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PubMed2005

Identifying lactone hydrolysis in pharmaceuticals. A tool for metabolite structural characterization.

Methods to characterize metabolic transformations in a rapid and reliable fashion are required for facilitating the development of all new pharmaceuticals. One metabolic transformation, which is the focus of this study, is lactone hydrolysis. For pharmaceuticals containing lactones, hydrolysis occurs readily due to both enzymatic and nonenzymatic processes. Hydrolysis affects both the bioavailability and the efficacy of lactone-containing drugs and pro-drugs. To facilitate the characterization of lactones and their corresponding hydrolysis products, we have developed a mass spectrometric method that can readily discriminate between a lactone and its corresponding carboxylic acid, even when these changes are accompanied by other modifications that occur during metabolism. This method uses characteristic product ions in MS/MS experiments, and the trends described herein can be applied broadly to several types of lactones. To demonstrate the efficacy of this approach, two different lactones that had undergone multiple modifications were characterized, and in both cases, lactone hydrolysis was readily discernible, based on the MS/MS data.

Carboxylic Acids↗
PubMed1986

Halo enol lactones: studies on the mechanism of inactivation of alpha-chymotrypsin.

In a previous investigation [Daniels, S. B., Cooney, E., Sofia, M. J., Chakravarty, P. K., & Katzenellenbogen, J. A. (1983) J. Biol. Chem. 258, 15046-15053], we demonstrated that alpha-aryl-substituted five- and six-membered ring halo enol lactones were effective inhibitors of chymotrypsin, and we proposed that they reacted by an enzyme-activated mechanism: acyl transfer to the active site serine generates a halomethyl ketone that remains tethered in the catalytic site until it alkylates an accessible nucleophilic residue. In this study, we have investigated in greater detail the process of chymotrypsin inactivation by an alpha-naphthyl-substituted five- and six-membered bromo enol lactone. Inactivation by both compounds appears to be active site directed, since the time-dependent inactivation is retarded by competing substrate. The possible involvement of a paracatalytic mechanism for inactivation (generation of a free, rather than active site bound, inactivating species) was investigated by comparing the inactivation efficiencies of the lactones with that of the bromomethyl keto acid hydrolysis products. The bromomethyl ketone derived from the five-membered lactone is ineffective, whereas that derived from the six-membered lactone is highly efficient. However, the possible involvement of the free keto acid in chymotrypsin inactivation by the six-membered lactone is ruled out by experiments involving selective scavenging. The long-term inactivation of chymotrypsin requires the presence of the bromine substituent and appears to involve an alkylation rather than an acylation reaction (hydrazine resistant). Furthermore, a 1:1 lactone:enzyme stoichiometry is demonstrated with the 14C-labeled six-membered lactone. These results are consistent with the mechanism-based inactivation process previously presented.

Chromatography, High Pressure Liquid↗
PubMed2006

Influence of cultivation site on sesquiterpene lactone composition of forage chicory (Cichorium intybus L.).

The forage potential of chicory (Cichorium intybus L.) has not been realized in southern West Virginia (WV) because ruminants are reluctant to consume the herbage. Chicory contains bitter sesquiterpene lactones that can adversely impact palatability. This study was undertaken to determine whether sesquiterpene lactone concentrations in chicory grown in southern WV differ from those in chicory grown in central Pennsylvania (PA) where chicory is grazed readily. Herbage was collected in 1997 and 1998 from cultivars Grasslands Puna (Puna), INIA le Lacerta (Lacerta), and Forage Feast established at research sites near State College, PA, and Beckley, WV. The total concentration of sesquiterpene lactones in WV-grown cultivars was 0.58% (dry matter basis) in Puna, 0.59% in Lacerta, and 0.79% in Forage Feast in 1997 and ranged from 1.03 (Lacerta) to 1.52% (Forage Feast) in 1998. In PA-grown cultivars, sesquiterpene lactones represented 0.16 (Puna), 0.18 (Lacerta), and 0.27% (Forage Feast) of the forage dry matter in 1997 and ranged from 0.32 (Lacerta) to 0.55% (Forage Feast) in 1998. Concentrations of lactucin, lactucopicrin, and total sesquiterpene lactones in Forage Feast exceeded those in the other cultivars grown at the same site. The lowest concentrations of lactucopicrin and total sesquiterpene lactones observed among WV-grown cultivars were higher (2-fold or more) than the highest concentrations present in cultivars grown the same year in PA. Mineral analyses of soils from the two cultivation sites indicate that P availability may influence sesquiterpene lactone composition of chicory herbage. Results provide a foundation for future studies of environmental effects on sesquiterpene lactone composition and palatability of chicory herbage.

