SCLEQVAKQI SAAYNAQTLP EAPDFAAYAR RCARLRTPSA MDFWRNFLAE
SEVTRLPHAS KGDEVAVIYP GECSPRSPPP GITMATAIKA AWAWVLHKRT GKLDVLFGQV
GSTRGIDIPG ATDIIGLCLN ITAVRVQFAG LQTVEDLLRM LQQQHMRALM YETADWTDIV
ANASSWPEGT ELDSVVLHEN FGGLPALDLG DAIGEMADPI FSLSTSNPLT LVTWPSTQTL
TSFLLTRENV FQKEYAEGLV TEFNQTLVQF LDFPESSLCS ISTCG
