Tautomycetin

Tautomycetin
Structure of Tautomycetin
Identifiers
IUPAC name
  • (3R,4R,5R,8S,9S,12R)-12-{(2S,3S,6R,8S,9R)-3,9-Dimethyl-8-[(3S)-3-methyl-4-oxopentyl]-1,7-dioxaspiro[5.5]undecan-2-yl}-5,9-dihydroxy-4-methoxy-2,8-dimethyl-7-oxotridecan-3-yl (3R)-3-hydroxy-3-(4-methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)propanoate
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC33H50O10
Molar mass606.753 g·mol−1
3D model (JSmol)
SMILES
  • CCC(=CC(=O)CC(C)CC(C)CCC(C(C)C(=O)CC(C(C)C(C)OC(=O)CC(C1=C(C(=O)OC1=O)C)O)O)O)C=C
InChI
  • InChI=S/C33H50O10/c1-9-24(10-2)15-25(34)14-19(4)13-18(3)11-12-26(35)21(6)28(37)16-27(36)20(5)23(8)42-30(39)17-29(38)31-22(7)32(40)43-33(31)41/h9,15,18-21,23,26-27,29,35-36,38H,1,10-14,16-17H2,2-8H3/b24-15- checkY
  • Key:VAIBGAONSFVVKI-IWIPYMOSSA-N checkY

Tautomycetin is a natural product first isolated from Streptomyces griseochromogenes, a bacterium found in the soil of the Zhejiang Province, China.[1] It was also later found in Penicillium urticae.[2] It is a linear polyketide very similar in structure to tautomycin, both of which contain a unique dialkylmaleic anhydride moiety, which is essential for their pharmacological activity.[3] Tautomycetin is a selective inhibitor of protein phosphatase 1.[4]

Biosynthesis

Biosynthesis of Tautomycetin

Much of the biosynthesis of tautomycetin has been deduced.[5] It is synthesized in S. griseochromogenes by two type I polyketide synthases, denoted by modules named TtnA and TtnB. After initial loading with acetyl-CoA, four methylmalonyl-CoAs and three malonyl-CoAs are added alternately by sequential Claisen condensation, followed by one ethylmalonyl-CoA. Each ketone of the incorporated acetate group is selectively modified by a ketoreductase (KR), dehydratase (DH), or enoylreductase (ER) as indicated. The dialkyl maleic anhydride moeity is synthesized separately by eight enzymes (TtnKLMNOPRS) and incorporated into the growing polyketide by esterification mediated via TtnK at the end of TtnA. The polyketide is released from TtnB, by a thioesterase TtnB-TE and undergoes oxidation at the C6 position, catalyzed by the enzyme TtnI. Finally, this intermediate undergoes an enzyme-catalyzed decarboxylation-dehydration to form the final compound, tautomycetin.

The total synthesis of tautomycetin has been reported.[6]

Pharmacology

Tautomycetin has been shown to have antibiotic and antifungal activities.[7] It has also been identified as a potent protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) inhibitor with IC50 values as low as 0.21 nM and 0.94 nM respectively, the lowest of over 40 natural product phosphatase inhibitors.[8] In addition, tautomycetin is a potent T cell-specific immunosuppressor [9][10] and has been investigated for treatment in grafting and transplantation.[11] It has useful anticancer properties, inducing apoptosis through the inhibition of several protein cascades in colorectal cancer and thyroid cancer.[12][13][14]