Animal Feed↗
PubMed1986

Enol lactone inhibitors of serine proteases. The effect of regiochemistry on the inactivation behavior of phenyl-substituted (halomethylene)tetra- and -dihydrofuranones and (halomethylene)tetrahydropyranones toward alpha-chymotrypsin: stable acyl enzyme intermediate.

We have found that alpha-aryl-substituted halo enol lactones (I and II) are effective mechanism-based inactivators for chymotrypsin. In this study, we have investigated, for comparative purposes, halo enol lactones with aryl functions situated beta and gamma to the lactone carbonyl group. We synthesized 4-phenyl-5(E)-(iodomethylidene)tetrahydro-2-furanone (1), 4-phenyl-5(E)-(iodomethylidene)dihydro-2-furanone (2), 4-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranone (3), and 5-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranone (4), using a halolactonization reaction to convert the appropriate phenyl-substituted acetylenic acid precursor into the corresponding 5(E)-(halomethylidene)furanone and 6(E)-(halomethylidene)pyranone system. The 4-phenylfuranone (1 and 2) and the 5-phenylpyranone (4) proved to be only reversible, competitive inhibitors. By contrast, the 4-phenyltetrahydropyranone (3) inactivated alpha-chymotrypsin in a time-dependent manner. This inactivation was very rapid but reversible, with regeneration of enzyme activity being spontaneous and hydrazine-accelerated, suggestive of the intermediacy of a stable acyl enzyme. Kinetic comparison of the iodomethylene lactone 3 with the corresponding protio lactone 25 indicates that the iodine accelerates the rate of chymotrypsin acylation but produces an acyl enzyme that is more hydrolytically labile than that formed from lactone 25. From the results of this study, we conclude that a phenyl group situated at C-3 (alpha to the lactone carbonyl group) in both the 5(E)-(iodomethylidene)tetrahydro-2-furanone (I) and 6(E)-(iodomethylidene)tetrahydro-2-pyranone (II) series is essential for their activity as mechanism-based irreversible inactivators of chymotrypsin. The corresponding beta-aryl-substituted lactones, by contrast, are potent acylating agents that lead to acyl enzymes of high stability.

Acylation↗
PubMed2006

Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2alpha-functionalization of 25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones.

An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S,24S)-2alpha-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50=7.4 pM) than 2 (IC50=6.3 nM).

Alkylation↗
PubMed2003

Synthetic method and biological activities of cis-fused alpha-methylene gamma-lactones.

A reliable method was developed for the synthesis of cis-fused alpha-methylene gamma-lactones via alpha-methyl gamma-lactones. Bromination of alpha-methyl gamma-lactones with LDA/CBr(4) or TMSOTf/PTAB and successive dehydrobromination with DBU or TBAF of the resulting alpha-bromo-alpha-methyl gamma-lactones gave the desired alpha-methylene gamma-lactones in high yield. This method was successfully applied to the synthesis of biologically active compounds. alpha-Methylene gamma-lactone derivatives 1c, 2c, 4c, and 17 showed cell growth inhibitory activity to P388 lymphocytic leukemia. They also showed significant activities to crop diseases. Thus, alpha-methylene gamma-lactone 1c showed preventive activity in controlling scab of apple caused by Venturia inaequalis. alpha-Methylene gamma-lactones 2c, 4c, 17, and 18 also showed significant preventive activities in controlling damping off of cucumber caused by Pythium aphanidermatum.

