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Teleocidin

Structural formula of teleocidin B-4
Names
Systematic IUPAC name
3H-Pyrrolo(4,3,2-gh)-1,4-benzodiazonin-3-one, 1,2,4,5,6,8-hexahydro-9-(1-ethenyl-1,5-dimethyl-4-hexenyl)-5-(hydroxymethyl)-1-methyl-2-(1-methylethyl)-
Other names
Lyngbyatoxin Lyngbyatoxin-a
Identifiers
UNII
Properties
C28H41N3O2
Molar mass 451.655 g·mol−1
Appearance Yellow crystalline powder
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Teleocidin, an indole alkaloid, is a toxic compound showing tumor promoting activity. When applied to mouse skin, it can induce carcinogenesis.[1] Different forms of teleocidin are recognized. Teleocidin A, also known as Lyngbyatoxin-a, is produced by the blue-green alga Lyngbya majuscual Gomont. Exposure to this toxin can cause dermatitis, known as ‘swimmer's itch’.[2] Next to this blue-green alga, the bacterium Streptomyces mediocidicus is able to produce teleocidin as well.[1] Teleocidin B, also produced by a strain of Streptomyces, is a slightly yellow colored crystalline powder. It is very hydrophobic but easily dissolves in e.g. methanol and ethanol. In organic solvents, teleocidin B is very stable, in alkaline solution it is relatively stable.[3]

History[edit]

During screening in the 1960s of toxic substances produced by Streptomyces against aquatic organisms like Japanese killifish (Oryzias latipes), one day a new toxic substance was found. This unknown substance was isolated from the cultured mycelium of Streptomyces 2A 1563.[4] This strain was considered to be a variant of the Streptomyces mediocidicus. The newly discovered substance was called teleocidin, named after the teleost fish Oryzias latipes.[5] At that moment it was already observed that teleocidin showed strong toxicity towards both aquatic organisms and mammalians. [4]

Later on, around 1987, researchers were interested in tumor promoters that were structurally different from the known tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), but equally active. After a screening on potent tumor promoters, two candidates were indicated, namely teleocidin and aplysiatoxin.[5] Teleocidin resembled TPA in biological and biochemical effects, which is why teleocidin is classified as a TPA-tumor promoter.[5]

Structure and reactivity[edit]

The common structure of teleocidin is an indole ring and a nine-membered lactam ring and is called indolactam.[5] The general molecular formula for teleocidin (which is the same as the B-1 form) is C28-H41-N3-O2 and it has a molecular weight of 451.651 g/mol.[6] Teleocidin also has other forms (see Available forms) of which teleocidin A has a molecular weight of 437.6241 g/mol and has the molecular formula C27-H39-N3-O2.[7] Furthermore, the hydrophobic monoterpenoid moiety located on the 6th and 7th position of the indole ring greatly enhances its biological activity and toxic characteristic.[8][9][10] This means that the molecule is always active and does not require an activating step or bio-transformation in order to have an effect.

Available forms[edit]

All forms of teleocidin are present in one of two forms, either the twist or sofa form, which are in equilibrium and are characterized by the cis- and trans-amide bond respectively.[8] This is due to the cis-trans isomerization of the amide bond and steric effects on substitute components of the nine-membered lactam ring. Furthermore, teleocidin has a total of six isomers, two teleocidin A isomers (A-1 and A-2) and four of teleocidin B (B-1 to B-4). More specifically, the two teleocidin A isomers are called (19R)-teleocidin for A-1, which is identical to lyngbyatoxin A and (19S)-teleocidin for A-2, while the four teleocidin B isomers are called C-19,C22-diastereomers. Furthermore, teleocidin B-1 is identical to des-O-methylolivoretin B while B-4 is identical to olivoretin D. All of these isomers in this teleocidin class have about the same activity and effects. [5][11]

Synthesis[edit]

The biosynthesis of teleocidin A and teleocidin B have both been experimentally tested and gave similar results. In the research of teleocidin A synthesis a gene cluster called the Ltx-gene cluster came forward as the gene cluster that transcribes for the proteins involved in the synthesis.[12] However, in the research of Teleocidin B synthesis a different gene cluster, called the Tle-gene cluster, came forward as the regulator of the transcription of proteins involved in the synthesis pathway.[13] Both clusters actually show a lot of similarities.

