Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of acute and chronic glucagon treatment on phenylalanine metabolism in vivo in the rat have been investigated. A single, large dose of glucagon (2 mg/kg, i.p.) increased metabolism of a large load of phenylalanine (1.27 g/kg) via hydroxylation and transamination. The increased metabolism was associated with increased activities of hepatic phenylalanine:pyruvate aminotransferase, tyrosine aminotransferase and phenylalanine hydroxylase. In rats administered this amount of phenylalanine, the p-hydroxyphenylpyruvate dioxygenase reaction was apparently rate limiting, as indicated by increased urinary excretion of p-hydroxyphenylpyruvate and p-hydroxyphenyllactate, in addition to urinary excretion of phenylpyruvate and phenyllactate. Chronic glucagon treatment (1.25 mg/kg every 12 hr for 8 days) increased oxidation of the large phenylalanine load and urinary excretion of phenylpyruvate and phenyllactate but not p-hydroxyphenylpyruvate or p-hydroxyphenyllactate. The increased excretion of phenylpyruvate and phenyllactate was associated with an increase in hepatic phenylalanine: pyruvate aminotransferase activity. The absence of p-hydroxyphenylpyruvate in the urine and the increased oxidation of phenylalanine imply that, in rats administered glucagon chronically, flux of p-hydroxyphenylpyruvate through the p-hydroxyphenylpyruvate dioxygenase reaction was increased. A kinetic assay for phenylalanine hydroxylase based on measurement of oxygen consumption in described.
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PMID:Glucagon stimulation of phenylalanine metabolism. The effects of acute and chronic glucagon treatment. 612 64

Recent studies have demonstrated that angiotensin II, catecholamines, and vasopressin can stimulate the phosphorylation of hepatic cytosolic proteins via a Ca2+-linked cyclic AMP-independent mechanism. The present study used high resolution, two-dimensional gel electrophoresis to determine if the proteins phosphorylated in response to the Ca2+-linked hormones were distinct from those affected by glucagon acting via the cyclic AMP-dependent pathway. Intact hepatocytes labeled with [32P]PO4(3-) were stimulated with glucagon, angiotensin II, l-norepinephrine, and vasopressin and over 100 phosphorylated proteins resolved by two-dimensional electrophoresis and autoradiography. Six important enzymes known to be regulated through covalent modification were positively identified, including phosphorylase, phosphofructokinase, pyruvate kinase, fructose-6-phosphate, 2-kinase, phenylalanine hydroxylase, and fructose-1,6-bisphosphatase. Computer analysis of the autoradiograms from control and hormone-treated cells demonstrated that glucagon increased the phosphorylation state of 12 phosphoproteins and reduced the phosphorylation of one protein with a Mr = 21,000 and a pI = 5.9. The Ca2+-linked hormones stimulated the phosphorylation of 7 phosphoproteins and also reduced the phosphorylation state of the 21,000-dalton protein. Angiotensin II, l-norepinephrine, and vasopressin had equivalent effects on protein phosphorylation. There were six protein substrates uniquely affected by glucagon and one phosphoprotein uniquely stimulated by the Ca2+-linked hormones. Seven substrates were affected by stimulation of the cell with either glucagon or the Ca2+-linked hormones. These results demonstrate that, while there is overlap in the substrates affected by glucagon and the Ca2+-linked hormones, each pathway is able to affect the phosphorylation of unique substrates. This finding suggests that the two types of hormones may have some distinct effects on hepatic function.U
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PMID:Glucagon and the Ca2+-linked hormones angiotensin II, norepinephrine, and vasopressin stimulate the phosphorylation of distinct substrates in intact hepatocytes. 629 Apr 94

Phenylalanine is transported rapidly into, but is not concentrated by, liver cells. Glucagon increased flux through phenylalanine hydroxylase; a half-maximal response was obtained at 0.7 nM. Under control conditions, 0.2-0.3 mol of phosphate were incorporated per mol of subunit of the hydroxylase at steady state. Glucagon increased this incorporation of phosphate into the hydroxylase to a maximal value of approx. 0.6 mol of phosphate per subunit; a half-maximal response was obtained at 0.3 nM. Glucagon, added simultaneously with [32P]Pi to liver cells, inhibited incorporation of 32P into the enzyme. The effects of glucagon were reproduced with dibutyryl cyclic AMP. Changes in phosphorylation correlated closely with changes in flux through phenylalanine hydroxylase in cell incubations.
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PMID:Phenylalanine hydroxylase in liver cells. Correlation of glucagon-stimulated enzyme phosphorylation with expressed activity. 672 66