Animals↗
PubMed1981

23,25-Dihydroxyvitamin D3: a natural precursor in the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone.

To elucidate the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone, two known metabolites of 25-hydroxyvitamin D3--23,25-dihydroxyvitamin D3 and 25,26-dihydroxyvitamin D3--were incubated individually with kidney homogenate prepared from vitamin D-supplemented chickens, a preparation known to produce the lactone from 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3-26,23-lactone produced in vitro was then separated, purified, identified, and quantitated by consecutive straight-phase and reverse-phase high-performance liquid chromatography. 23,25-Dihydroxyvitamin D3 is a far better substrate for production of 25-hydroxyvitamin D3-26,23-lactone than is 25,26-dihydroxyvitamin D3. Production of lactone is highly selective for the natural 23(S)-hydroxy-23,25-dihydroxyvitamin D3 while both epimers of 25,26-dihydroxyvitamin D3 resulted in small amounts of product comigrating with natural lactone. It appears that 23(S),25-dihydroxyvitamin D3, but not 25,26-dihydroxyvitamin D3, is a natural precursor in the synthesis of 25-hydroxyvitamin D3-26,23-lactone; this result also implies that the configuration of the lactone at C-23 is S.

24,25-Dihydroxyvitamin D 3↗
PubMed1995

Pharmacological correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 of SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.

Adult↗
PubMed2002

N-acylhomoserine lactones undergo lactonolysis in a pH-, temperature-, and acyl chain length-dependent manner during growth of Yersinia pseudotuberculosis and Pseudomonas aeruginosa.

In gram-negative bacterial pathogens, such as Pseudomonas aeruginosa and Yersinia pseudotuberculosis, cell-to-cell communication via the N-acylhomoserine lactone (AHL) signal molecules is involved in the cell population density-dependent control of genes associated with virulence. This phenomenon, termed quorum sensing, relies upon the accumulation of AHLs to a threshold concentration at which target structural genes are activated. By using biosensors capable of detecting a range of AHLs we observed that, in cultures of Y. pseudotuberculosis and P. aeruginosa, AHLs accumulate during the exponential phase but largely disappear during the stationary phase. When added to late-stationary-phase, cell-free culture supernatants of the respective pathogen, the major P. aeruginosa [N-butanoylhomoserine lactone (C4-HSL) and N-(3-oxododecanoyl)homoserine lactone (3-oxo-C12-HSL)] and Y. pseudotuberculosis [N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL)] AHLs were inactivated. Short-acyl-chain compounds (e.g., C4-HSL) were turned over more extensively than long-chain molecules (e.g., 3-oxo-C12-HSL). Little AHL inactivation occurred with cell extracts, and no evidence for inactivation by specific enzymes was apparent. This AHL turnover was discovered to be due to pH-dependent lactonolysis. By acidifying the growth media to pH 2.0, lactonolysis could be reversed. By using carbon-13 nuclear magnetic resonance spectroscopy, we found that the ring opening of homoserine lactone (HSL), N-propionyl HSL (C3-HSL), and C4-HSL increased as pH increased but diminished as the N-acyl chain was lengthened. At low pH levels, the lactone rings closed but not via a simple reversal of the ring opening reaction mechanism. Ring opening of C4-HSL, C6-HSL, 3-oxo-C6-HSL, and N-octanoylhomoserine lactone (C8-HSL), as determined by the reduction of pH in aqueous solutions with time, was also less rapid for AHLs with more electron-donating longer side chains. Raising the temperature from 22 to 37 degrees C increased the rate of ring opening. Taken together, these data show that (i) to be functional under physiological conditions in mammalian tissue fluids, AHLs require an N-acyl side chain of at least four carbons in length and (ii) that the longer the acyl side chain the more stable the AHL signal molecule.

