MALB_MALAU
ID MALB_MALAU Reviewed; 369 AA.
AC L0E2Y5;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 19.
DE RecName: Full=Prenyltransferase malB {ECO:0000303|PubMed:23213353};
DE EC=2.5.1.- {ECO:0000269|PubMed:31548667};
DE AltName: Full=Malbrancheamide biosynthesis cluster protein B {ECO:0000303|PubMed:23213353};
GN Name=malB {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, AND CATALYTIC ACTIVITY.
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 -!- 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; AGA37262.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E2Y5; -.
DR SMR; L0E2Y5; -.
DR GO; GO:0004659; F:prenyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:InterPro.
DR CDD; cd13929; PT-DMATS_CymD; 1.
DR InterPro; IPR017795; Aro_prenylTrfase_DMATS.
DR PANTHER; PTHR40627; PTHR40627; 1.
DR Pfam; PF11991; Trp_DMAT; 1.
DR TIGRFAMs; TIGR03429; arom_pren_DMATS; 1.
PE 1: Evidence at protein level;
KW Prenyltransferase; Transferase.
FT CHAIN 1..369
FT /note="Prenyltransferase malB"
FT /id="PRO_0000448774"
FT BINDING 87
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 100
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 189
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 191
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
SQ SEQUENCE 369 AA; 41225 MW; 4961BCF24F811D89 CRC64;
MPSQSPYHAL SRYFSFPNRD HQAWWTGKGP LLGNMLADAG YPEQQQYQYL TLFNLHLIPA
LGPSESHGAG IDGAEWKSLL SGSGKLEFSM TYRKSAVSLR IAFEPTSLLA GTKKDVFNKR
RTQQLLGDLE RLDIDIDTVL YHPLFDTLVV SDEEEAALQN AGTVIPDSSR TQQLLALNLI
EGNVRADLYV YPYVKALATG TASSTLLWAA VKKIDRYNRF RDALSILKGY FETYPSSTTN
PMFLSSDLAA PRNAFCRLFF SETNFSWERV QHLWTLGGTL SDKPTLKGLE LAKILWDILG
ISTAPASPDS FPLLFTFELR PEQPYLRQKL GIPVSGLTES AIANACVAFF ERLGWDDHAA
SYRTNLSAY
