MALE_MALAU
ID MALE_MALAU Reviewed; 438 AA.
AC L0E2P7;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Prenyltransferase malE {ECO:0000303|PubMed:23213353};
DE EC=2.5.1.- {ECO:0000269|PubMed:31548667};
DE AltName: Full=Malbrancheamide biosynthesis cluster protein E {ECO:0000303|PubMed:23213353};
GN Name=malE {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, CATALYTIC ACTIVITY, AND PATHWAY.
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: Prenyltransferase; part of the gene cluster that mediates the
CC biosynthesis of malbrancheamide, a dichlorinated fungal indole alkaloid
CC that belongs to a family of natural products containing a
CC 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 -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-3-(indol-3-ylmethyl)-6,7,8,8a-tetrahydropyrrolo[1,2-
CC a]pyrazin-1-one + dimethylallyl diphosphate = (S)-3-{[2-(1,1-
CC dimethylallyl)-indol-3-yl]methyl}-6,7,8,8a-tetrahydropyrrolo[1,2-
CC a]pyrazin-1-one + diphosphate; Xref=Rhea:RHEA:62288,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57623, ChEBI:CHEBI:145652,
CC ChEBI:CHEBI:145655; Evidence={ECO:0000269|PubMed:31548667};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62289;
CC Evidence={ECO:0000269|PubMed:31548667};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-hydroxy-3-(indol-3-ylmethyl)-6H,7H,8H-5lambda(5)-
CC pyrrolo[1,2-a]pyrazine + dimethylallyl diphosphate = 1-hydroxy-3-{[2-
CC (1,1-dimethylallyl)-indol-3-yl]methyl}-6H,7H,8H-5lambda(5)-
CC pyrrolo[1,2-a]pyrazine + diphosphate; Xref=Rhea:RHEA:62736,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57623, ChEBI:CHEBI:145657,
CC ChEBI:CHEBI:145928; Evidence={ECO:0000269|PubMed:31548667};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62737;
CC Evidence={ECO:0000269|PubMed:31548667};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:31548667}.
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 tryptophan dimethylallyltransferase family.
CC {ECO:0000305}.
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DR EMBL; JQ708193; AGA37265.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E2P7; -.
DR SMR; L0E2P7; -.
DR BioCyc; MetaCyc:MON-21924; -.
DR GO; GO:0004659; F:prenyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:InterPro.
DR GO; GO:0044249; P:cellular biosynthetic process; IEA:UniProt.
DR GO; GO:1901576; P:organic substance biosynthetic process; IEA:UniProt.
DR CDD; cd13929; PT-DMATS_CymD; 1.
DR InterPro; IPR033964; Aro_prenylTrfase.
DR InterPro; IPR017795; Aro_prenylTrfase_DMATS.
DR InterPro; IPR012148; DMATS-type_fun.
DR PANTHER; PTHR40627; PTHR40627; 1.
DR Pfam; PF11991; Trp_DMAT; 1.
DR PIRSF; PIRSF000509; Trp_DMAT; 1.
DR SFLD; SFLDS00036; Aromatic_Prenyltransferase; 1.
DR TIGRFAMs; TIGR03429; arom_pren_DMATS; 1.
PE 1: Evidence at protein level;
KW Prenyltransferase; Transferase.
FT CHAIN 1..438
FT /note="Prenyltransferase malE"
FT /id="PRO_0000448775"
FT BINDING 92
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 106
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 192
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 194
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 259
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 261
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 346
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 411
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
SQ SEQUENCE 438 AA; 49509 MW; 6A540FC30F0A8BC9 CRC64;
MTAGPMGNKS TSDIDSVLVY KSLSRYLKFS ENEEGWWHKT APLLNKILAA AKYDVHLQYR
YLVFYYAACV SALGPYPQRF SSSITRSGLP VEFSVNYQNN SKPIVRIGYE PISHLSGTER
DPYNHKTASE IVATLSKIQP DFDPRLFNYF VHQLSVNKAE SDVLNGANVE GSEMKSQTAF
GFDLVNGEIS VKGYAFPAMK CQVSQQSLSQ LLKAAINGLK GEFDCAFGLV DEYMERCGGY
NQFSFVSWDC VVPAKSRFKV YGVHNDVTWK KIEDIWTLGG QATSGNVTKG LELLKELWTL
IDLDEGERGY TGRFDDANDN GSNIQSPMVW NYELRPNNPW PLAKFYFPVH GENDMKIVKG
LARFFENRGW TELARSYVQT VSSFFPDRDL NQTQRLVSWI SFAYTEKTGV YLSVYYHSSA
DYLWISESGE KRGQGDGA
