Jadomycin

A jadomycin is a natural product produced by Streptomyces venezuelae ISP5230 (ATCC10712[1]), the organism which is most well known for making the antibiotic chloramphenicol. The name jadomycin is applied to a family of related angucyclines which are distinguished by the E ring (usually an oxoazolone ring), which is derived from an amino acid. The amino acid incorporation which forms the E-ring is a chemical reaction, rather than enzymatic, an uncommon occurrence in biosynthesis. As such a number of jadomycins incorporating different amino acids have been discovered. Jadomycin A was the first compound of this family to be isolated and constitutes the angucylic backbone with L-isoleucine incorporated into the E-ring.[2] A related analog, jadomycin B, is modified by glycosylation with a 2,6-dideoxy sugar, L-digitoxose.[3] Jadomycins have cytotoxic and antibacterial properties.

Jadomycin B
Names
Other names
Jadomycin L-isoleucine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
  • A: InChI=1S/C24H21NO6/c1-4-11(3)19-24(30)31-23-13-8-10(2)9-15(27)16(13)18-20(25(19)23)22(29)17-12(21(18)28)6-5-7-14(17)26/h5-9,11,19,23,26-27H,4H2,1-3H3/t11-,19-,23-/m0/s1
    Key: AVMSKCRHMKXYOO-JNVIWZAMSA-N
  • B: InChI=1S/C30H31NO9/c1-5-13(3)24-30(37)40-29-16-9-12(2)10-17(32)21(16)23-25(31(24)29)28(36)22-15(27(23)35)7-6-8-19(22)39-20-11-18(33)26(34)14(4)38-20/h6-10,13-14,18,20,24,26,29,32-34H,5,11H2,1-4H3/t13-,14-,18+,20-,24-,26-,29-/m0/s1
    Key: BSBSCJRAEMDCHC-FTERDKBNSA-N
  • N: InChI=1S/C28H26N2O10/c1-10-6-13-20(15(31)7-10)22-23(30-14(28(37)38)8-18(33)29-27(13)30)26(36)21-12(25(22)35)4-3-5-17(21)40-19-9-16(32)24(34)11(2)39-19/h3-7,11,14,16,19,24,27,31-32,34H,8-9H2,1-2H3,(H,29,33)(H,37,38)/t11-,14-,16+,19-,24-,27+/m0/s1
    Key: GYNMVHWDURGLEN-FKHGBPLUSA-N
  • S: InChI=1S/C27H25NO10/c1-10-6-13-19(15(30)7-10)21-22(28-14(9-29)27(35)38-26(13)28)25(34)20-12(24(21)33)4-3-5-17(20)37-18-8-16(31)23(32)11(2)36-18/h3-7,11,14,16,18,23,26,29-32H,8-9H2,1-2H3/t11-,14-,16+,18-,23-,26?/m0/s1
    Key: YJZPHITXTBWGEN-IUHCOWDHSA-N
  • W: InChI=1S/C35H30N2O9/c1-15-10-20-27(23(38)11-15)29-30(37-22(35(43)46-34(20)37)12-17-14-36-21-8-4-3-6-18(17)21)33(42)28-19(32(29)41)7-5-9-25(28)45-26-13-24(39)31(40)16(2)44-26/h3-11,14,16,22,24,26,31,34,36,38-40H,12-13H2,1-2H3/t16-,22-,24+,26-,31-,34?/m0/s1
    Key: LQAICFQKBUVZMC-XSMVYFONSA-N
  • A: CC[C@H](C)[C@H]1C(=O)O[C@@H]2N1C3=C(C4=C(C=C(C=C24)C)O)C(=O)C5=C(C3=O)C(=CC=C5)O
  • B: CC[C@H](C)[C@H]1C(=O)O[C@@H]2N1C3=C(C4=C(C=C(C=C24)C)O)C(=O)C5=C(C3=O)C(=CC=C5)O[C@H]6C[C@H]([C@H]([C@@H](O6)C)O)O
  • N: C[C@H]1[C@@H]([C@@H](C[C@@H](O1)OC2=CC=CC3=C2C(=O)C4=C(C3=O)C5=C(C=C(C=C5O)C)[C@H]6N4[C@@H](CC(=O)N6)C(=O)O)O)O
  • S: C[C@H]1[C@@H]([C@@H](C[C@@H](O1)OC2=CC=CC3=C2C(=O)C4=C(C3=O)C5=C(C=C(C=C5C6N4[C@H](C(=O)O6)CO)C)O)O)O
  • W: C[C@H]1[C@@H]([C@@H](C[C@@H](O1)OC2=CC=CC3=C2C(=O)C4=C(C3=O)C5=C(C=C(C=C5C6N4[C@H](C(=O)O6)CC7=CNC8=CC=CC=C87)C)O)O)O
Properties
C30H31NO9
Molar mass 549.576 g·mol−1
Appearance Deep red-purple solid
Solubility Soluble in various organic solvents
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Biosynthesis

