MALD_MALAU
ID MALD_MALAU Reviewed; 336 AA.
AC L0E2T7;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 18.
DE RecName: Full=NmrA-like family domain-containing oxidoreductase malD {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305};
DE AltName: Full=Malbrancheamide biosynthesis cluster protein D {ECO:0000303|PubMed:23213353};
GN Name=malD {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: NmrA-like family domain-containing oxidoreductase; part of
CC the gene cluster that mediates the biosynthesis of malbrancheamide, a
CC dichlorinated fungal indole alkaloid that belongs to a family of
CC natural products containing a characteristic bicyclo[2.2.2]diazaoctane
CC core (PubMed:23213353, PubMed:31548667, PubMed:28777910). The first
CC step of malbrancheamide biosynthesis involves coupling of L-proline and
CC L-tryptophan by malG, a bimodular NRPS, to produce L-Pro-L-Trp aldehyde
CC through reductive offloading (PubMed:23213353, PubMed:31548667). This
CC compound undergoes spontaneous cyclization and dehydration to give a
CC dienamine which is reverse prenylated at C-2 by malE (PubMed:31548667).
CC The other prenyltransferase present in the cluster, malB, displays
CC modest 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 NmrA-type oxidoreductase family.
CC {ECO:0000305}.
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DR EMBL; JQ708193; AGA37264.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E2T7; -.
DR SMR; L0E2T7; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR008030; NmrA-like.
DR Pfam; PF05368; NmrA; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW NADP; Oxidoreductase.
FT CHAIN 1..336
FT /note="NmrA-like family domain-containing oxidoreductase
FT malD"
FT /id="PRO_0000448777"
FT BINDING 12..17
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 40..44
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 61..62
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 82..84
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 140
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 163..166
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
SQ SEQUENCE 336 AA; 37569 MW; 501C5F7A5C5FBDB2 CRC64;
MDTGKRLVTV FGGTGNQGSS VVRSLLAHKD KLFHVRVITR DPTSEKAQAC AKLGAELVKA
DGFNKSETVS AFMGSWGAFV NTNSDEEIYK IPGGRSDYDL GSTVLDATKE AGVKHVVYSS
GLNLCKYTNG RVHSEGFESK YYVEQYGRRK GFQTFTPIVP ASFMEAFLAE SFCQSLGGFP
WFKRDTGEYL LATPPYGGDE RMPWVSVEDD FGDIVHGIFL DPDSYHLKTI QGSSELISFE
KMVEDFMEVT GEKARYVRLK SWVDIPLDGT SCREEMRAIF HSMYSNGGKW FVPDESEIDT
ATTLKKEAKL AQGVTDGSLT AFKDWIHKQW ERRLPN