Body Fluids↗
PubMed1984

Stereo-retained and stereo-selective lactonization of four diastereoisomers of 23,25,26-trihydroxyvitamin D3 in homogenates of kidney from vitamin D-supplemented chicks.

To elucidate the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone, various vitamin D3 derivatives were incubated individually with kidney homogenates prepared from vitamin D3-supplemented chicks, a preparation known to produce the 25-hydroxyvitamin D3-26,23-lactone from 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3-26, 23-lactone produced in vitro was then separated, purified, identified, and quantitated by consecutive analysis by high-pressure liquid chromatography. The naturally occurring 23(S), 25(R)-25-hydroxyvitamin D3-26,23-lactone was produced from 23(S),25-dihydroxyvitamin D3, 25(R),26-dihydroxyvitamin D3, and 23(S),25(R),26-trihydroxyvitamin D3. 23(S),25 (S)-25-Hydroxyvitamin D3-26,23-lactone was synthesized from 25(S),26-dihydroxyvitamin D3 and 23(S),25(S),26-trihydroxyvitamin D3. The relative amounts of 25-hydroxyvitamin D3-26,23-lactones generated from the following vitamin D3 derivatives used as substrate (23(S),25(S),26-trihydroxyvitamin D3; 23(R),25(R),26-trihydroxyvitamin D3; 23(S),25(R),26-trihydroxyvitamin D3; 23(R),25(S),26-trihydroxyvitamin D3; 23(S), 25-dihydroxyvitamin D3; 23(R),25-dihydroxyvitamin D3; 25(S),26-dihydroxyvitamin D3; and 25(R),26-dihydroxyvitamin D3) are, respectively, 15:1.7:24:3.3:2.5:0:1:1.7. These results indicate that when the lactonization at C-23 and C-26 positions of various vitamin D3 derivatives occurred the stereochemical configuration at their C-23 and/or C-25 positions was not changed and the difference of the stereochemical configurations determined the rate of lactonization.

Animals↗
PubMed1996

High-performance liquid chromatography-thermospray mass spectrometry of 5,6-dihydroxyeicosatrienoate-1,5-lactone from tissue homogenates.

We have developed a method for the analysis of 5,6-dihydroxyeicosatrienoate-1,5-lactone (5,6-DiHETriE-delta-lactone) in tissue homogenates, supplemented with NADPH and arachidonic acid [20:4(n-6)] as a substrate. During the incubation and the extraction, most of the 5,6-epoxyeicosatrienoic acid (5,6-EpETriE) was converted to 5,6-dihydroxyeicosatrienoic acid (5,6-DiHETriE), and most of the 5,6-DiHETriE was converted to 5,6-DiHETriE-delta-lactone. Consequently, the chief degradation product of 5,6-EpETriE and 5,6-DiHETriE in the incubation mixture was 5,6-DiHETriE-delta-lactone. 5,6-DiHETriE-delta-lactone, corresponding to [20:4(n-6)], was shown to be characterized by a high intensity of quasimolecular ions (MH+ and MNH4+), using ion analysis obtained by reversed-phase HPLC-thermospray MS. On selected-ion monitoring (SIM) chromatograms of 5,6-DiHETriE-delta-lactone and with deuterium-labeled 15(S)-hydroxyeicosatetraenoic acid as the internal standard, the regression equation of the peak-area ratio and the amount of 5,6-DiHETriE-delta-lactone was y = 12.2x + 0.7 (r = 0.9996). 5,6-Epoxygenase activity was represented as the sum of the amount of 5,6-DiHETriE-delta-lactone, 5,6-EpETriE and 5,6-DiHETriE per mg protein, after 30 min in an incubation mixture. The activity from rat brain homogenate decreased considerably with growth of the rat.

