Pladienolide B

Pladienolide B

Names
IUPAC name [(2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3S)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate
Identifiers
CAS Number	445493-23-2
3D model (JSmol)	Interactive image
ChemSpider	17330476
PubChem CID	16202130
CompTox Dashboard (EPA)	DTXSID701098499
InChI InChI=1S/C30H48O8/c1-8-24(33)21(5)29-25(37-29)16-18(2)10-9-11-19(3)28-20(4)12-13-26(36-22(6)31)30(7,35)15-14-23(32)17-27(34)38-28/h9-13,18,20-21,23-26,28-29,32-33,35H,8,14-17H2,1-7H3/b10-9+,13-12+,19-11+/t18-,20+,21-,23-,24+,25-,26+,28-,29-,30-/m1/s1 Key: SDOUORKJIJYJNW-QHOUZYGJSA-N
SMILES CC[C@@H]([C@@H](C)[C@@H]1[C@H](O1)C[C@H](C)/C=C/C=C(\C)/[C@@H]2[C@H](/C=C/[C@@H]([C@](CC[C@H](CC(=O)O2)O)(C)O)OC(=O)C)C)O
Properties
Chemical formula	C30H48O8
Molar mass	536.706 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Pladienolide B is a natural product produced by bacterial strain, Streptomyces platensis MER-11107, which is a gram-positive bacteria isolated from soil in Japan. Pladienolide B is a molecule of interest due to its potential anti-cancer properties. Its anti-cancer mode of action includes binding to the SF3B complex in the U2 snRNP (small nuclear ribonuclear protein) in the human spliceosome.

Biosynthesis

As a polyketide, pladienolide B is synthesized in the polyketide synthase (PKS) type I pathway, a biosynthetic pathway that is derived from the fatty acid synthase (FAS) pathway. Polyketides are formed through the condensation of acyl-thioester units. The synthesis of pladienolide B begins with acyl transferase loading propionyl CoA onto the holo (activated) acyl carrier protein (ACP). The molecule is then extended ten times, each time by two carbon units, by iterative PKS (Figure 1). Figure 1 indicates the loading unit (malonyl CoA or methylmalonyl CoA) and tailoring enzymes for each module (turquoise enzyme clusters in part c of Figure 1). After the ten elongation modules, the active site serine residue of thioesterase (TE) acts as a nucleophile by attacking the ketone directly bound to CoA-SH. This nucleophilic attack causes CoA-SH to leave and thus transfers the elongated chain to TE. Then the hydroxyl group on carbon 11 acts as a nucleophile by attacking the terminal ketone so that carbons 1-11 form a cyclic, 12-membered ring, releasing TE in the process. This concludes the PKS portion of the biosynthesis, and thus results in the pladienolide B backbone structure.

Post-PKS modifications: Acetyl-transferase (AT) transfers an acetyl group to carbon 7. The following step is either that a P450 I enzyme (PldB C6-hydroxylase) adds a hydroxyl group on carbon 6, and/or that an epoxide group is added between carbons 18 and 19 by P450 II (PldD C18-C19-epoxidase). Based on the purification results of these post-PKS compounds by Boothe et al., it seems that either hydroxylation or acetylation could occur first, but Boothe et al. found a that hydroxylation seems to occur first more than twice as often as acetylation occurs first. However, regardless of hydroxylation or acetylation occurring first, the result of these tailoring steps yields pladienolide B (Figure 1).

Figure 1: Gene clusters (a) S. platensis Mer-11107 and (b) S. platensis AS6200/MA5455; and pladienolide B biosynthesis with tailoring and post-PKS modifications.

Carbons are numbered using the traditional IUPAC naming system in which C1 is the ketone carbon in the ring, and C23 is the terminal carbon on the chain.