MALF_MALAU
ID MALF_MALAU Reviewed; 590 AA.
AC L0E159;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 25-MAY-2022, entry version 21.
DE RecName: Full=FAD-linked oxidoreductase malF {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305};
DE AltName: Full=Malbrancheamide biosynthesis cluster protein F {ECO:0000303|PubMed:23213353};
DE Flags: Precursor;
GN Name=malF {ECO:0000303|PubMed:23213353};
OS Malbranchea aurantiaca.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Onygenales; Onygenaceae; Malbranchea.
OX NCBI_TaxID=78605;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=RRC1813;
RX PubMed=23213353; DOI=10.1039/c2md20029e;
RA Li S., Anand K., Tran H., Yu F., Finefield J.M., Sunderhaus J.D.,
RA McAfoos T.J., Tsukamoto S., Williams R.M., Sherman D.H.;
RT "Comparative analysis of the biosynthetic systems for fungal
RT bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(-)-notoamide,
RT paraherquamide and malbrancheamide pathways.";
RL Med. Chem. Commun. 3:987-996(2012).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=18986806; DOI=10.1016/j.bmcl.2008.10.057;
RA Miller K.A., Figueroa M., Valente M.W., Greshock T.J., Mata R.,
RA Williams R.M.;
RT "Calmodulin inhibitory activity of the malbrancheamides and various
RT analogs.";
RL Bioorg. Med. Chem. Lett. 18:6479-6481(2008).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=19185562; DOI=10.1016/j.ab.2009.01.002;
RA Gonzalez-Andrade M., Figueroa M., Rodriguez-Sotres R., Mata R.,
RA Sosa-Peinado A.;
RT "An alternative assay to discover potential calmodulin inhibitors using a
RT human fluorophore-labeled CaM protein.";
RL Anal. Biochem. 387:64-70(2009).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=20939762; DOI=10.3109/14756366.2010.518964;
RA Figueroa M., Gonzalez-Andrade M., Sosa-Peinado A., Madariaga-Mazon A.,
RA Del Rio-Portilla F., Gonzalez M.C., Mata R.;
RT "Fluorescence, circular dichroism, NMR, and docking studies of the
RT interaction of the alkaloid malbrancheamide with calmodulin.";
RL J. Enzym. Inhib. Med. Chem. 26:378-385(2011).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=25643751; DOI=10.1111/jphp.12346;
RA Madariaga-Mazon A., Hernandez-Abreu O., Estrada-Soto S., Mata R.;
RT "Insights on the vasorelaxant mode of action of malbrancheamide.";
RL J. Pharm. Pharmacol. 67:551-558(2015).
RN [6]
RP FUNCTION.
RX PubMed=28777910; DOI=10.1021/jacs.7b06773;
RA Fraley A.E., Garcia-Borras M., Tripathi A., Khare D., Mercado-Marin E.V.,
RA Tran H., Dan Q., Webb G.P., Watts K.R., Crews P., Sarpong R.,
RA Williams R.M., Smith J.L., Houk K.N., Sherman D.H.;
RT "Function and structure of MalA/MalA', iterative halogenases for late-stage
RT C-H functionalization of indole alkaloids.";
RL J. Am. Chem. Soc. 139:12060-12068(2017).
RN [7]
RP FUNCTION.
RX PubMed=31548667; DOI=10.1038/s41557-019-0326-6;
RA Dan Q., Newmister S.A., Klas K.R., Fraley A.E., McAfoos T.J., Somoza A.D.,
RA Sunderhaus J.D., Ye Y., Shende V.V., Yu F., Sanders J.N., Brown W.C.,
RA Zhao L., Paton R.S., Houk K.N., Smith J.L., Sherman D.H., Williams R.M.;
RT "Fungal indole alkaloid biogenesis through evolution of a bifunctional
RT reductase/Diels-Alderase.";
RL Nat. Chem. 11:972-980(2019).
