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targets (4)
for drugs
Identification
Name Cerulenin
Accession Number DB01034 (APRD00703)
Type small molecule
Groups approved
Description

Cerulenin is an antifungal antibiotic that inhibits sterol and fatty acid biosynthesis. In fatty acid synthesis, reported to bind in equimolar ratio to b-keto-acyl-ACP synthase. In sterol synthesis, inhibits HMG-CoA synthetase activity. It is also shown to inhibit feeding and induce dramatic weight loss in mice. It is found naturally in the Cephalosporium caerulensfungus. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Helicocerin
Brand name mixtures Not Available
Categories
  • Antibiotics, Antifungal
  • Fatty Acid Synthesis Inhibitors
CAS number 17397-89-6
Weight Average: 223.2683
Monoisotopic: 223.120843415
Chemical Formula C12H17NO3
InChI Key InChIKey=GVEZIHKRYBHEFX-GHMZBOCLSA-N
InChI
InChI=1S/C12H17NO3/c1-2-3-4-5-6-7-8-9(14)10-11(16-10)12(13)15/h2-3,5-6,10-11H,4,7-8H2,1H3,(H2,13,15)/t10-,11-/m1/s1
Plain Text
IUPAC Name
(2R,3S)-3-(nona-4,7-dienoyl)oxirane-2-carboxamide
SMILES
CC=CCC=CCCC(=O)[C@H]1O[C@H]1C(N)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Amino Ketones
  • Carboxylic Acids and Derivatives
Substructures
  • Alkanes and Alkenes
  • Amino Ketones
  • Ethers
  • Carbamates and Derivatives
  • Heterocyclic compounds
  • Carboxamides and Derivatives
  • Carboxylic Acids and Derivatives
  • Epoxides
  • Ketones
Pharmacology
Indication For use as a biochemical tool, Cerulenin is shown to cause dramatic weight loss in animals
Pharmacodynamics Cerulenin is an antifungal antibiotic isolated from Cephalosporium caerulens. It interrupts fungal growth by inhibiting the biosynthesis of sterols and fatty acids (inhibits bacterial fatty acid synthesis). It also inhibits HMG-CoA synthetase activity. Cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.
Mechanism of action Irreversibly binds to fatty acid synthase, specifically b-ketoacyl-acyl carrier protein synthase (FabH, FabB and FabF condensation enzymes). A number of tumor cells and cell lines have been observed to have highly upregulated expression and activity of fatty acid synthase (FAS). Inhibition of FAS by cerulenin leads to cytotoxicity and apoptosis in human cancer cell lines, an effect believed to be mediated by the accumulation of malonyl-coenzyme A in cells with an upregulated FAS pathway.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Oral, mouse LD50: 547 mg/kg. Symptoms of overexposure include moderate to severe erythema (redness) and moderate edema (raised skin), nausea, vomiting, and headache.
Affected organisms
  • Humans and other mammals
  • Fungi
  • Bacteria
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 93.5 oC
Experimental Properties
Property Value Source
water solubility Slightly soluble PhysProp
logP 1.2 PhysProp
Predicted Properties
Property Value Source
water solubility 1.60e+00 g/l ALOGPS
logP 1.38 ALOGPS
logP 1.50 ChemAxon Molconvert
logS -2.14 ALOGPS
pKa 18.69 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 72.69 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 62.54 ChemAxon Molconvert
polarizability 23.90 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Huang P, Zhu S, Lu S, Dai Z, Jin Y: [An experimental study on cerulenin induced apoptosis of human colonic cancer cells] Zhonghua Bing Li Xue Za Zhi. 2000 Apr;29(2):115-8. Pubmed
  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. 2002 Feb;51 Suppl 1:S91-5. Pubmed
External Links
Resource Link
KEGG Compound C12058 Link_out
PubChem Compound 5282054 Link_out
PubChem Substance 46508217 Link_out
ChemSpider 26530 Link_out
ChEBI 171741 Link_out
ChEMBL 171741 Link_out
Therapeutic Targets Database DAP000659 Link_out
HET CER Link_out
Drug Product Database 0 Link_out
Wikipedia http://en.wikipedia.org/wiki/Cerulenin Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (25.4 KB)
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. 3-oxoacyl-[acyl-carrier-protein] synthase 1