Animals↗
PubMed2004

Zr[bis(salicylidene)ethylenediaminato]-mediated Baeyer-Villiger oxidation: stereospecific synthesis of abnormal and normal lactones.

Baeyer-Villiger oxidation of racemic bicyclic cyclobutanones with Zr[bis(salicylidene)ethylenediaminato] (salen) complex 1 as catalyst in the presence of a urea-hydrogen peroxide adduct was found to proceed enantiospecifically. The enantiotopos selection in the oxidation was governed primarily by the Zr(salen) catalyst, although migratory aptitude (methine > methylene > methyl) in Baeyer-Villiger oxidation affected the selection to a varied extent, depending on the substrate structures; one enantiomer of cyclobutanones gave exclusively a normal lactone expected from the migratory aptitude, and the other enantiomer gave an abnormal lactone preferentially, the formation of which is counter to the migratory aptitude. Furthermore, the rates of abnormal lactone formation were found to be faster than those of normal lactone formation in most of the oxidations examined. For example, the enantiomer of racemic bicyclo[3.2.0]heptan-6-one giving an abnormal lactone reacted 2.2 times faster than the other enantiomer giving a normal lactone. To our knowledge, this example of chemocatalytic Baeyer-Villiger oxidation giving an abnormal lactone in preference to a normal lactone has been previously unreported. This unusual behavior is likely to be attributable to strict control of stereoelectronic demand in Baeyer-Villiger oxidation and chiral recognition by complex 1.

Journal Article↗
PubMed1999

Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1alpha,25-dihydroxyvitamin D3.

We examined the effects of two novel 1alpha,25-dihydroxyvitamin D3-26,23-lactone (1alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60) differentiation using the evaluation system of the vitamin D nuclear receptor (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analogues. We found that the 1alpha,25-lactone analogues (23S)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9647), and (23R)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9648) bound much more strongly to the VDR than the natural (23S, 25R)-1alpha,25(OH)2D3-26,23-lactone, but did not induce cell differentiation even at high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells induced by 1alpha,25(OH)2D3 was inhibited by either TEI-9647 or TEI-9648 but not by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol-13-acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI-9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective antagonist of both 1alpha,25(OH)2D3 (10(-8) M) mediated induction of p21(WAF1, CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7 cells transfected with cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase gene and cDNA of the human VDR. Collectively the results strongly suggest that our novel 1alpha,25-lactone analogues, TEI-9647 and TEI-9648, are specific antagonists of 1alpha, 25(OH)2D3 action, specifically VDR/DRE-mediated genomic action. As such, they represent the first examples of antagonists, which act on the nuclear VDR.

Animals↗
PubMed2005

N-Acylhomoserine lactone quorum-sensing molecules are modified and degraded by Rhodococcus erythropolis W2 by both amidolytic and novel oxidoreductase activities.

The Rhodococcus erythropolis strain W2 has been shown previously to degrade the N-acylhomoserine lactone (AHL) quorum-sensing signal molecule N-hexanoyl-L-homoserine lactone, produced by other bacteria. Data presented here indicate that this Gram-positive bacterium is also capable of using various AHLs as the sole carbon and energy source. The enzymic activities responsible for AHL inactivation were investigated in R. erythropolis cell extracts and in whole cells. R. erythropolis cells rapidly degraded AHLs with 3-oxo substituents but exhibited relatively poor activity against the corresponding unsubstituted AHLs. Investigation of the mechanism(s) by which R. erythropolis cells degraded AHLs revealed that 3-oxo compounds with N-acyl side chains ranging from C8 to C14 were initially converted to their corresponding 3-hydroxy derivatives. This oxidoreductase activity was not specific to 3-oxo-AHLs but also allowed the reduction of compounds such as N-(3-oxo-6-phenylhexanoyl)homoserine lactone (which contains an aromatic acyl chain substituent) and 3-oxododecanamide (which lacks the homoserine lactone ring). It also reduced both the D- and L-isomers of n-(3-oxododecanoyl)-L-homoserine lactone. A second AHL-degrading activity was observed when R. erythropolis cell extracts were incubated with N-(3-oxodecanoyl)-L-homoserine lactone (3O,C10-HSL). This activity was both temperature- and pH-dependent and was characterized as an amidolytic activity by HPLC analysis of the reaction mixture treated with dansyl chloride. This revealed the accumulation of dansylated homoserine lactone, indicating that the 3O,C10-HSL amide had been cleaved to yield homoserine lactone. R. erythropolis is therefore capable of modifying and degrading AHL signal molecules through both oxidoreductase and amidolytic activities.