CC -!- FUNCTION: FAD-linked oxidoreductase; part of the gene cluster that
CC mediates the biosynthesis of malbrancheamide, a dichlorinated fungal
CC indole alkaloid that belongs to a family of natural products containing
CC a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353,
CC PubMed:31548667, PubMed:28777910). The first step of malbrancheamide
CC biosynthesis involves coupling of L-proline and L-tryptophan by malG, a
CC bimodular NRPS, to produce L-Pro-L-Trp aldehyde through reductive
CC offloading (PubMed:23213353, PubMed:31548667). This compound undergoes
CC spontaneous cyclization and dehydration to give a dienamine which is
CC reverse prenylated at C-2 by malE (PubMed:31548667). The other
CC prenyltransferase present in the cluster, malB, displays modest
CC activity, suggesting that may be a redundant gene in the pathway
CC (PubMed:31548667). Subsequently, a [4+2] Diels-Alder cyclo-addition
CC catalyzed by the bifunctional enzyme malC forms the characteristic
CC bicyclo[2.2.2]diazaoctane ring of premalbrancheamid (PubMed:31548667).
CC Finally, the flavin-dependent halogenase malA catalyzes the iterative
CC dichlorination of the indole ring of premalbrancheamide to yield C-9
CC monochlorinated malbrancheamide B, C-8 monochlorinated
CC isomalbrancheamide B, and dichlorinated malbrancheamide
CC (PubMed:31548667, PubMed:28777910). MalA is also able to brominate
CC premalbrancheamide at C-9 to yield malbrancheamide C, and, to a lesser
CC extend, at C-8 to yield isomalbrancheamide C (PubMed:28777910).
CC Finally, malA can brominate C-9 monochlorinated malbrancheamide B at C-
CC 8 to yield malbrancheamide D, or C-8 monochlorinated isomalbrancheamide
CC B at C-9 to produce isomalbrancheamide D (PubMed:28777910).
CC {ECO:0000269|PubMed:23213353, ECO:0000269|PubMed:28777910,
CC ECO:0000269|PubMed:31548667}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- BIOTECHNOLOGY: Malbrancheamides have the ability to inhibit calmodulin,
CC calmodulin-dependent phosphodiesterase (PDE1), and induce both
CC endothelium-independent and endothelium-dependent relaxant effects,
CC suggesting their potential as vasorelaxant agents.
CC {ECO:0000269|PubMed:18986806, ECO:0000269|PubMed:19185562,
CC ECO:0000269|PubMed:20939762, ECO:0000269|PubMed:25643751}.
CC -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; JQ708193; AGA37266.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E159; -.
DR SMR; L0E159; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 2.
DR InterPro; IPR012951; BBE.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF08031; BBE; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Oxidoreductase; Signal.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..590
FT /note="FAD-linked oxidoreductase malF"
FT /id="PRO_5003940680"
FT DOMAIN 117..303
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 44
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 80
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 103
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 178
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 396
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 590 AA; 63275 MW; 70BAE8A624C77B54 CRC64;
MKYTATFALL ILAIGIQTQR RSTICRCRQE DACWPTTAEW SSLNQSIDGK LRHLRPVGLP
CQQSAYHKEK CDEVLAMTHN SSWRVDHPES LQLVSWESWP EKNQSCQIVR EAVDGCAQGR
IPLYSAAVES TKQVQQAVSF AKHRNLRLVV RNTGHDMAGR SSAPGSLQIL TSGLKGINYT
ENFVPFITQG SAEPMGPAVT IGAGILTGEL YATGSEKGFV VLGGACSTVG IAGGFIQSGG
MGILSPSKGL GSDHVLQVEI VTADGSHIIA NQYQNEDLFW AVRGGGGGTF GVITSVTLRA
FADLPATVTG IQINTPSADA IFWAGVKTVL SILPELTDAG NSARMIVLPA SSTGGASASF
EGYTFNKKGA VSLLALQRAL DDFGIPFKLS HDFQGNLSRF LAAPKGVDLA GISVIPGSVF
LSYDLVASKD GPAKVTSALS DLRLGPGSSF SVDAFGGGQV VNNKNRINSA VHPDWRSALL
SLTVGRGVPP GYTLETLKSI ESELENDQLP RLRSLEGGRK GAYLAVAYPN EVYFQDSFWG
KNYDRLLKVK RAWDPEDLFI TRVGVGSERW DDEGMCTRAD SGLWHALARF