Pharmacological action: yes
Actions: inhibitor

Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Specific for elongation from C-10 to unsaturated C-16 and C-18 fatty acids

Organism class: bacterial
UniProt ID: P0A953 Link_out
Gene: fabB
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kauppinen S, Siggaard-Andersen M, von Wettstein-Knowles P: beta-Ketoacyl-ACP synthase I of Escherichia coli: nucleotide sequence of the fabB gene and identification of the cerulenin binding residue. Carlsberg Res Commun. 1988;53(6):357-70. Pubmed
  2. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. Pubmed
  3. Slabaugh MB, Leonard JM, Knapp SJ: Condensing enzymes from Cuphea wrightii associated with medium chain fatty acid biosynthesis. Plant J. 1998 Mar;13(5):611-20. Pubmed
  4. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. Pubmed
  5. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. Pubmed
  6. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. Pubmed
  7. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. Pubmed

2. 3-oxoacyl-[acyl-carrier-protein] synthase 2

Pharmacological action: yes
Actions: inhibitor

Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Has a preference for short chain acid substrates and may function to supply the octanoic substrates for lipoic acid biosynthesis

Organism class: bacterial
UniProt ID: P0AAI5 Link_out
Gene: fabF
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Heath RJ, White SW, Rock CO: Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002 May;58(6):695-703. Epub 2002 Mar 7. Pubmed
  2. Schujman GE, Choi KH, Altabe S, Rock CO, de Mendoza D: Response of Bacillus subtilis to cerulenin and acquisition of resistance. J Bacteriol. 2001 May;183(10):3032-40. Pubmed
  3. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. Pubmed
  4. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. Pubmed
  5. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. Pubmed
  6. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. Pubmed
  7. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. Pubmed

3. 3-oxoacyl-[acyl-carrier-protein] synthase 3

Pharmacological action: yes
Actions: inhibitor

Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Catalyzes the first condensation reaction which initiates fatty acid synthesis and may therefore play a role in governing the total rate of fatty acid production. Possesses both acetoacetyl-ACP synthase and acetyl transacylase activities. Has some substrate specificity for acetyl-CoA. Its substrate specificity determines the biosynthesis of straight-chain of fatty acids instead of branched-chain

Organism class: bacterial
UniProt ID: P0A6R0 Link_out
Gene: fabH
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Young K, Jayasuriya H, Ondeyka JG, Herath K, Zhang C, Kodali S, Galgoci A, Painter R, Brown-Driver V, Yamamoto R, Silver LL, Zheng Y, Ventura JI, Sigmund J, Ha S, Basilio A, Vicente F, Tormo JR, Pelaez F, Youngman P, Cully D, Barrett JF, Schmatz D, Singh SB, Wang J: Discovery of FabH/FabF inhibitors from natural products. Antimicrob Agents Chemother. 2006 Feb;50(2):519-26. Pubmed
  2. Heath RJ, White SW, Rock CO: Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002 May;58(6):695-703. Epub 2002 Mar 7. Pubmed
  3. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. Pubmed
  4. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. Pubmed
  5. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. Pubmed
  6. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. Pubmed
  7. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. Pubmed

4. Fatty acid synthase

Pharmacological action: yes
Actions: inhibitor

Fatty acid synthetase catalyzes the formation of long- chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein

Organism class: human
UniProt ID: P49327 Link_out
Gene: FASN Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Oskouian B, Saba JD: YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae. Mol Gen Genet. 1999 Mar;261(2):346-53. Pubmed
  2. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, Pizer ES: Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 2001 Feb 15;61(4):1493-9. Pubmed
  3. Heiligtag SJ, Bredehorst R, David KA: Key role of mitochondria in cerulenin-mediated apoptosis. Cell Death Differ. 2002 Sep;9(9):1017-25. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Flavin R, Peluso S, Nguyen PL, Loda M: Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010 Apr;6(4):551-62. Pubmed
  6. Lupu R, Menendez JA: Pharmacological inhibitors of Fatty Acid Synthase (FASN)—catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol. 2006 Dec;7(6):483-93. Pubmed
  7. Ronnett GV, Kim EK, Landree LE, Tu Y: Fatty acid metabolism as a target for obesity treatment. Physiol Behav. 2005 May 19;85(1):25-35. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:08

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.