4-Butyrolactone↗
PubMed2006

N-acyl-homoserine lactone-mediated quorum-sensing in Azospirillum: an exception rather than a rule.

Forty Azospirillum strains were tested for their ability to synthesize N-acyl-homoserine lactones (AHLs). AHL production was detected for four strains belonging to the lipoferum species and isolated from a rice rhizosphere. AHL molecules were structurally identified for two strains: Azospirillum lipoferum TVV3 produces 3O,C(8)-HSL (N-3-oxo-octanoyl-homoserine-lactone), C(8)-HSL (N-3-octanoyl-homoserine-lactone), 3O,C(10)-HSL (N-3-oxo-decanoyl-homoserine-lactone), 3OH,C(10)-HSL (N-3-hydroxy-decanoyl-homoserine-lactone) and C(10)-HSL (N-3-decanoyl-homoserine-lactone), whereas A. lipoferum B518 produced 3O,C(6)-HSL (N-3-oxo-hexanoyl-homoserine-lactone), C(6)-HSL (N-3-hexanoyl-homoserine-lactone), 3O,C(8)-HSL, 3OH,C(8)-HSL and C(8)-HSL. Genes involved in AHL production were characterized for A. lipoferum TVV3 by generating a genomic library and complementing an AHL-deficient strain with sensor capabilities. Those genes, designated alpI and alpR, were found to belong to the luxI and luxR families, respectively. When cloned in a suitable heterologous host, alpI and alpR could direct the synthesis of the five cognate AHLs present in A. lipoferum TVV3. These two adjacent genes were found to be located on a 85 kb plasmid. Southern hybridization experiments with probes alpI/R indicated that genes involved in AHL production in the three other AHL-producing strains were not closely related to alpI and alpR. This study demonstrates that AHL-based quorum-sensing is not widespread among the genus Azospirillum and could be found only in some A. lipoferum strains.

4-Butyrolactone↗
PubMed1991

Effects of 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone and its intermediate metabolites on bone metabolism in vivo and in vitro.

Which intermediate metabolite of 23(S)25(R)-1 alpha,25-(OH)2D3-26,23-lactone causes the unique biological functions of 1 alpha,25-(OH)2D3-26,23-lactone different from that of 1 alpha,25-(OH)2D3 was examined comparatively. The three intermediate metabolites, 1 alpha,25(R)26-(OH)3D3, 1 alpha,23(S)25(R)26-(OH)4D3, and 23(S)25(R)-1 alpha,25-(OH)2D3-26,23-lactol stimulated bone resorption, as 1 alpha,25-(OH)2D3 did, in vitamin D-deficient rats. On the other hand, 1 alpha,25-(OH)2D3-26,23-lactone only inhibited bone resorption. 1 alpha,25-(OH)2D3, 1 alpha,25-(OH)2D3-26,23-lactone and the other three metabolites stimulated MNC formation from hematopoietic blast cells in a manner correlated with their binding affinities for the 1 alpha,25-(OH)2D3 receptor. However, CM obtained from 1 alpha,25-(OH)2D3-26,23-lactone-treated MC3T3-E1 cells inhibited MNC formation, probably by the action of some inhibitory factors elaborated by the cells treated with 1 alpha,25-(OH)2D3-26,23-lactone, whereas CM obtained from 1 alpha,25-(OH)2D3 or other metabolite-treated MC3T3-E1 cells stimulated MNC formation. These facts indicate that only 1 alpha,25-(OH)2D3-26,23-lactone has an inhibitory action of bone resorption and that the lactone ring plays a major part in its expression.

