PHQE_PENFE
ID PHQE_PENFE Reviewed; 265 AA.
AC L0E2Z4;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Short-chain dehydrogenase/reductase phqE {ECO:0000303|PubMed:23213353};
DE EC=1.1.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Paraherquamide biosynthesis cluster protein E {ECO:0000303|PubMed:23213353};
GN Name=phqE {ECO:0000303|PubMed:23213353};
OS Penicillium fellutanum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=70095;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC STRAIN=ATCC 20841 / MF5123;
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] {ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM}
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH COFACTOR AND
RP SUBSTRATE, FUNCTION, COFACTOR, 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: Short-chain dehydrogenase/reductase; part of the gene cluster
CC that mediates the biosynthesis of paraherquamide, a fungal indole
CC alkaloid that belongs to a family of natural products containing a
CC characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The
CC first steps in the biosynthesis of paraherquamide is the production of
CC the beta-methyl-proline precursor from L-isoleucine (Probable). They
CC require oxidation of a terminally hydroxylated L-isoleucine to the
CC corresponding aldehyde by enzymes which have still to be identified
CC (Probable). Spontaneous cyclization and dehydration would yield the 4-
CC methyl pyrolline-5-carboxylic acid, which is then reduced by the
CC pyrroline-5-carboxylate reductase phqD leading to the beta-methyl-
CC proline precursor (Probable). The next step of paraherquamide
CC biosynthesis involves coupling of beta-methyl-proline and L-tryptophan
CC by the bimodular NRPS phqB, to produce a monooxopiperazine intermediate
CC (Probable). The reductase (R) domain of phqB utilizes NADPH for hydride
CC transfer to reduce the thioester bond of the T domain-tethered linear
CC dipeptide to a hemithioaminal intermediate, which spontaneously cleaves
CC the C-S bond to release the aldehyde product (PubMed:31548667). This
CC compound undergoes spontaneous cyclization and dehydration to give a
CC dienamine which is reverse prenylated at C-2 by the reverse
CC prenyltransferase phqJ (Probable). The other prenyltransferase present
CC in the cluster, phqI may be a redundant gene in the pathway (Probable).
CC During biosynthetic assembly, the key step to produce the polycyclic
CC core is catalyzed by the bifunctional reductase and intramolecular
CC [4+2] Diels-Alderase, phqE, resulting in formation of the [2.2.2]
CC diazaoctane intermediate preparaherquamide (PubMed:31548667). Following
CC formation of preparaherquamide, an indole 2,3-epoxidation-initiated
CC pinacol-like rearrangement is catalyzed by the phqK FAD-dependent
CC monooxygenase (Probable). The prenyltransferase phqA, the cytochrome
CC P450 monooxygenase phqL, and the FAD-linked oxidoreductase phqH (or the
CC cytochrome P450 monooxygenase phqM), are proposed to be involved in the
CC formation of the pyran ring (Probable). The FAD-dependent monooxygenase
CC phqK is likely responsible for generation of the spiro-oxindole, and
CC the N-methylation is likely mediated by the phqN methyltransferase
CC leading to the isolable natural product paraherquamide F (Probable).
CC However, the order of these biosynthetic steps has still to be
CC determined (Probable). In late-stage paraherquamide biosynthesis, the
CC third P450 monooxygenase, phqO, is probably responsible for the C-14
CC hydroxylation, transforming paraherquamide F to paraherquamide G, and
CC paraherquamide E to the final product paraherquamide A (Probable). The
CC expansion from the 6-membered ring pyran (in paraherquamides F and G)
CC to the 7-membered dioxepin ring (in paraherquamides A and E) represents
CC a poorly understood but intriguing process that probably involves the
CC 2-oxoglutarate-dependent dioxygenase phqC (Probable). Finally, the
CC remaining members of the paraherquamide cluster, including phqI as well
CC as phqM (or phqH), do not have a clearly prescribed role and appear to
CC be redundant (Probable). {ECO:0000269|PubMed:23213353,
CC ECO:0000269|PubMed:31548667, ECO:0000305|PubMed:23213353}.
CC -!- COFACTOR:
CC Name=NADP(+); Xref=ChEBI:CHEBI:58349;
CC Evidence={ECO:0000269|PubMed:31548667};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; JQ708195; AGA37272.1; -; Genomic_DNA.
DR PDB; 6NKK; X-ray; 2.30 A; A/B/C/D/E/F=1-265.
DR PDB; 6NKM; X-ray; 1.90 A; A/B/C/D/E/F=1-265.
DR PDBsum; 6NKK; -.
DR PDBsum; 6NKM; -.
DR AlphaFoldDB; L0E2Z4; -.
DR SMR; L0E2Z4; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR002347; SDR_fam.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alkaloid metabolism; Membrane; NADP; Oxidoreductase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..265
FT /note="Short-chain dehydrogenase/reductase phqE"
FT /id="PRO_0000448869"
FT TRANSMEM 25..45
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 18..42
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P50162"
FT BINDING 23
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKM"
FT BINDING 24
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 26
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 46
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 47
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 50
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 76
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKM"
FT BINDING 131
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK"
FT BINDING 203
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT BINDING 205
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:31548667,
FT ECO:0007744|PDB:6NKK, ECO:0007744|PDB:6NKM"
FT TURN 11..14
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 16..20
FT /evidence="ECO:0007829|PDB:6NKM"
FT TURN 21..23
FT /evidence="ECO:0007829|PDB:6NKK"
FT HELIX 25..36
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 40..46
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 48..61
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 67..69
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 70..74
FT /evidence="ECO:0007829|PDB:6NKM"
FT TURN 80..82
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 83..95
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 102..105
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 121..125
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 128..131
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 133..141
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 142..144
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 153..157
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 160..162
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 170..189
FT /evidence="ECO:0007829|PDB:6NKM"
FT TURN 190..192
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 193..200
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 206..212
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 213..215
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 216..225
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 226..231
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 235..247
FT /evidence="ECO:0007829|PDB:6NKM"
FT STRAND 255..259
FT /evidence="ECO:0007829|PDB:6NKM"
FT HELIX 262..264
FT /evidence="ECO:0007829|PDB:6NKM"
SQ SEQUENCE 265 AA; 27528 MW; 70EA24697EED5C49 CRC64;
MTPAPTPRTD QLHGSRVLVI GGTSGIGFAV CAAALGHGAI VTIVGSNAQK LKDSVARLKS
SFPSTDPDDI VAVRCDLSNS DTVEQDIEKA LQLAAGNSKI NHIVITAADM TAPPPLEDLT
VDSVQRPGII RLVAPLMVAK HLPKYMNKCP QSSLTLTSGA HCLRPDPGWT VISGYCGAVE
AMSRGLAIDL KPLRVNVVAP GAVLTEAVKD ILGDAYDAAV EMAEAKSTVG QTGSPESVAQ
AYIYLMKDHY ASGSVVSTNG GMLLV
