Pleuromutilin

Source: Wikipedia, the free encyclopedia.
Pleuromutilin
Names
Preferred IUPAC name
(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-Ethenyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propanocyclopenta[8]annulen-8-yl hydroxyacetate
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
ECHA InfoCard
 100.004.316 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C22H34O5/c1-6-20(4)11-16(27-17(25)12-23)21(5)13(2)7-9-22(14(3)19(20)26)10-8-15(24)18(21)22/h6,13-14,16,18-19,23,26H,1,7-12H2,2-5H3/t13-,14+,16-,18+,19+,20-,21+,22+/m1/s1 ☒N
    Key: ZRZNJUXESFHSIO-BKUNHTPHSA-N ☒N
  • C[C@@H]1CC[C@@]23CCC(=O)[C@H]2[C@@]1([C@@H](C[C@@]([C@H]([C@@H]3C)O)(C)C=C)OC(=O)CO)C
Properties
C22H34O5
Molar mass 378.509 g/mol
Melting point 170-171 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Pleuromutilin and its derivatives are antibacterial drugs that inhibit

50S subunit of ribosomes.[1][2]

This class of antibiotics includes the licensed drugs

investigational drug azamulin.[citation needed
]

History

Pleuromutilin was discovered as an antibiotic in 1951.

fungi Omphalina mutila (formerly Pleurotus mutilus) and Clitopilus passeckerianus (formerly Pleurotus passeckerianus),[3] and has also been found in Drosophila subatrata, Clitopilus scyphoides, and some other Clitopilus species.[5]

Total synthesis

The total synthesis of pleuromutilin has been reported.[6][7][8][9]

Biosynthesis

Pleuromutilin belongs to the class of secondary metabolites known as terpenes, which are produced in fungi through the mevalonate pathway (MEP pathway).[10] Its synthetic bottleneck lays on the production of the precursor GGPP and the following formation of the tricyclic structure, which is catalyzed by Pl-cyc, a bifunctional diterpene synthase (DTS). This Cyclase shows a new class II DTS activity, catalyzes a ring contraction and the formation of a 5-6-bicyclic ring structure. Specifically, DTS shows two catalytic distinguishable domains: On the one hand it has at the N-terminal region a class II DTS domain, which catalyzes a cascade cyclization, resulting in a decalin core. Subsequently, variable 1,2-proton and methyl shifts occur to translocate the carbocation towards one of the two interconnecting C-atoms and this intermediate induces a base-catalyzed ring contraction. Therefore, class II DTS promotes in general a ring contraction during the cyclisation of GGPP. On the other hand, at the C-terminal end it has a class I DTS domain, which catalyzes a conjugated dephosphorylation, generating the 8-membered cyclic core, followed by a 1,5-proton shift and a stereospecific hydroxylation to obtain premutilin.[11]

Proposed biosynthetic pathway of pleuromutilin.[12][13] The left part of the scheme represents a general biosynthetic approach for Geranylgeranyl pyrophosphate (GGPP). The following cyclisation steps to the pleuromutilin tricyclic core will be provided by class II and class I terpene synthase domain of Pl-cyc. Final catalytic, stereospecific hydroxylation at C-11 and C-3 (Pl-p450-1, Pl-p450-2), regiospecific oxidation of the 3-hydroxy group to a ketone (Pl-sdr), acetyl-group-transfer at OH-14 (Pl-atf) and final hydroxylation at the α-acetyl position (Pl-p450-3) will lead to pleuromutilin.[11]

Additionally, three

mutilin. Acetyltransferase (Pl-atf) catalyzes the transfer of acetyl group to 14-OH of mutilin. Finally, Pl-p450-3 hydroxylates the α-methyl group of the acetyl side chain generating pleuromutilin.[14][15]

References

  1. S2CID 11479628
    .
  2. PMID 27958389
    .
  3. ^
    PMID 16589015
    .
  4. S2CID 41588014
    .
  5. S2CID 22127410
    .
  6. S2CID 102155530
    .
  7. S2CID 96627402
    .
  8. S2CID 46105984
    .
  9. S2CID 206658420
    .
  10. PMID 11078528
    .
  11. ^
    S2CID 58661785
    .
  12. doi:10.1016/S0040-4020(01)90949-4
    .
  13. S2CID 34616923
    .
  14. ^
    PMID 29184068
    .
  15. PMID 27143514
    .

Further reading
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