Chemistry:C-1027

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C-1027 or lidamycin is an antitumor antibiotic consisting of a complex of an enediyne chromophore and an apoprotein.[1][2][3][4] [5][6] It shows antibiotic activity against most Gram-positive bacteria.[7] It is one of the most potent cytotoxic molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.

C-1027's chromophore contains a nine-membered enediyne that is responsible for most of the molecule's biological activity.[7] Unlike other enediynes, this molecule contains no triggering mechanism. It is already primed to undergo the cycloaromatization reaction without external activation to produce the toxic 1,4-benzenoid diradical species. C-1027 can induce oxygen-independent interstrand DNA crosslinks in addition to the oxygen-dependent single- and double-stranded DNA breaks typically generated by other enediynes. This unique oxygen-independent mechanism suggests that C-1027 may be effective against hypoxic tumor cells.[8]

C-1027 Mechanism

C-1027 shows promise as an anticancer drug and is currently undergoing phase II clinical trials in China,[9] with a 30% success rate.[10] It can induce apoptosis in many cancer cells and recent studies have indicated that it induces unusual DNA damage responses to double-strand breaks, including altering cell cycle progression and inducing chromosomal aberrations.[6]

Biosynthesis

Enediyne

The structure of C-1027 is composed of a nine-membered enediyne complex, a deoxygenated aminosugar, a β-amino acid, and a benzoxazolinate moiety. Enediynes contain a double bond between two triple bonds, and their biosynthesis is distinct from other known polyketide and fatty-acid synthesis paradigms. The enediyne PKS, PKSE, from S. globisporusresponsible for the biosynthesis of the C-1027 enediyne is an ACP dependent protein with ketoacylsynthase (KS), acyltransferase (AT), ketoreductase (KR), and dehydratase (DH) domains.[11] PKSE also contains a C-termianal PPTase domain, and the process is terminated by a thioesterase (TE). Starting with acetyl-CoA, PKSE iteratively combines 7 units of malonyl-CoA creating an intermediate heptaene, which is then catalyzed by accessory enzymes into a 9 membered enediyne.[12] There is also a remarkable similarity between the biosynthesis of 9-membered and 10-membered enediynes such as the anticancer drug Calicheamicin.[13]

Enediyne Biosynthesis

Deoxy Aminosugar

The deoxy aminosugar found in C-1027 is derived from 5-glucose-1-phosphate. The C-1027 gene cluster contains a thymine diphosphate glucose synthetase (SgcA1), a TDP-glucose 4,6-dehydratase (SgcA2), a TDP-4-keto-6-deoxyglucose epimerase (SgcA2), a C-methyl transferase (SgcA3), an amino transferase (SgcA4), an N-methyl transferase (SgcA5), and a glycosyl transferase (SgcA6). These are all the necessary enzymes to synthesize the deoxy aminosugar and attach it to the enediyne core.[11]

Deoxy Aminosugar Biosynthesis

β-Amino Acid

The β-amino acid moiety is a non-ribosomal peptide synthesized from tyrosine. The necessary enzymes for its biosynthesis include a phenol hydroxylase (SgcC), a nonribosomal peptide synthetase adenylation enzyme (SgcC1), an NRPS peptidyl–carrier protein (SgcC2), a halogenase (SgcC3), an aminomutase (SgcC4), and an NRPS-condensation enzyme (SgcC5). All of these enzymes are encoded for within the C-1027 biosynthetic gene cluster.[11]

B-Amino Acid Biosynthesis

Benzoxazolinate

The benzoxazolinate moiety is synthesized from chorismate, which itself is biosynthesized from the shikimate pathway. Chorismate is sequentially acted upon by a 2-amino-2-deoxyisochorismate synthase, and an iron–sulfur FMN-dependent ADIC dehydrogenase to synthesize 3-enolpyruvoylanthranilate (OPA). OPA is then further catalyzed into the benzoxazolinate precursor for C-1027.[14]

Benzoxazolinate Biosynthesis

C-1027

The four building blocks are then combined into C-1027, although the exact mechanisms and order of this is relatively unknown.[11]

