Lactone inhibition

There is an expanding body of evidence to suggest that sesquiterpene lactones inhibit the synthesis NO synthetase. One such compound is an ambrosanolides-type sesquiterpene known as cumanin characterized from Ambrosia psilostachya. This sesquiterpene inhibit the enzymatic activity of NO synthetase with an IC50 value of 9.38 xM (49). Another example is the well-known artemisinin, a sesquiterpene used as an alternative drug in the treatment of severe and multidrug-resistant malaria, which inhibits NO synthesis in cytokine-stimulated human astrocytoma T67 cells (50). 

Both glycosidases (61) and amylases (62) are inhibited by certain lactones, as is lysozyme, D-glucono-1,5-lactone, for example, is presumed to inhibit amylase by acting as a transition state analog because it closely approximates a half-chair conformation. However, as stated by Laszlo et al. (62), lactone inhibition cannot establish whether distortion of substrate occurs during binding, as in lysozyme, or after bond splitting to form the carbonium ion, as in proton catalysis. 

J Balsinde, EA Dennis. Bromoenol lactone inhibits magnesium-dependent phospha-tidate phosphohydrolase and blocks triacylglycerol biosynthesis in mouse P388D1 macrophages. J Biol Chem 271 31937-31941, 1996. 

Ritchie AJ, Jansson A, Stallberg J, Nilsson P, Lysaght P, Cooley MA (2005) The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone inhibits T-cell differentiation and cytokine production by a mechanism involving an early step in T-cell activation. Infect Immun 73 1648... 

WONG, H.R., MENENDEZ, I.Y., Sesquiterpene lactones inhibit inducible nitric oxide synthase gene expression in cultured rat aortic smooth muscle cells., Biochem. Biophys. Res. Comm., 1999,262,375-380. 

FK506 macrocyclic lactone inhibition as FKBP/FK506 complex... 

Finally, from Hellanthus tuberosus the sesquiterpene heliangine has been isolated, possessi an o6-methylene butyrolactone moiety. This lactone inhibits the elongation of Avena coleoptile sections and promotes root formation of Phaseolus cuttings (Eef. 1h - 19) ... 

The maximum rates of hydrolysis of synthetic a-D-glucopyranosides and isomaltose by a purified extracellular a-D-glucosidase (pH optimum 5—6, temperature optimum 75°C) from the thermophile B. thermoglucosidus have been compared. Tris, 4-nitrophenyl a-D-xylopyranoside, D-glucose, and D-glucono-1,5-lactone inhibited the hydrolysis of 4-nitrophenyl a-D-glucopyranoside by the enzyme, whose activity was also inhibited by heavy-metal ions but not by H edta, 4-chloromercuribenzoate, and iodoacetate. 

Laszlo, E., Hollo, J., Hoschke, A. and Sarosi, G. (1978) The active center of amylolytic enzymes. I. A study by means of lactone inhibition of the role of "halfchair" glycosyl conformation at the active center of amylolytic enzymes, Carbohydr. Res., 61, 387-394. 

D-Glucono-1,4-lactone inhibited the synthesis of the D-mannan and the jS-(l - 3)-D-glucan in living cells of P. polymorpba, whereas the synthesis of the j8-(l -> 6)-D-glucan was unaffected. ... 

Inhibition of configuration-retaining glycosidases by lactones, piperidines, and tetrazoles 99AG(E)750. 

Lactones. Physiologically active lactones such as parasorbic acid, coumarin, scopoletin, and protoanemonin occur in many plant families (Figure 2). The lactones may perform a regulatory function in the plant, and have been shown to inhibit germination and to repress root growth [reviewed in detail by Hemberg 61), Evenari 36,37), and Borner 12)]. 

Coumarin, the lactone of o-hydroxycinnamic acid, and some of its derivatives have been isolated from many plant species 31). Thimann and Bonner 141) attributed the growth-inhibiting effects of coumarin to its action on enzyme sulfhydryl groups. Inhibitory effects of coumarin on Avena coleoptiles and pea stem sections could be overcome by 2,3-dimercaptopropanol (BAL). Coumarin has also been reported to disrupt mitosis 29,30). 

Figure 2. Structural formulas of some lactones isolated from plants which have a growth-inhibiting action...

Chelidonic acid has been found to exist in the free state in many plants (122). A concentration as high as 10 2 M, calculated on a fresh-weight basis, has been measured. Leopold et al. (89) found that chelidonic acid functioned as a growth inhibitor in the pea straight-growth test. Some inhibition was obtained at 10 5 M and 50% inhibition was measured at 10 4 M. Growth was promoted in the presence of IAA. This action is similar to that noted for coumarin and other unsaturated lactones. As with lactones, the inhibitory effect of chelidonic acid could be relieved by pretreatment of the tissue with BAL. 

Various phenolic acids have been reported to inhibit IAA oxidase (9, 52,120), and other phenols may act as cofactors of IAA oxidase (144). In general, the cofactors of IAA oxidase are monophenols, whereas the inhibitors of the system are polyphenols, with o-dihy-droxyphenols being the most inhibitory (52, 65). Unsaturated lactones have also been reported to inhibit IAA oxidase (2, 52). 

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

A quantitative interpretation of aldonolactone inhibition in terms of an adaptation of the active site to a transition state approaching a planar, glycosyl oxocarbonium ion is made difficult for several reasons. Due to the interconversion between the 1,4- and 1,5-lactones, and their hydrolysis to the aldonic acids, their use is limited to kinetic studies with incubation times of 10 min or less. This was not realized by most investigators prior to 1970. In many cases, only the 1,4-lactone can be isolated its (partial) conversion into... 

The effect of lactone ring-size on the inhibition was studied, for N-acetyl-)3-D-glucosaminidase from bovine epididymis, with lactones and lactone derivatives unable to undeigo ring-isomerization, by Pokomy and co-workers. From a comparison of Kj values for 2-acetamido-2-deoxy-D-glu-cono-1,5-lactone (0.45 nM) with the 1,4-lactone (4.5 fiM) and of Kj for the methyl ) -furanoside with that for the pyranose (4 mM), it was concluded that the 1,4-lactone has an 10-fold lower inhibitory potency than the 1,5-lactone. The weak inhibition by the 5,6-O-isopropylidene derivative of the... 

Inhibition of Glycosidases by AIdono-l,S-lactones and Aldohexoses Expressed by the Dissociation Constant K of the Enzyme-Inhibitor Complex... 

IC with bovine enzyme which is very similar to the human one. Inhibitor concentration for 50% inhibition. K of substrate (phenyl a-D-mannopyranoside). K of substrate (4-nitrophenyl a-D-manno-pyranoside). K of substrate (4-nitrophenyl D-glucosiduronic acid). K of substrate (4-nitrophenyl 2-acetamido-2-deoxy- o-glueoside). Inhibitors were chitotetraono-1,5-lactone and chitotetraose, respectively. 

The results of inhibition studies with aldonolactones and 5-amino-5-deoxyaldonolactams may be summarized as follows y -D-glycosidases are inhibited by 1,5-lactones and the lactams some 100- to > 10,000-fold better than by the parent aldoses, with Kj values from 200 //Mto <0.1 nM. Al-dono-1,4-lactones are probably no better inhibitors than aldoses or polyols of comparable structure, with the possible exception s of 2-acetamido-2-deoxy-D-glucono-1,4-lactone. 

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