The jadomycin biosynthetic gene cluster is well characterized. Jadomycin biosynthesis encompasses type II polyketide synthase (T2Pks) assembly to generate the angucycline component,[4] and a dideoxy sugar pathway, to generate the sugar donor NDP-L-digitoxose.[5] Studies have implicated JadG, an FAD-dependent oxygenase, in the ring cleavage required for incorporation of amino acids.[6] JadS, the glycosyltransferase that transfers L-digitoxose, has been shown to be flexible with respect to the sugar donor.[7][8][9]

Analogs based on E-ring modification

Jadomycin analogs have been obtained through culture of S. venezuelae in the presence of a single amino acid. The diversity of jadomycins includes those incorporating naturally occurring amino acids,[10] non-proteinogenic amino acids,[11][12] and synthetic amino acids with handles enabling further chemical modification.[13][14]

References
  1. "Streptomyces venezuelae Ehrlich et al. ATCC ® 10712™". www.atcc.org. Retrieved 2017-05-31.
  2. Ayer, Stephen W.; McInnes, A. Gavin; Thibault, Pierre; Walter, John A.; Doull, Janice L.; Parnell, Tracy; Vining, Leo C. (1991-10-28). "Jadomycin, a novel 8H-benz[b]oxazolo[3,2-f]phenanthridine antibiotic from streptomyces venezuelae ISP5230". Tetrahedron Letters. 32 (44): 6301–6304. doi:10.1016/0040-4039(91)80152-V.
  3. DOULL, JANICE L.; AYER, STEPHEN W.; SINGH, AMRIT K.; THIBAULT, PIERRE (1993-05-25). "Production of a novel polyketide antibiotic, jadomycin B, by Streptomyces venezuelae following heat shock". The Journal of Antibiotics. 46 (5): 869–871. doi:10.7164/antibiotics.46.869. ISSN 0021-8820. PMID 8514643.
  4. Han, Lei; Yang, Keqian; Ramalingam, Eswar; Mosher, Roy H.; Vining, Leo C. (1994). "Cloning and characterization of polyketide synthase genes for jadomycin B biosynthesis in Streptomyces venezuelae ISP5230". Microbiology. 140 (12): 3379–3389. doi:10.1099/13500872-140-12-3379. PMID 7881555.
  5. Wang, Liru; White, Robert L.; Vining, Leo C. (2002). "Biosynthesis of the dideoxysugar component of jadomycin B: genes in the jad cluster of Streptomyces venezuelae ISP5230 for l-digitoxose assembly and transfer to the angucycline aglycone". Microbiology. 148 (4): 1091–1103. doi:10.1099/00221287-148-4-1091. PMID 11932454.
  6. Tibrewal, Nidhi; Pahari, Pallab; Wang, Guojun; Kharel, Madan K.; Morris, Caleb; Downey, Theresa; Hou, Yanpeng; Bugni, Tim S.; Rohr, Jürgen (2012). "Baeyer–Villiger C–C Bond Cleavage Reaction in Gilvocarcin and Jadomycin Biosynthesis". Journal of the American Chemical Society. 134 (44): 18181–18184. doi:10.1021/ja3081154. PMC 3498853. PMID 23102024.
