Protein: Flavin-dependent halogenase rdc2 (EC 1.14.14.-) (Hypothemycin biosynthesis cluster protein rdc2) (Non-heme halogenase rdc2) (B3FWT7)
Organism: Metacordyceps chlamydosporia (Nematophagous fungus) (Pochonia chlamydosporia)
Function: Flavin-dependent halogenase; part of the gene cluster that mediates the biosynthesis of radicicol, a resorcylic acid lactone (RAL) that irreversibly inhibits the HSP90 molecular chaperone, an important target for cancer chemotherapy. Within the cluster, rdc2 is involved in the chlorination of the resorcylic acid lactone (RAL) structure to convert monocillin I into radicicol. Also chlorinates monocillin II to produce 6-cholomonocillin II and monocilllin IV to produce 13-chloromonocillin IV. In contrast to most fungal halogenases, rdc2 has a broad substrate specificity and can accept a variety of macrolactones as the substrates to generate chlorinated derivatives, including dihydroresorcylide, zearalenone, curvularin, or even curcumin. Rdc2 is able to dichlorinate dihydroresorcylide and monocillin IV. Dihydroresorcylide is first chlorinated at position 11 to produce 11-chlorodihydroresorcylide which can be further chlorinated by rdc2 at possition 13. Mororeover, rdc2 can incorporate bromine into dihydroresorcylide to yield the corresponding mono- and di-brominated derivatives. Finally, rdc2 is also able to halogenate the isoquinolines 4-hydroxyisoquinoline and 6-hydroxyisoquinoline into 3-chloro-4-hydroxyisoquinoline and 5-chloro-6-hydroxyisoquinoline, respectively. The radicicol cluster encodes only two apparent post-PKS enzymes, a cytochrome P450 monooxygenase (rdc4) and a non-heme halogenase (rdc2) that could introduce the epoxide and the chlorine, respectively. If this cluster includes all the genes required for radicicol biosynthesis, the remaining structural features of radicicol are presumably generated by the PKSs rdc1 and rdc5. The C-2' ketone could arise if the R-PKS rdc5 and NR-PKS rdc1 each carry out four iterations, in contrast to the five iteration-three iteration split for the hypothemycin PKSs. The origin of the cis 5',6' double bond is not known. The radicicol R-PKS rdc5 ER domain may catalyze either double bond isomerization or reduction in the third iteration (Probable).
InterPro domains:
- IPR050816: Flavin-dependent Halogenases in Natural Product Biosynthesis (family) [1-413]
- IPR036188: FAD/NAD(P)-binding domain superfamily (homologous_superfamily) [2-431]
- IPR006905: Flavin-dependent halogenase (family) [9-333]
Sequence:
MSVPKSCTILVAGGGPAGSYAAAALAREGNDVVLLEADQHPRYHIGESMLPSLRPLLRFIDLEDKFDAHGFQKKLGAAFKLTSKREGSHGPRGYSWNVVRSESDEILFNHARESGAQAFQGIKINAIEFEPYEEEYPNGEKVANPGKPTSAKWSSKDGSSGDIAFKYLVDATGRIGIMSTKYLKNRHYNEGLKNLAIWGYYKNNIPWAQGTPRENQPFFEGMRDGAGWCWTIPLHNGTVSVGAVMRKDLFFEKKKSLGENATNTQIMAECMKLCPTIGELLAPAELVSDIKQATDYSYSATAYAGPNFRIVGDAGCFIDPFFSSGHHLAVAGALAAAVSINASIKGDCTEYEASRWHAKKVDEGYTLFLLVVMAALKQIRMQENPVLSDVDEDGFDRAFQFLRPEAVKKFTKEDVAQTIDFAVHALNNMAELDMDIPEHMINGDKEGENGVTNGNNGAAKTAGLASNMEKLTNDEEKVLNGLRILGKAAPGGTLADFEGTAIDGLMPRLEHGKLGLNKV
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016491 (oxidoreductase activity), GO:0016705 (oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009058 (biosynthetic process), GO:0019748 (secondary metabolic process), GO:0044550 (secondary metabolite biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005737 (cytoplasm), GO:0005622 (intracellular anatomical structure)