Cerulenin Explained

Cerulenin is an antifungal antibiotic that inhibits fatty acid and steroid biosynthesis. It was the first natural product antibiotic known to inhibit lipid synthesis.[1] In fatty acid synthesis, it has been reported to bind in equimolar ratio to b-keto-acyl-ACP synthase, one of the seven moieties of fatty acid synthase, blocking the interaction of malonyl-CoA. It also has the related activity of stimulating fatty acid oxidation through the activation of CPT1, another enzyme normally inhibited by malonyl-CoA. Inhibition involves covalent thioacylation that permanently inactivates the enzymes.[2] These two behaviors may increase the availability of energy in the form of ATP, perhaps sensed by AMPK, in the hypothalamus.[3]

In sterol synthesis, cerulenin inhibits HMG-CoA synthetase activity.[4] It was also reported that cerulenin specifically inhibited fatty acid biosynthesis in Saccharomyces cerevisiae without having an effect on sterol formation.[4] But in general conclusion, cerulenin has inhibitory effects on sterol synthesis.

Cerulenin causes a dose-dependent decrease in HER2/neu protein levels in breast cancer cells, from 14% at 1.25 to 78% at 10 milligrams per liter, and targeting of fatty acid synthase by related drugs has been suggested as a possible treatment.[5] Antiproliferative and pro-apoptotic effects have been shown in colon cells as well.[6] At an intraperitoneal dose of 30 milligrams per kilogram, it has been shown to inhibit feeding and induce dramatic weight loss in mice by a mechanism similar to, but independent or downstream of, leptin signaling.[7] It is found naturally in the industrial strain Cephalosporium caerulens (Sarocladium oryzae, the sheath rot pathogen of rice).

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Notes and References

  1. Volpe . J J . Vagelos . P R . Mechanisms and regulation of biosynthesis of saturated fatty acids. . Physiological Reviews . American Physiological Society . 56 . 2 . 1976 . 0031-9333 . 10.1152/physrev.1976.56.2.339 . 339–417. 6981 .
  2. Straub SG, Yajima H, Komatsu M, Aizawa T, Sharp GW . The effects of cerulenin, an inhibitor of protein acylation, on the two phases of glucose-stimulated insulin secretion . Diabetes . 51 Suppl 1 . 90001. S91–5 . February 2002 . 11815464 . 10.2337/diabetes.51.2007.S91. free .
  3. Reviewed in Ronnett GV, Kleman AM, Kim EK, Landree LE, Tu Y . Fatty acid metabolism, the central nervous system, and feeding . Obesity (Silver Spring) . 14 . 201S–207S . August 2006 . Suppl 5 . 17021367 . 10.1038/oby.2006.309 . free .
  4. Ohno T, Awaya J, Kesado T, Nomura S, Omura S . Mechanism of Action of CM-55, a Synthetic Analogue of the Antilipogenic Antibiotic Cerulenin . Antimicrob. Agents Chemother. . 6 . 4 . 387–92 . October 1974 . 4157441 . 10.1128/aac.6.4.387. 444657.
  5. Menendez JA, Vellon L, Mehmi I . Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells . . 101 . 29 . 10715–20 . July 2004 . 15235125 . 10.1073/pnas.0403390101 . 490000. etal. free . 2004PNAS..10110715M .
  6. Huang P, Zhu S, Lu S, Dai Z, Jin Y . [An experimental study on cerulenin induced apoptosis of human colonic cancer cells] . zh . Zhonghua Bing Li Xue Za Zhi . 29 . 2 . 115–8 . April 2000 . 11866903 .
  7. Ghosh MK, Amudha R, Jayachandran S, Sakthivel N . Detection and quantification of phytotoxic metabolites of Sarocladium oryzae in sheath rot-infected grains of rice . Lett. Appl. Microbiol. . 34 . 6 . 398–401 . 2002 . 12028418 . 10.1046/j.1472-765X.2002.01111.x. free .

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