PubMed · 15418128
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H SIEDEK, O MYSLIVEC. 1950-04-22. [Levulose therapy].. https://pubmed.ncbi.nlm.nih.gov/15418128/
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Fructophilic lactic acid bacteria (FLAB) are a group of lactic acid bacteria with unique growth characteristics, that is, poor growth on glucose. Their growth is enhanced in the presence of fructose or external electron acceptors. These organisms inhabit fructose-rich environments such as flowers, fruits, and pollinating insects, particularly honey bees. Apilactobacillus spp. and Fructobacillus spp. are representatives of FLAB, although they belong to phylogenetically distant clades. These organisms commonly possess markedly small genomes with a low number of coding DNA sequences. Furthermore, their genomes are characterized by a markedly reduced number of genes involved in carbohydrate transport and metabolism. Genome reduction in FLAB reflects convergent adaptation to fructose-rich environments rather than general genome streamlining. The two distinct FLAB genera, Fructobacillus and Apilactobacillus, independently lost more than 100 genes in statistically similar orders. In contrast, genes involved in carbohydrate and amino acid metabolism exhibited reversed orders of loss between the two genera. Furthermore, FLAB genomes lack an intact bifunctional alcohol/aldehyde dehydrogenase gene (adhE), which causes their poor growth on glucose. A comparative genomic study suggested the evolutionary process underlying adhE gene decay during adaptation to the fructose-rich environments, including pollinating insects. In conclusion, FLAB represent a unique example of habitat-driven convergent reductive evolution that can be investigated across multiple biological scales - from individual genes to whole genomes - in the diverse LAB group with a wide range of habitats, and partially share the fructophilic evolution with eukaryotic yeasts found in fructose-rich habitats.
As a preliminary study of the utility of the natural stable-isotopic differentiation of batch samples produced by different synthetic pathways, multi-stable-isotopic analyses (delta(13)C, delta(15)N, delta(18)O, deltaD) of 53 samples of the antiepileptic drug, Topiramate, produced by three different synthetic pathways (designated "A," "B," "C") were performed. From the outset, we note that there are two fundamental variables that determine the stable-isotopic composition of materials-the stable-isotopic composition of the reagents and starting intermediates, and the isotope fractionation that occurs during manufacture of the product. In this study, the stable-isotopic composition of the raw materials was not controlled and we report here data obtained for a suite of samples that was produced by three synthetic pathways. Graphical examination of these data reveals marked data clustering by synthetic pathway, though in some cases with some overlapping values within standard errors. In general, the isotopic composition of Topiramate from the A and B pathways is distinct from the C pathway. The isotopic data from the A and B pathways typically abut each other, sometimes partially overlapping. The deuterium/hydrogen- (deltaD) and oxygen (delta(18)O) isotopic compositions are each significantly linearly related with the paired carbon (delta(13)C) isotopic composition indicating possible isotopic end-members for the raw materials of the present sample suite. Given that H and O typically derive from meteoric water, the linear correlations with delta(13)C indicate that a mixture of carbon sources (viz., perhaps terrestrial C3 photosynthetic organic carbon and marine C3 organic carbon) were used in the production of the batches tested. If the H and O analyzed were derived from meteoric water, then an elementary comparison of the span of the deltaD (DeltadeltaD = 54.6 +/- 2.1 per thousand) and of the delta(18)O (Deltadelta(18)O = 4.71 +/- 0.26 per thousand) values in the Topiramate samples to that of the global isotopic gradients indicates that the water retained in the samples spanned from as much as 11 degrees of latitude (or, approximately 760 statute miles North-to-South). The present isotope results (delta(13)C, delta(15)N, delta(18)O, deltaD) form an initial database against which future samples can be compared to infer specific synthetic pathways. It is clear that to perform a rigorous test of the variables controlling the stable-isotopic composition of pharmaceutical materials that both the stable-isotopic composition of the starting materials and synthetic isotope fractionation must be controlled in future studies.
Under the chromatographic conditions used in these studies we observed time- and concentration-dependent formation of N-1-Deoxy-fructos-1-yl glutathione as the major glycation product formed in the mixtures of GSH with glucose. N-1-Deoxy-fructos-1-yl glutathione had a characteristic positively charged ion with m/z=470 Th in its LC-MS spectra. Mixtures of glutathione disulfide and glucose generated two compounds: N-1-Deoxy-fructos-1-yl GSSG (m/z=775 Th) as major adduct and bis di-N, N'-1-Deoxy-fructos-1-yl GSSG (m/z=937 Th) as the minor one. All three compounds showed a resonance signal at 55.2 ppm in the 13C-NMR spectra as C1 methylene group of deoxyfructosyl, which represents direct evidence that they are Amadori compounds. All three compounds purified from GSSG/Glc or GSH/Glc mixtures also showed LC-MS/MS fragmentation patterns identical to those of the synthetically synthesized N-1-Deoxy-fructos-1-yl glutathione, N-1-Deoxy-fructos-1-yl GSSG and bis di-N, N'-1-Deoxy-fructos-1-yl GSSG. N-1-Deoxy-fructos-1-yl glutathione was shown to be a poor substrate for glutathione peroxidase (6.7% of the enzyme's original specific activity) and glutathione-S-transferase (25.7% of the original enzyme's specific activity). Glutathione reductase failed to recycle the disulfide bond within the structure of di-substituted bis di-N, N'-1-Deoxy-fructos-1-yl GSSG. It showed only 1% of the original enzyme's specific activity, but retained its ability to reduce the disulfide bond within the structure of N-1-Deoxy-fructos-1-yl GSSG by 57% of its original specific activity. Since the GSH concentration in diabetic lens is significantly decreased and the glucose concentration can increase 10-fold and higher, the formation of Amadori products of the different forms of glutathione with this monosaccharide may be favored under these conditions and could contribute to a lowering of glutathione levels and an increase of oxidative stress observed in diabetic lens.