References

  1. ↑ Cheng XC, Kihara T, Ying X, Uramoto M, Osada H, Kusakabe H, et al. (January 1989). "A new antibiotic, tautomycetin". The Journal of Antibiotics. 42 (1): 141–144. doi:10.7164/antibiotics.42.141. PMID 2921220.
  2. ↑ Sakuda S, Miki K, Kitaoka S, Reugjitchachawaly M, Yamada Y (January 1995). "Isolation of tautomycetin as a regulator of secondary metabolite production for Penicillium urticae". Bioscience, Biotechnology, and Biochemistry. 59 (1): 133–134. doi:10.1271/bbb.59.133. PMID 7765963.
  3. ↑ Cheng XC, Ubukata M, Isono K (July 1990). "The structure of tautomycetin, a dialkylmaleic anhydride antibiotic". The Journal of Antibiotics. 43 (7): 890–896. doi:10.7164/antibiotics.43.890. PMID 2387780.
  4. ↑ Choy MS, Swingle M, D'Arcy B, Abney K, Rusin SF, Kettenbach AN, et al. (December 2017). "PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors". Journal of the American Chemical Society. 139 (49): 17703–17706. doi:10.1021/jacs.7b09368. PMC 5729109. PMID 29156132.
  5. ↑ Li W, Luo Y, Ju J, Rajski SR, Osada H, Shen B (March 2009). "Characterization of the tautomycetin biosynthetic gene cluster from Streptomyces griseochromogenes provides new insight into dialkylmaleic anhydride biosynthesis". Journal of Natural Products. 72 (3): 450–459. doi:10.1021/np8007478. PMC 2967020. PMID 19191560.
  6. ↑ Oikawa H (November 2002). "Synthesis of specific protein phosphatase inhibitors, tautomycin and tautomycetin toward structure-activity relationship study". Current Medicinal Chemistry. 9 (22): 2033–2053. doi:10.2174/0929867023368818. PMID 12369869.
  7. ↑ Cheng XC, Kihara T, Ying X, Uramoto M, Osada H, Kusakabe H, et al. (January 1989). "A new antibiotic, tautomycetin". The Journal of Antibiotics. 42 (1): 141–144. doi:10.7164/antibiotics.42.141. PMID 2921220.
  8. ↑ Mitsuhashi S, Matsuura N, Ubukata M, Oikawa H, Shima H, Kikuchi K (September 2001). "Tautomycetin is a novel and specific inhibitor of serine/threonine protein phosphatase type 1, PP1". Biochemical and Biophysical Research Communications. 287 (2): 328–331. doi:10.1006/bbrc.2001.5596. PMID 11554729.
  9. ↑ Shim JH, Lee HK, Chang EJ, Chae WJ, Han JH, Han DJ, et al. (August 2002). "Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction". Proceedings of the National Academy of Sciences of the United States of America. 99 (16): 10617–10622. Bibcode:2002PNAS...9910617S. doi:10.1073/pnas.162522099. PMC 124991. PMID 12149481.
  10. ↑ Chae WJ, Choi JM, Yang JJ, Lee SK (December 2004). "T Cell-specific immunosuppression using tautomycetin or PTD-conjugated protein drugs". Yonsei Medical Journal. 45 (6): 978–990. doi:10.3349/ymj.2004.45.6.978. PMID 15627288.
  11. ↑ Han DJ, Jeong YL, Wee YM, Lee AY, Lee HK, Ha JC, et al. (February 2003). "Tautomycetin as a novel immunosuppressant in transplantation". Transplantation Proceedings. 35 (1): 547. doi:10.1016/s0041-1345(02)03905-2. PMID 12591525.
  12. ↑ Mitsuhashi S, Shima H, Li Y, Tanuma N, Okamoto T, Kikuchi K, Ubukata M (November 2008). "Tautomycetin suppresses the TNFalpha/NF-kappaB pathway via inhibition of IKK activation". International Journal of Oncology. 33 (5): 1027–1035. PMID 18949366.
  13. ↑ Kim JH, Lee TY, Park J, Ha H, Kang SW, Kim YS (May 2005). "Effects of tautomycetin on proliferation and fibronectin secretion in vascular smooth muscle cells and glomerular mesangial cells". Transplantation Proceedings. 37 (4): 1959–1961. doi:10.1016/j.transproceed.2005.02.082. PMID 15919517.
  14. ↑ Adler JT, Cook M, Luo Y, Pitt SC, Ju J, Li W, et al. (April 2009). "Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3beta". Molecular Cancer Therapeutics. 8 (4): 914–920. doi:10.1158/1535-7163.MCT-08-0712. PMC 2670470. PMID 19372564.
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