  7. Jakeman, David L.; Borissow, Charles N.; Graham, Cathy L.; Timmons, Shannon C.; Reid, Taryn R.; Syvitski, Ray T. (2006-08-29). "Substrate flexibility of a 2,6-dideoxyglycosyltransferase". Chemical Communications (35): 3738–3740. doi:10.1039/B608847C. ISSN 1364-548X. PMID 17047829.
  8. Forget, S. M.; Na, Jungwook; McCormick, N. E.; Jakeman, D. L. (2017-03-28). "Biosynthetic 4,6-dehydratase gene deletion: isolation of a glucosylated jadomycin natural product provides insight into the substrate specificity of glycosyltransferase JadS". Organic & Biomolecular Chemistry. 15 (13): 2725–2729. doi:10.1039/C7OB00259A. ISSN 1477-0539. PMID 28291274.
  9. Li, Liyuan; Pan, Guohui; Zhu, Xifen; Fan, Keqiang; Gao, Wubin; Ai, Guomin; Ren, Jinwei; Shi, Mingxin; Olano, Carlos (2017-04-20). "Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase". Applied Microbiology and Biotechnology. 101 (13): 5291–5300. doi:10.1007/s00253-017-8256-y. ISSN 0175-7598. PMID 28429060. S2CID 11777539.
  10. Jakeman, David L.; Farrell, Spring; Young, Wendy; Doucet, René J.; Timmons, Shannon C. (2005-03-01). "Novel jadomycins: incorporation of non-natural and natural amino acids". Bioorganic & Medicinal Chemistry Letters. 15 (5): 1447–1449. doi:10.1016/j.bmcl.2004.12.082. PMID 15713404.
  11. Jakeman, David L.; Graham, Cathy L.; Reid, Taryn R. (2005-12-01). "Novel and expanded jadomycins incorporating non-proteogenic amino acids". Bioorganic & Medicinal Chemistry Letters. 15 (23): 5280–5283. doi:10.1016/j.bmcl.2005.08.047. PMID 16185863.
  12. Forget, Stephanie M.; Robertson, Andrew W.; Overy, David P.; Kerr, Russell G.; Jakeman, David L. (2017-05-18). "Furan and Lactam Jadomycin Biosynthetic Congeners Isolated from Streptomyces venezuelae ISP5230 Cultured with Nε-Trifluoroacetyl-l-lysine". Journal of Natural Products. 80 (6): 1860–1866. doi:10.1021/acs.jnatprod.7b00152. ISSN 0163-3864. PMID 28520425.
  13. Dupuis, Stephanie N.; Robertson, Andrew W.; Veinot, Thomas; Monro, Susan M. A.; Douglas, Susan E.; Syvitski, Ray T.; Goralski, Kerry B.; McFarland, Sherri A.; Jakeman, David L. (2012-04-02). "Synthetic diversification of natural products: semi-synthesis and evaluation of triazole jadomycins". Chemical Science. 3 (5): 1640. doi:10.1039/C2SC00663D. ISSN 2041-6539.
  14. Robertson, Andrew W.; Martinez-Farina, Camilo F.; Smithen, Deborah A.; Yin, Huimin; Monro, Susan; Thompson, Alison; McFarland, Sherri A.; Syvitski, Raymond T.; Jakeman, David L. (2015). "Eight-Membered Ring-Containing Jadomycins: Implications for Non-enzymatic Natural Products Biosynthesis". Journal of the American Chemical Society. 137 (9): 3271–3275. doi:10.1021/ja5114672. PMID 25692677. S2CID 207117538.
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