https://www.gastrojournal.org/article/S0016-5085(82)80339-9/pdf

Utilization of nutrients by isolated epithelial cells of the rat colon.

A variety of neurotransmitters, hormones, and other regulatory agents affect the phosphorylation of specific proteins in their target tissues. The types of stimuli that share this common effect on protein phosphorylation include numerous substances that do not act through cyclic AMP. These and other observations suggest that many different classes of regulatory substances achieve certain of their biological effects by altering the phosphorylation of specific proteins.

http://science.sciencemag.org/content/sci/199/4325/146.full.pdf

Phosphorylated proteins as physiological effectors

The colonic epithelium in ulcerative colitis: an energy-deficiency disease?

Dichloroacetate (DCA) exerts multiple effects on pathways of intermediary metabolism. It stimulates peripheral glucose utilization and inhibits gluconeogeneis, thereby reducing hyperglycemia in animals and humans with diabetes mellitus. It inhibits lipogenesis and cholesterolgenesis, thereby decreasing circulating lipid and lipoprotein levels in short-term studies in patients with acquired or hereditary disorders of lipoprotein metabolism. By stimulating the activity of pyruvate dehydrogenase, DCA facilitates oxidation of lactate and decreases morbidity in acquired and congenital forms of lactic acidosis. The drug improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat. DCA may also enhance regional lactate removal and restoration of brain function in experimental states of cerebral ischemia. DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. Other toxic effects of DCA may be species-specific and reflect marked interspecies variation in pharmacokinetics. Despite its potential toxicity and limited clinical experience, DCA and its derivatives may prove to be useful in probing regulatory aspects of intermediary metabolism and in the acute or chronic treatment of several metabolic disorders.

The pharmacology of dichloroacetate.

1. The effects of Ca2+ (mainly by using EGTA buffers), pH, ATP and ADP on the activity of the 2-oxoglutarate dehydrogenase complex from pig heart were explored. 2. Ca2+ (about 30 micrometer) resulted in a decrease in the apparent Km for 2-oxoglutarate from 2.1 to 0.16 mM (at pH 7) without altering the maximal velocity. At 0.1 mM-oxoglutarate there was a 4--5-fold activation by Ca2+, with an apparent Km for Ca2+ of 1.2 micrometer. A similar activation was also observed with Sr2+ (Km 15.1 micrometer), but not wised markedly from pH 7.4 TO 6.6. The effects of Ca2+ remained evident over this pH range. 4. In the presence of Mg2+, ATP resulted in a marked increase in the apparent Km for oxoglutarate, whereas ADP greatly decreased thisp arameter. The concentrations of adenine nucleotide required for half-maximal effects were about 10 micrometer in each case. 5. The effects of the adenine nucleotides and Ca2+ on the apparent Km for oxoglutarate appeared to be essentially independent of each other, reversible, and demonstrable in the presence of end product inhibition by NADH and obtained. 6. Effects similar to those described above were also observed on the activity of 2-oxoglutarate dehydrogenase from rat heart and brown adipose tissue. 7. We discuss the mechanisms controlling this enzyme's activity and compare these regulatory features with those of NAD-isocitrate dehydrogenase and the pyruvate dehydrogenase system, which are also sensitive to Ca2+ and adenine nucleotides.

/pdf/the-effects-of-calcium-ions-and-adenine-nucleotides-on-the-3363j7w0al.pdf

The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex.

Dichloroacetate and other halogenated carboxylic acids can activate pyruvate dehydrogenase in rat heart and in rat heart mitochondria by effecting conversion of phosphorylated (inactive) pyruvate dehydrogenase into an active (dephosphorylated) form. These compounds are inhibitors of pig heart pyruvate dehydrogenase kinase. Pig heart pyruvate dehydrogenase phosphate phosphatase requires both Mg2+and Ca2+ for activity. Evidence is given for a dual metal requirement of the phosphatase in rat fat cell mitochondria. It is concluded that Mg2+ and Ca2+ are essential cofactors for the phosphatase but that their physiological significance as regulators remains to be established. Pig heart pyruvate dehydrogenase kinase is inhibited by high concentrations of magnesium and by low concentrations of calcium.

Susan Whitehouse

Papers

Regulation of mammalian pyruvate dehydrogenase.