C-1027 Biosynthesis

References

  1. ↑ Hu, Jilan; Xue, Yu-Chuan; Xie, Mei-Yu; Zhang, Rui; Otani, Toshio; Minami, Yoshinori; Yamada, Yuji; Marunaka, Teruyoshi (1988). "A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity.". The Journal of Antibiotics 41 (11): 1575–1579. doi:10.7164/antibiotics.41.1575. PMID 3198491. 
  2. ↑ Otani, Toshio; Minami, Yoshinori; Marunaka, Teruyoshi; ZHANG, Rui; Xie, Mei-Yu (1988). "A new macromolecular antitumor antibiotic, C-1027. II. Isolation and physico-chemical properties.". The Journal of Antibiotics 41 (11): 1580–1585. doi:10.7164/antibiotics.41.1580. PMID 3198492. 
  3. ↑ Zhen, Yong-Su; Ming, Xiu-Ying; Yu, Bin; Otani, Toshio; Saito, Hitoshi; Yamada, Yuji (1989). "A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity.". The Journal of Antibiotics 42 (8): 1294–1298. doi:10.7164/antibiotics.42.1294. PMID 2759910. 
  4. ↑ Ken-ichiro, Yoshida; Minami, Yoshinori; Azuma, Ryotaro; Saeki, Mayuko; Otani, Toshio (1993). "Structure and cycloaromatization of a novel enediyne, C-1027 chromophore". Tetrahedron Lett. 34 (16): 2637–2640. doi:10.1016/S0040-4039(00)77644-1. 
  5. ↑ "Complexity and simplicity in the biosynthesis of enediyne natural products". Natural Product Reports 27 (4): 499–528. April 2010. doi:10.1039/b908165h. PMID 20336235. 
  6. ↑ 6.0 6.1 "Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice". Acta Pharmacologica Sinica 30 (7): 1025–32. July 2009. doi:10.1038/aps.2009.75. PMID 19575006. 
  7. ↑ 7.0 7.1 "C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage". Biochemistry 33 (19): 5947–54. May 1994. doi:10.1021/bi00185a036. PMID 8180224. 
  8. ↑ "Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus". Journal of Natural Products 74 (3): 420–4. March 2011. doi:10.1021/np100825y. PMID 21250756. Bibcode: 2011JNAtP..74..420C. 
  9. ↑ "Draft genome sequence of Streptomyces globisporus C-1027, which produces an antitumor antibiotic consisting of a nine-membered enediyne with a chromoprotein". Journal of Bacteriology 194 (15): 4144. August 2012. doi:10.1128/JB.00797-12. PMID 22815456. 
  10. ↑ "Enediynes: Exploration of microbial genomics to discover new anticancer drug leads". Bioorganic & Medicinal Chemistry Letters 25 (1): 9–15. January 2015. doi:10.1016/j.bmcl.2014.11.019. PMID 25434000. 
  11. ↑ 11.0 11.1 11.2 11.3 Liu, Wen; Christenson, Steven; Standage, Scott; Shen, Ben (2002). "Biosynthesis of the Enediyne Antitumor Antibiotic C-1027". Science 297 (5584): 1170–1173. doi:10.1126/science.1072110. PMID 12183628. Bibcode: 2002Sci...297.1170L. 
  12. ↑ "A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis". Proceedings of the National Academy of Sciences 105 (5): 1460–1465. 2008. doi:10.1073/pnas.0711625105. PMID 18223152. Bibcode: 2008PNAS..105.1460Z. 
  13. ↑ "The Calicheamicin Gene Cluster and Its Iterative Type I Enediyne PKS". Science 297 (5584): 1173–1176. 2002. doi:10.1126/science.1072105. PMID 12183629. Bibcode: 2002Sci...297.1173A. 
  14. ↑ "Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism". Proceedings of the National Academy of Sciences 105 (2): 494–499. 2008. doi:10.1073/pnas.0708750105. PMID 18182490. Bibcode: 2008PNAS..105..494V. 



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