  • They both contain an open reading frame (ORF) that encodes for an two-module nonribosomal peptide-synthetase (NRPS) protein that develops into a linear dipeptide containing an A-domain specific for L-Val, an A-domain specific for L-TRP, an N-methylation domain, a peptidyl carrier protein and a Red-domain. This is done bij LtxA and TLeA respectively.
  • They both contain an ORF that encodes for a cytochrome P450 monooxygenase. This is done by LtxB and TleB respectively.
  • They both contain an ORF that encodes for a reverse prenyltransferase. This is done by LtxC and TleC respectively.
  • They both contain an ORF that encodes for a fourth protein. In LtxD it is related to a family of oxidase/reductase-type proteins, whereas in TleD it encodes for protein involved in methylation. It must be mentioned that the ORF encoding for TleD is not located in the Tle-cluster.

The P450-dependent monooxygenase serves as a catalyst in the oxidation and subsequent cyclization of the earlier mentioned dipeptide, whilst the reverse prenyltransferase performs the transfer of a geranyl pyrophosphate (GPP) to carbon-7 of the indole ring which is accompanied by the loss of pyrophosphate. TleD is responsible for installing a methyl group on the geranyl moiety precursor.[13]

Reactions[edit]

Teleocidin B can be transformed into hydroteleocidin B by catalytic hydrogenation of Teleocidin B.

Teleocidin B absorbs 1 to 2 moles of hydrogen by the catalytic reduction with platinum dioxide in ethanol or glacial acetic acid to give a hydrogenated derivative, which was tentatively named as hydroteleocidin B. Hydroteleocidin B proves to be very stable against alkaline hydrolysis, but relatively easily hydrolyzed with mineral acids.[4]

Teleocidin tests  positive for diazo, phosphomolibdate, Tollen's, Dragendorff's, pyrrol, fluorescein chloride, brom, Baeyer's and concentrated sulfric acid reactions, and is soluble in carbon tetrachloride, benzene, chloroform, methanol, ethanol, acetone, ethyl-acetate and ether.[4]

The phorbol 13-acetate component of the twist form can react with the PKCδ Cys2 domain, which results in binding of the alkaloid.[8]

Mechanisms of action[edit]

Binding Protein kinase C receptor (PKC) plays a role in cellular responses to various agonists, which include hormones and neurotransmitters.[14] Sustained activation of PKC is also vital for cell proliferation and differentiation.[15] since PKC effects cell proliferation and differentiation, the enzyme has also been linked to tumor promotion. PKC is activated by increased quantities of the glyceride diacylglycerol, which, when binded, increase the affinity of PKC for Ca2+.[16] Diacylglycerol is produced through the hydrolysis of inositol phospholipids, which in return is stimulated by higher amounts of Ca2+, effectively leading to prolonged activation of PKC.[14] Teleocidin’s structure allows it to competitively bind to PKC instead of diacylglycerol, which shifts the Ca2+ optimum, thus increasing the affinity.[17] In fact, teleocidin increases the affinity to such a high level that PKC gets activated even though there is no net increase in Ca2+.[18]The activation of the enzyme results in induced signal transduction, eventually inducing cell proliferation and differentiation, and thus, tumor promotion.[3] Studies hypothesize that the activation of PKC by teleocidin leads to higher amounts of reactive oxygen, which can lead to tumor promotion.[15]

Metabolism[edit]

(-)-Indolactam V (ILV) is the major toxic component of teleocidin and should be the main focus for detoxification of this compound. ILV can be metabolized by cytochrome P-450-containing mixed function oxidases while supplementing those with NADPH and MgCl2. This reaction with ILV gives three metabolites in the form of two diastereomers of (-)-2-oxy-ILV and (-)-N13-desmethyl-ILV. These metabolites have significantly lower carcinogenic properties compared to ILV itself.[10]

Efficacy and side effects[edit]

Efficacy[edit]

Since all teleocidins are available equally in the two isomeric forms (twist and sofa) and only the twist isomer is an active compound, the efficacy of teleocidin would be around 50%.[8]

Adverse effects[edit]

Teleocidin B enhances, just like the tumor promoter TPA, the production of the infectious Epstein-Barr virus (EBV) in cells of the EBV-genome-carrying lymphoblastoid producer cell line (P3HR-1). [19]

Toxicity[edit]

Teleocidin appeared to have toxic effects on fishes like Oryzias latipes, other aquatic organisms and towards the skin of mammalians. Towards other organisms like bacteria, yeasts, molds, diatoms and protozoa, no  inhibitory effects have been observed up to 100 microgram per milliliter. This makes teleocidin different from other toxicants like antibiotics produced by Streptomyces, which have an inhibitory effect on e.g. bacteria.[4]