Animals↗
PubMed1988

1 alpha,25-Dihydroxyvitamin D3[1 alpha,25-(OH)2D3]-26,23-lactone inhibits 1,25-(OH)2D3-mediated fusion of mouse bone marrow mononuclear cells.

Vitamin D3 and its hormonally active metabolite 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] can be metabolized to a number of daughter metabolites, including 1 alpha,25-(OH)2D3-26,23-lactone; this latter compound has four diastereoisomers. The 23(S),25(R)-lactone (naturally occurring) and the 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactone are both known to be able to inhibit bone resorption induced by 1 alpha,25-(OH)2D3 under in vivo or in vitro conditions. To understand the mechanism of the inhibitory action of these two isomers on bone resorption we investigated the effects of 1 alpha,25-(OH)2D3-26,23-lactone on unfractionated mouse bone marrow cells in vitro. The addition of 1 alpha,25-(OH)2D3 to these cultures dose-dependently stimulated the formation of multinucleated cells over a range of 10(-9) - 10(-7) M. The 23(S),25(S)- and 23(R),25(R)-1 alpha,25-(OH)2D3-26,23-lactones also increased the number of multinucleated cells, whereas the 23(S),25(R)- and 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactones failed to do so. In addition, these latter two diastereomers inhibited the 1 alpha,25-(OH)2D3 stimulation of multinucleated cell formation, although the 23(S),25(S)- and 23(R),25(R)-1 alpha,25-(OH)2D3-26,23-lactones and 24R,25-(OH)2D3 did not. These multinucleated cells responded to calcitonin and contained tartrate-resistant acid phosphatase, both of which are characteristic of osteoclasts. The present data suggest that inhibition of multinucleated cell formation is the mechanism by which the 23(S),25(R)- or 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactone inhibits bone resorption induced by 1 alpha,25-(OH)2D3.

Acid Phosphatase↗
PubMed1990

Biological activity assessment of 1 alpha,25-dihydroxyvitamin D3-26,23-lactone and its intermediate metabolites in vivo and in vitro.

The biological activity of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone, and three intermediate metabolites of the lactone in vivo and in vitro was comparatively examined. The three intermediate metabolites, 1 alpha,25(R)26(OH)3D3, 1 alpha,23(S)25(R)26(OH)4D3, and 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactol, stimulated increases, as did 1 alpha,25(OH)2D3, in intestinal calcium transport and serum calcium level in vitamin D-deficient rats fed a low-calcium diet. On the other hand, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone increased the calcium transport but decreased the serum calcium level. 1 alpha,25(OH)2D3,23(S)25(R)-Lactone and the other three metabolites stimulated multinucleate cell formation from hematopoietic blast cells in a manner correlated with their binding affinities for the 1 alpha,25(OH)2D3 receptor. But 23(S)25(R)-lactone did not show any inhibitory effect on the multinucleate cell formation induced by 1 alpha,25(OH)2D3 in contrast to the results obtained from unfractionated marrow cultures. Conditioned medium obtained from 23(S)25(R)-lactone-treated MC3T3-E1 cells inhibited the formation, probably by the action of some inhibitory factors elaborated by the cells treated with the lactone, whereas conditioned medium obtained from 1 alpha,25(OH)2D3 or other metabolite-treated MC3T3-E1 cells stimulated the formation. These findings suggest that 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone might inhibit bone resorption through an inhibition of osteoclastic cell formation and that other vitamin D3 metabolites stimulate bone resorption by development of new osteoclastic cells in addition to indirect osteoclast activation.

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