We show that phenylalanine is able to control the extent of activation and, as a result, the catalytic activity of rat liver phenylalanine hydroxylase in vivo, in perfused liver, and in vitro. Both phosphorylated and unphosphorylated enzyme activities are controlled by phenylalanine activation and, overall, this mechanism appears to be a major means of regulating the enzyme's activity in rat liver. At normal phenylalanine levels in vivo, phenylalanine hydroxylase is at most 1-4% activated, and phosphorylated enzyme (glucagon-induced) appears at most 5-7% activated under similar conditions. In both cases, a phenylalanine load increased the percentage of activated enzyme found in vivo to about 40% of maximal. In perfused rat livers, a plasma phenylalanine concentration of only 4 times normal induced a 4-fold increase in the amount of activated enzyme present and a corresponding functional increase in the rate of phenylalanine hydroxylation by the tissue. Under the latter conditions, more than 25% of the amino acid could be hydroxylated in a single pass through the organ. Purified phosphorylated phenylalanine hydroxylase must be activated to be catalytically active. The activation with phenylalanine, at equilibrium, is a cooperative process, and the phosphorylated enzyme is activated more rapidly at pH 6.8 and 8.0 and at lower phenylalanine concentration than the unphosphorylated species. Overall, phosphorylation appears to allow phenylalanine hydroxylase to be more easily activated at relatively low phenylalanine concentrations.
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PMID:Regulation of phenylalanine hydroxylase activity by phenylalanine in vivo, in vitro, and in perfused rat liver. 698 44

1. Methods are described for monitoring the metabolic flux through phenylalanine hydroxylase, the tyrosine catabolic pathway and phenylalanine: pyruvate transaminase in isolated liver cell incubations. 2. The relationship between hydroxylase flux and phenylalanine concentration is sigmoidal. 3. Glucagon increases hydroxylase activity at low, near-physiological, substrate concentrations only. The hormone does not affect the rate of formation of phenylpyruvate. 4. Experimental diabetes (for 10 days) increases phenylalanine catabolism, and this is further increased by glucagon. 5. These results are discussed in the light of the known mechanisms for control of phenylalanine hydroxylase activity in vitro.
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PMID:Phenylalanine metabolism in isolated rat liver cells. Effects of glucagon and diabetes. 732 31

Phenylalanine hydroxylase catalyzes the major regulatory step of the phenylalanine degradation pathway. In view of the glucogenic nature of phenylalanine breakdown, and hence its potential contribution to glucose homeostasis, we have investigated the impact of streptozotocin-induced diabetes upon the expression of rat phenylalanine hydroxylase. Northern blot analysis revealed that induction of diabetes was associated with an increase in the in vivo abundance of hepatic phenylalanine hydroxylase-specific mRNA. This increase in mRNA abundance was maintained for at least 8 hr in liver cells isolated from diabetic animals. In contrast, phenylalanine hydroxylase immunoreactivity and enzymic activity decreased, over the 8 hr incubation period, to levels similar to those observed in liver cells from normal animals. These changes were retarded, but not prevented, by the presence of dexamethasone in incubation media. In liver cells from normal animals the abundance of phenylalanine hydroxylase-specific mRNA, immunoreactivity and enzymic activity, were largely insensitive to treatment with dexamethasone and/or glucagon over an 8 hr incubation period. It is concluded that, whereas diabetes-related alterations in phenylalanine hydroxylase-specific mRNA abundance persist after isolation of liver cells, changes in phenylalanine hydroxylase protein abundance do not. Additionally, in contrast to certain other enzymes (e.g. phosphoenolpyruvate carboxykinase) it is not possible to mimic diabetes-related alterations in the expression of phenylalanine hydroxylase, in liver cells from normal animals, by simple hormonal manipulation of incubation media. This implies that other additional factors must also contribute to diabetes-related alterations in hepatic enzyme expression.
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PMID:Differential effects of streptozotocin-induced diabetes on phenylalanine hydroxylase protein and mRNA abundance in isolated rat liver cells. 892 6


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