Rabbits can get an elevated blood-pressure when they receive an intravenous dose of teleocidin. Application of teleocidin on the skin of the rabbit can lead to “irritations, intense hyperemia, redness of mucous membranes, formation of a puruloid exudate, necrosis and desquamation of the mouth, nose, eyes, ears and skin in the rabbit”.[4]

Application of teleocidin in combination with the tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA), leads to a high tumor incidence and tumor yield in mice. Thereby, teleocidin seems to have an effect similar to 12-O-tetradecanoylphorbol-13-acetate (TPA).[1] TPA also can induce tumor promotion in some-models of two-stage carcinogenesis.[20]

Toxicity of teleocidin A (in mice)
Lethal Dose Value
LD50 (intravenous) 0.2 mg/kg body weight [3]
LD50 (oral) 2 mg/kg bodyweight [21]
LDLo (intraperitoneal) 0.3 mg/kg bodyweight [22]

In human leukocytes, teleocidin B can lead to DNA strand break damage.[23] Furthermore, addition of teleocidin to human T-enriched lymphocytes leads to aggregation of the cells. Addition of this toxin to unfractionated lymphocytes led to moderate aggregation, and no aggregation was seen with B-enriched lymphocytes.[24]

References[edit]

  1. ^ a b c Fujiki, H.; Suganuma, M.; Hakii, H.; Bartolini, G.; Moore, R. E.; Takayama, S.; Sugimura, T. (1984-07-01). "A two-stage mouse skin carcinogenesis study of lyngbyatoxin A". Journal of Cancer Research and Clinical Oncology. 108 (1): 174–176. doi:10.1007/BF00390993. ISSN 0171-5216.
  2. ^ ChemIDPlus: Lynbyatoxin-a
  3. ^ a b c Takashima, Matao; Sakai, Heiichi; Mori, Rimpei; Arima, Kei (1962). "A New Toxic Substance, Teleocidin, Produced by Streptomyces. Part III. Production, Isolation and Chemical Characterization of Teleocidin B." Journal of Agricultural and Biological Chemistry. 26 (10): 660–678. doi:10.1080/00021369.1962.10858025.
  4. ^ a b c d e f Takashima, Matao; Sakai, Heiichi (1960). "A New Toxic Substance, Teleocidin, Produced by Streptomyces. Part I. Production, Isolation and Chemical Studies & Part II. Biological Studies of Teleocidin". Bulletin of the Agricultural Chemical Society of Japan. 24 (7): 647–655. doi:10.1080/03758397.1960.10857741.
  5. ^ a b c d e Advances in cancer research. Volume 49. Klein, George, 1925-, Weinhouse, Sidney, 1909-. Orlando, Fla.: Academic Press. 1987. ISBN 9780120066490. OCLC 261224625.{{cite book}}: CS1 maint: others (link)
  6. ^ Chambers, Michael. "ChemIDplus - Teleocidins - PEYTUVXFLCCGCC-YGHSORLUSA-N - Similar structures search, synonyms, formulas, resource links, and other chemical information". chem.nlm.nih.gov. Retrieved 2018-03-29.
  7. ^ Chambers, Michael. "ChemIDplus - Teleocidin A - KISDGNGREAJPQR-OICBGKIFSA-N - Lyngbyatoxin A - Similar structures search, synonyms, formulas, resource links, and other chemical information". chem.nlm.nih.gov. Retrieved 2018-03-29.
  8. ^ a b c d Endo, Yasuyuki; Takehana, Shunji; Ohno, Michihiro; Driedger, Paul E.; Stabel, Silvia; Mizutani, Miho Y.; Tomioka, Nobuo; Itai, Akiko; Shudo, Koichi (1998-04-01). "Clarification of the Binding Mode of Teleocidin and Benzolactams to the Cys2 Domain of Protein Kinase Cδ by Synthesis of Hydrophobically Modified, Teleocidin-Mimicking Benzolactams and Computational Docking Simulation". Journal of Medicinal Chemistry. 41 (9): 1476–1496. doi:10.1021/jm970704s. ISSN 0022-2623.
  9. ^ Irie, Kazuhiro; Nakagawa, Yu; Tomimatsu, Satoru; Ohigashi, Hajime. "Biosynthesis of the monoterpenoid moiety of teleocidins via the non-mevalonate pathway in Streptomyces". Tetrahedron Letters. 39 (43): 7929–7930. doi:10.1016/s0040-4039(98)01764-x.
