PubMed · 4204136
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T D Hockaday, K G Alberti. 1972. Diabetic coma.. https://doi.org/10.1016/s0300-595x(72)80042-2
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The nitrate-reducing bacterial strain BunN is able to grow with acetone and nitrate under anoxic conditions. Dialyzed crude cell-free extracts of acetone-plus-nitrate-grown cells of strain BunN catalyzed the exchange of 14CO2 into acetoacetate in an ADP-dependent reaction. The rates of exchange catalyzed by extracts of acetate-grown or 3-hydroxybutyrate-grown cells were only 13% of that catalyzed by extracts of acetone-grown cells. The activity was enzymic since it was destroyed by boiling and was proportional to the amount of added extract. The optimal acetoacetate concentration was 100 mM and the apparent Km was 11.1 mM. The pH optimum was 6.5, the exchange was not dependent on the addition of biotin, and the activity was not inhibited by avidin. The exchange activity was not stimulated (less than two fold) by a variety of metal ions or by a range of possible cofactors. Under optimal conditions (100 mM acetoacetate, 5 mM ADP, 10 mM NaHCO3, pH 6.5, under N2), the exchange activity was 2.7 nmol.min-1.mg protein-1; 2% of the in vivo carboxylation activity of acetone-plus-nitrate-grown cultures. It is suggested that the exchange reaction is a partial reaction catalyzed by the enzyme (or enzyme complex) that carboxylates acetone, and that the methods developed in this study provide a means with which to investigate this reaction further.
Perhexiline maleate, originally classified as a calcium antagonist, is in use as an antianginal agent. The mechanism of its protective effect is unknown, but there is speculation that it involves a modification of myocardial substrate utilization, in which glycolytic sources are used rather than fatty acids. This hypothesis was tested by employing [13C]NMR isotopomer analysis to measure substrate selection in the working rat heart. Substrate utilization was measured from a mixture of substrates present at their physiological concentration, as follows: acetoacetate, glucose, lactate and long-chain fatty acids. Control perfusions were compared with those perfused with perhexiline. It was found that perhexiline increased lactate utilization, which reduced the extent of fatty acid and endogenous substrate oxidation. There was also a significant increase in cardiac output for a small and insignificant increase in oxygen consumption, which suggested an improvement in myocardial efficiency. Thus, it was confirmed by direct measurement that this drug does modify substrate oxidation, which suggests that further investigations of the role that this agent can play in the management of ischemic heart disease would be beneficial.
Prior evidence has suggested that propionyl-L-carnitine improves function in ischemic hearts by providing carnitine for dissipation of acyl-CoA derivatives and propionate for enrichment of the citric acid cycle. Because contractile failure in hearts oxidizing ketone bodies is due to sequestration of free coenzyme A, which can be reversed by the addition of anaplerotic substrates that enrich the citric acid cycle, experiments were performed to determine whether the addition of propionyl-L-carnitine (2 mM) can improve performance in working rat hearts utilizing acetoacetate (7.5 mM). Whereas the addition of propionyl-L-carnitine to acetoacetate resulted in a sustained improvement in the work output of the heart, the addition of propionate (2 mM) or L-carnitine (2 mM) alone to acetoacetate had negligible effects on contractile function. Propionyl-L-carnitine increased the uptake of acetoacetate by 130%, whereas beta-hydroxybutyrate release was minimal and unchanged compared with other groups. These observations show that rates of acetoacetate oxidation are increased commensurate with increased contractile function. Tissue metabolite data indicate that the utilization of propionyl-L-carnitine did not lead to accumulation of citric acid cycle intermediates in the span from citrate to 2-oxoglutarate but to an increase in the tissue content of malate. The results show that addition of propionyl-L-carnitine in hearts oxidizing acetoacetate results in improved mechanical performance that is comparable to the mechanical performance of hearts perfused with glucose as the only substrate. This improvement is most likely conferred by anaplerosis, as suggested by enhanced rates of acetoacetate utilization and citric acid flux.