PubMed · 6795381
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G F Cahill. 1981. Ketosis.. https://doi.org/10.1038/ki.1981.155
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Insulin secretion by the beta cell depends on anaplerosis in which insulin secretagogues are metabolized by mitochondria into molecules that are most likely exported to the extramitochondrial space where they have signaling roles. However, very little is known about the products of anaplerosis. We discovered an experimental paradigm that has begun to provide new information about these products. When various intracellular metabolites were applied in combination to overnight-cultured rat or human pancreatic islets or to INS-1 832/13 cells, they interacted synergistically to strongly stimulate insulin release. When these same metabolites were applied individually to these cells, insulin stimulation was poor. Discerning the contributions of the individual compounds to metabolism has begun to allow us to dissect some of the pathways involved in insulin secretion, which was not possible from studying individual secretagogues. Monomethyl succinate (MMS) combined with a barely stimulatory concentration of alpha-ketoisocaproate (KIC) (2 mm) stimulated insulin release in cultured rat islets 18-fold (versus 21-fold for 16.7 mm glucose). MMS plus low glucose (2 mm) or pyruvate (5 mm) gave 11- and 9-fold stimulations. These agents also potentiated MMS-induced insulin release in fresh islets, and KIC plus MMS gave synergistic insulin release in cultured human islets. In INS-1 cells, neither MMS nor KIC (10 mm) was an insulin secretagogue, but when added together KIC (2 mm) and MMS stimulated insulin release 7-fold (versus 12-fold for glucose). In islets and INS-1 cells, conditions that stimulated insulin release caused large relative increases in acetoacetate, which is a precursor of pathways to short chain acyl-CoAs. Liquid chromatography-tandem mass spectrometry measurements of acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethylglutaryl-CoA, and malonyl-CoA confirmed that they were increased by insulin secretagogues. The results suggest a new mechanism of insulin secretion in which anaplerosis increases short chain acyl-CoAs that have roles in insulin exocytosis.
In this study, whole cells of Saccharomyces uvarum SW-58 were applied in an aqueous-organic solvent biphasic system for the asymmetric reduction of ethyl 4,4,4-trifluoroacetoacetate to ethyl (R)-4,4,4-trifluoro-3-hydroxybutanoate [(R)-2]. The results of reduction in different aqueous-organic solvent biphasic systems showed that dibutylphthalate provided the best compromise between the biocompatibility and the partition of substrate and product among the solvents tested. To optimize the reaction, several factors such as reaction pH, temperature, shaking speed, volume ratio of the aqueous phase to the organic phase and ratio of biomass/substrate were investigated. It was found that the change of these factors obviously influenced the conversion and initial reaction rate, and had a minor effect on the enatiomeric excess of the product. Under the optimal conditions, 85.0% of conversion and 85.2% of enatiomeric excess were achieved. The bioconversion in the biphasic system was more efficient compared with that in the monophasic aqueous system, and product concentration as high as 54.6 g/L was reached in the organic phase without addition of co-enzyme.
CuI/trans-4-hydroxy-l-proline-catalyzed coupling reaction of 2-iodotrifluoroacetanilides with 2-methylacetoacetates took place at -45 degrees C to create alpha-aryl all-carbon quaternary centers enantioselectively. Up to 93% ee was achieved when tert-butyl ester was used. The combination of ligand, ortho substituent (participation of NHCOCF3), and solvent effects was shown to account for these unprecedentedly mild reaction conditions.