A model study on the mechanism of inhibition of fatty acyl desaturases by cyclopropene fatty acids

Quintana, Jordi; Barrot, M.; Fabriás, Gemma; Camps, Francisco

doi:10.1016/s0040-4020(98)00611-5

Cited by 20 publications

(17 citation statements)

References 25 publications

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“…Additionally, we demonstrated that the 1,2-dialkylcyclopropene unit is required for inhibition, since, whereas 10,11-methylenehexadec-10-enoic acid inhibits both the D 11 and D 9 desaturases of S. littoralis (Gosalbo et al, 1994), the corresponding 3-carboxycyclopropene and 3-cyclopropenone are inactive (Quintana et al, 1998). Furthermore, 7,8-methylenehexadec-7-enoic acid, which does not conform to the rule of Fogerty, was completely inactive on all the desaturases of S. littoralis in the experimental conditions used (Quintana et al, unpublished).…”

Section: Discussionmentioning

confidence: 84%

Inhibition of the acyl-CoA desaturases involved in the biosynthesis of Spodoptera littoralis sex pheromone by analogs of 10,11-methylene-10-tetradecenoic acid

Rodríguez

Camps

Fabriás

2004

Insect Biochemistry and Molecular Biology

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Section: Discussionmentioning

confidence: 84%

Inhibition of the acyl-CoA desaturases involved in the biosynthesis of Spodoptera littoralis sex pheromone by analogs of 10,11-methylene-10-tetradecenoic acid

Rodríguez

Camps

Fabriás

2004

Insect Biochemistry and Molecular Biology

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“…Overexpression of the M. tuberculosis desA3 gene in M. bovis BCG, but not of desA1 or desA2, resulted in increased synthesis of oleic acid and ∆ 9 desaturase activity in the recombinant strain [67]. Moreover, sterculic acid (9,10-cyclopropene fatty acid derived from methylation of oleic acid), which is a potent and specific inhibitor of the ∆ 9 desaturase [146][147], was shown to inhibit incorporation of [1,2-14 C]acetate into oleic acid and to have no effect on mycolic acid synthesis, and to inhibit the growth of M. bovis BCG [67]. These results indicate that oleic acid is not a precursor of mycolic acids, ISO targets a ∆ 9 desaturase system, and inhibition of oleic acid synthesis is sufficient to kill M. bovis BCG.…”

Section: Isoxyl (Thiocarlide Iso)mentioning

confidence: 99%

Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis - An Update

Basso¹,

Santos²

2005

MCRO

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Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis, and infects approximately 32 % of the world's human population. It is estimated that 8.2 million new TB cases occurred worldwide in the year 2000, with approximately 1.8 million deaths in the same year, and more than 95 % of those were in developing countries. The interruption of centuries of decline in case rates of TB occurred, in most cases, in the late 1980s and involved the USA and some European countries due to increased poverty in urban settings and the immigration from TB high-burden countries. Thus, no sustainable control of TB epidemics can be reached in any country without properly addressing the global epidemic. The reemergence of TB as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat M. tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are α-alkyl, β-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, α-methyl ketone, or α-methyl methylethers groups, and, as shown more recently, by unsaturations. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straightchain saturated fatty acids to provide the α-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. Pyrazinamide was thought to inhibit fatty acid synthase type I, thereby reducing the synthesis of precursor of mycolic acids. However, current experimental evidence indicates that it has no defined target of action. The main focus of our contribution is on new data describing the mode of action of antitubercular drugs that inhibit mycolic acid biosynthesis, and description of inhibitors of fatty acid synthase type II enzymes as potential lead compounds that may allow the development of new antitubercular agents.

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“…After early reports on the activity of sterculic acid (9,10-methyleneoctadec-9-enoic acid) as a potent inhibitor of the D 9 stearoyl-CoA desaturase, [11] the inhibitory effect of cyclopropene fatty acids on different acyl-CoA desaturases has been the subject of several publications. [12] Although the mechanism of inhibition is still controversial, [12] it is well established that a) sterculic acid inhibits the D 9 desaturation of different aliphatic acids, regardless of the chain length; [13] b) among several synthetic cyclopropene fatty acids, only those compounds with the ring at C9 and/or C10 are effective inhibitors of the D 9 desaturase; [14] and c) a structural analogue of sterculic acid with an exocyclic double bond does not inhibit the desaturation of stearic to oleic acid. [15] In light of these reports, the cyclopropene-containing ceramide erythro-1 was designed as a putative inhibitor of dihydroceramide desaturation.…”

Section: Dedicated To Professor Francisco Campsmentioning

confidence: 99%

Synthesis of a Cyclopropene Analogue of Ceramide, a Potent Inhibitor of Dihydroceramide Desaturase

Triola

Fabriàs

Llebaría

2001

Angew. Chem. Int. Ed.

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A model study on the mechanism of inhibition of fatty acyl desaturases by cyclopropene fatty acids

Cited by 20 publications

References 25 publications

Inhibition of the acyl-CoA desaturases involved in the biosynthesis of Spodoptera littoralis sex pheromone by analogs of 10,11-methylene-10-tetradecenoic acid

Inhibition of the acyl-CoA desaturases involved in the biosynthesis of Spodoptera littoralis sex pheromone by analogs of 10,11-methylene-10-tetradecenoic acid

Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis - An Update

Synthesis of a Cyclopropene Analogue of Ceramide, a Potent Inhibitor of Dihydroceramide Desaturase

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