Triacsin ©

1. Discovery, producing organism and structures1-4)
Microbial inhibitors of fatty acid metabolism werescreened by an assay system using acyl-CoA synthetase I (ACS-I)-deficient (L-7) and fatty acid synthase(FAS)-deficient(A-1) mutants of Candida lipolytica.
Triacsins were isolated from the culture broth of theactinomycete strain SK-1894 and recognized as acylCoA synthetase inhibitors since they showed inhibitory activity against growth of mutant A-1, but notagainst mutant L-72,3). Triacsins C and D were identified as WS-1228 A and B, respectively, originallyisolated as vasodilators4). No correlation was observed
between the two activities. The first total synthesis oftriacsin C (WS-1228A) was reported by Tanaka et al.5)

Fatty acid

ACS-II

Acyl–CoAAcyl–CoAPeroxisomers

Lipid

ACS-I

FAS

Malonyl–CoA

ACC

β-Oxidation

Acetyl–CoA

GlucoseFatty acid metabolism of C. lipolytica
N N N OH

H3C

Triacsin A
N N N OH

H3C

Triacsin B
N N N OH

H3C

Triacsin C (WS-1228A)
N N N OH

H3C

Streptomyces sp. SK-1894

Triacsin D (WS-1228B)

2. Physical data (Triacsin C) 1)
Yellow powder. C11H17N3O ; mol wt 207. Sol. in acetone, EtOAc, EtOH. Insol. in H2O.
3. Biological activity6)
1) Inhibition of long chain acyl-CoA synthetase
Enzyme source
Pseudomonas fraji
Pseudomonas aeruginosa
Rat liverRaji cells
HSDMICI cells
Long chain ACS
Arachidonoyl-CoA synthetase
Candida lipolytica
ACS –I

IC50 (µM)
Triacsin A Triacsin B Triacsin C Triacsin DReference

26171812> 150> 200> 200> 100

173.68.76.3>150>200>200>100

1556NTNTNTNT0.48
8.5NTNT77> 50

4.0>50		5.52) N-Hydroxytriazene moiety is essential for acyl-CoA synthetase inhibition.
Triacsin A or CNNNOHCHONo inhibitory activityibition!!

l for inhEssentia

3) Triacsin A inhibits P. aeruginosa acyl-CoA synthetase competitively with respect to the substrate oleic acid (Km 101 µM, Ki 8.97 µM) and non-competitively with respect to CoA andATP6).
4) Inhibitory activity against the acyl-CoA synthase family7-11)
Isoform

Main substrate

CharacteristicInhibition by triacsin C

Saccharomyces cerevisiae7)
Faa1p
C14:0, C15:0
Activate imported FA, phospholipid synthesis
Faa2p
C9:0 - C13:0
Activate endogenous FA, similar to mammalian ACS
Faa3p
C16:1, C18:1
Phospholipid synthesis, similar to Faa1p
Faa4p
C14:0, C16:0
Activate imported FA, N-myristoylation		C16:1, C18:1
Rat8, 9)ACS1
C12-18 (sat.)
All tissues, triacylglycerol synthesis		
C16-20 (unsat.)
ACS210) C12:0-C18:0
Brain11)
ACS3
C12-14 (sat.)
Brain, lipid synthesis		
C16-20 (unsat.)
ACS4
C20:4, C20:5
Steroidogenic tissues, triacylglycerol synthesis
ACS5C12-18 (sat.)
Intestine, involved in ß-oxidation		
C16-20 (unsat.)
Faap; fatty acid activation protein, ACS; acyl-CoA synthetase, NT; not tested>500 µM
80 nM>500 µM
4.5 µM
4-6 µM
NTNT
4-6 µM>10 µM

4. Application12-21)
1) Triacsins were found to be lethal to animal cells but not to microorganisms12). This may be
due to the different end products (free fatty acid or acyl-CoA) produced by fatty acid synthases.
Animal cells

Microorganisms
Acetyl–CoAAcetyl–CoAMalonyl–CoA

Fatty acidsynthase

Fatty acid
Acyl–CoA(Acyl–ACP)
synthetase
Acyl–CoA (Acyl–ACP)

Fatty acidMalonyl–CoATriacsins

Fatty acid synthase
Fatty acids
Acyl–CoA synthetase
Acyl–CoA2) Triacsin C inhibited the macrophage-derived foam cell formation completely by depletingacyl-CoA required for synthesizing cholesteryl esters (CE) and triacylglycerols (TG)14).
PS containing lipospme
Cholesterol
Phospholipid
Scavenger receptor

Lysosome

ACATOH

ACS

CE

SCOA

TG
Lipid droplets

EROH

Fatty acid

PS: Phosphatidylserine
ACS: Acyl-CoA synthetase
ACAT: Acyl-CoA:cholesterol acyltransferase

Triacsin3) Complete inhibition of HIV gag myristoylation by triacsin C caused inhibition of HIV particle
budding15).

Gag particle
Budding
Plasma membrane
Host cellO

HN-GlyCoA

NH2 -GlyACS
OH

SCOAO

Myristic acidNMTO

Myristoyl-CoA

Triacsin C-COOH

Gag protein
ACS: Acyl-CoA synthetase
NMT: N-Myristoyltransferase

4) Triacsins are used as useful tools in cell biology and biochemistry14-21).
1. Function of fatty acyl-CoA14,15,22,23)
2. Metabolism of lipid-related bioactive compounds18,19) and lipoprotein20)
5) Triacsin C exhibited antimalarial activity against both Kl and FCR strain of P. falciparum.25)
5. Triacsin C is commercially available from Biomol Kyowa Medix.

6. References
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4.		
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5.		
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10.		
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11.		
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16.		
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17.		
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20.		
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22.		
E. Iorio et al., Biophys. Acta 1634, 1-14 (2003)
23.		
M. Shimabukuro et al., Proc. Natl. Acad. Sci, USA 95, 2498-2502 (1998)
24.		
A. M. Hall et al., J. Biol. Chem. 278, 43008-43013 (2003)
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