Pikromycin

Pikromycin
IUPAC name (3R,5R,6S,7S,9R,11E,13S,14R)-14-ethyl-13-hydroxy-3,5,7,9,13-pentamethyl-2,4,10-trioxooxacyclotetradec-11-en-6-yl 3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranoside
Other names Picromycin
Identifiers
CAS number	19721-56-3 Y
PubChem	5282037
ChemSpider	4445267 Y
ChEBI	CHEBI:29665
Jmol-3D images	{{#if:O=C2[C@@H]([C@@H](O[C@@H]1O[C@@H](C[C@H](N(C)C)[C@H]1O)C)[C@@H](C)C[C@H](C(=O)/C=C/[C@@](O)(C)[C@H](OC(=O)[C@@H]2C)CC)C)C|Image 1
SMILES O=C2[C@@H]([C@@H](O[C@@H]1O[C@@H](C[C@H](N(C)C)[C@H]1O)C)[C@@H](C)C[C@H](C(=O)/C=C/[C@@](O)(C)[C@H](OC(=O)[C@@H]2C)CC)C)C
InChI InChI=1S/C28H47NO8/c1-10-22-28(7,34)12-11-21(30)15(2)13-16(3)25(18(5)23(31)19(6)26(33)36-22)37-27-24(32)20(29(8)9)14-17(4)35-27/h11-12,15-20,22,24-25,27,32,34H,10,13-14H2,1-9H3/b12-11+/t15-,16+,17-,18+,19-,20+,22-,24-,25+,27+,28+/m1/s1 Y Key: UZQBOFAUUTZOQE-VSLWXVDYSA-N Y InChI=InChI=1S/C28H47NO8/c1-10-22-28(7,34)12-11-21(30)15(2)13-16(3)25(18(5)23(31)19(6)26(33)36-22)37-27-24(32)20(29(8)9)14-17(4)35-27/h11-12,15-20,22,24-25,27,32,34H,10,13-14H2,1-9H3/b12-11+/t15-,16+,17-,18+,19-,20+,22-,24-,25+,27+,28+/m1/s1
Properties
Molecular formula	C28H47NO8
Molar mass	525.67 g mol−1
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic macrolide to be isolated.^[1] Pikromycin is synthesized through a type I polyketide synthase system in Streptomyces venezuelae, a species of Gram-positive bacterium in the Streptomyces genus. ^[2] Pikromycin is derived from narbonolide, a 14-membered ring macrolide. ^[3] Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as ertythromycins and new epothilones. ^[4]

Biosynthesis

The pikromycin polyketide synthase of Streptomyces venezuelae contains four polypeptides: PikAI, PikAII, PikAIII, and PikAIV. These polypeptides contain a loading module, six extension molecules, and a thioesterase domain that that terminated the biosynthetic procedure. ^[5] In Figure 1, each circle corresponds to a PKS mutilifuctional protein, where ACP is acyl carrier protein, KS is keto-ACP synthase, KSQ is a keto-ACP synthase like domain, AT is acyltransferase, KR is keto ACP reductase, KR with cross is inactive KR, DH is hydroxyl-thioester dehydratase, ER is enoyl reductase, TEI is thioesterase domain I, TEII is type II thioesterase. ^[6] Des corresponds to the enzymes utilized in desosamine biosynthesis and transfer, which include DesI-DesVIII.

Figure 2 represents the desosamine deoxyamino sugar biosynthetic pathway. DesI-DesVI (des locus of pikromycin PKS) encodes all the enzymes needed to obtain TDP-desoamine from TDP-glucose. DesVII and DesVIII activities transfer desoamine to narbonolide and narbomycin is obtained. PikC cytochrome P450 hydrolase catalyzes the hydroxylation of narbomycin to obtain pikromycin. ^[7]

Figure 1: Domain organization of PKS for Narbonolide, a precursor of Pikromycin

Figure 2: Pikromycin Formation through the desosamine deoxyamino sugar biosynthetic pathway

See also

• polyketide synthase

References

1. ↑ Brockmann, H. and Henkel, W. (1951). "Pikromycin, ein bitter schmeckendes Antibioticum aus Actinomyceten". ntibiotica aus Actinomyceten, 84: 184–288. doi:10.1002/cber.19510840306. 
2. ↑ Y. Xue and D. Sherman (2001). "Biosynthesis and Combinatorial Biosynthesis of Pikromycin-Related Macrolides in Streptomyces venezuelae". Metabolic Engineering 3: 15–26. doi:10.1006/mben.2000.0167. 
3. ↑ Maezawa, T. Hori, A. Kinumaki and M. Suzuki (1973). "Biological conversion of narbonolide to picromycin". The Journal of Antibiotics 26: 771–775. PMID 4792390. 
4. ↑ J.D. Kittendorf and D.H. Sherman (2009). "The Methymycin/Pikromycin Biosynthetic Pathway: A Model for Metabolic Diversity in Natural Product". Bioorg Med Chem 17: 2137–2146. doi:10.1016/j.bmc.2008.10.082. 
5. ↑ S. Guptaa, V. Lakshmanan, B.S. Kima, R. Fecik, and K. A. Reynolds (2008). "Generation of Novel Pikromycin Antibiotic Products Through Mutasynthesis". Chembiochem 10: 1609–1616. doi:10.1002/cbic.200700635. 
6. ↑ D.L. Akey, J.D. Kittendorf, J.W. Giraldes, R.A. Fecik, D.H. Sherman, and J.L. Smith (2006). "Structural basis for macrolactonization by the pikromycin thioesterase.". Nature Chemical Biology 2: 537–542. 
7. ↑ Y. Xue and D. Sherman (2001). "Biosynthesis and Combinatorial Biosynthesis of Pikromycin-Related Macrolides in Streptomyces venezuelae". Metabolic Engineering 3: 15–26. doi:10.1006/mben.2000.0167.