  10. ^ a b Hagiwara, Nobuyuki; Irie, Kazuhiro; Tokuda, Harukuni; Koshimizu, Koichi (1987-07-01). "The metabolism of indole alkaloid tumor promoter, (−)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes". Carcinogenesis. 8 (7): 963–965. doi:10.1093/carcin/8.7.963. ISSN 0143-3334.
  11. ^ Fujiki, H.; Suganuma, M.; Ninomiya, M.; Yoshizawa, S.; Yamashita, K.; Takayama, S.; Hitotsuyanagi, Y.; Sakai, S.; Shudo, K. (1988-08-01). "Similar, potent tumor-promoting activity of all isomers of teleocidins A and B in a two-stage carcinogenesis experiment on the skin of CD-1 mice". Cancer Research. 48 (15): 4211–4214. ISSN 0008-5472. PMID 3134123.
  12. ^ Edwards, Daniel J.; Gerwick, William H. (2004-09-22). "Lyngbyatoxin biosynthesis: sequence of biosynthetic gene cluster and identification of a novel aromatic prenyltransferase". Journal of the American Chemical Society. 126 (37): 11432–11433. doi:10.1021/ja047876g. ISSN 0002-7863. PMID 15366877.
  13. ^ a b Awakawa, Takayoshi; Zhang, Lihan; Wakimoto, Toshiyuki; Hoshino, Shotaro; Mori, Takahiro; Ito, Takuya; Ishikawa, Jun; Tanner, Martin E.; Abe, Ikuro (2014-07-16). "A methyltransferase initiates terpene cyclization in teleocidin B biosynthesis". Journal of the American Chemical Society. 136 (28): 9910–9913. doi:10.1021/ja505224r. ISSN 1520-5126. PMID 24992358.
  14. ^ a b Nishizuka, Y. (1992-10-23). "Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C". Science (New York, N.Y.). 258 (5082): 607–614. ISSN 0036-8075. PMID 1411571.
  15. ^ a b O'Brian, C. A.; Ward, N. E. (December 1989). "Biology of the protein kinase C family". Cancer Metastasis Reviews. 8 (3): 199–214. ISSN 0167-7659. PMID 2697470.
  16. ^ Osada, H.; Magae, J.; Watanabe, C.; Isono, K. (July 1988). "Rapid screening method for inhibitors of protein kinase C". The Journal of Antibiotics. 41 (7): 925–931. ISSN 0021-8820. PMID 3138226.
  17. ^ Fujiki, H.; Suganuma, M. (1999). "Unique features of the okadaic acid activity class of tumor promoters". Journal of Cancer Research and Clinical Oncology. 125 (3–4): 150–155. ISSN 0171-5216. PMID 10235468.
  18. ^ Fujiki, H.; Tanaka, Y.; Miyake, R.; Kikkawa, U.; Nishizuka, Y.; Sugimura, T. (1984-04-30). "Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin". Biochemical and Biophysical Research Communications. 120 (2): 339–343. ISSN 0006-291X. PMID 6233970.
  19. ^ Yamamoto, H.; Katsuki, T.; Hinuma, Y.; Hoshino, H.; Miwa, M.; Fujiki, H.; Sugimura, T. (1981-08-15). "Induction of Epstein-Barr virus by an new tumor promoter, teleocidin, compared to induction by TPA". International Journal of Cancer. 28 (2): 125–129. ISSN 0020-7136. PMID 6274809.
  20. ^ Sung, You Me; He, Guobin; Fischer, Susan M. (2005-10-15). "Lack of expression of the EP2 but not EP3 receptor for prostaglandin E2 results in suppression of skin tumor development". Cancer Research. 65 (20): 9304–9311. doi:10.1158/0008-5472.CAN-05-1015. ISSN 0008-5472. PMID 16230392.
  21. ^ Chatten, Leslie G. "Cell physiology and pharmacology". Journal of Pharmaceutical Sciences. 57 (11). doi:10.1002/jps.2600571156.
  22. ^ Cardellina, J. H.; Marner, F. J.; Moore, R. E. (1979-04-13). "Seaweed dermatitis: structure of lyngbyatoxin A". Science (New York, N.Y.). 204 (4389): 193–195. ISSN 0036-8075. PMID 107586.
  23. ^ Troll, W.; Wiesner, R. (1985). "The role of oxygen radicals as a possible mechanism of tumor promotion". Annual Review of Pharmacology and Toxicology. 25: 509–528. doi:10.1146/annurev.pa.25.040185.002453. ISSN 0362-1642. PMID 3890710.
  24. ^ "Activation of human lymphocytes by tumor promoter teleocidin". Biochemical and Biophysical Research Communications. 100 (2): 888–893. 1981-05-29. doi:10.1016/S0006-291X(81)80256-2. ISSN 0006-291X.
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