Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat liver phenylalanine hydroxylase catalyzes the tetrahydropterin-dependent oxidation of phenylalanine to tyrosine, according to equation 1. In addition to the naturally-occurring coenzyme, tetrahydrobiopterin (BH4), certain synthetic analogs of BH4 such as 6-methyltetrahydropterin (6MPH4) have high cofactor activity. (formula; see text) The hydroxylase can be activated by a variety of reversible and irreversible modifications, including those caused by partial proteolysis, by interaction with phospholipids such as lysolecithin, by alkylation of a single sulfhydryl group, by phosphorylation catalyzed by cAMP-dependent protein kinase, and by preincubation with its substrate, phenylalanine. All of these modes of activation greatly increase the hydroxylase activity in the presence of BH4, whereas the activity in the presence of 6MPH4 is increased only slightly. The ratio of hydroxylase activity in the presence of BH4 compared to the activity in the presence of 6MPH4, therefore, is a useful index of the state of activation of the enzyme. Of the various activation mechanisms listed above, only phosphorylation of the enzyme and phenylalanine-activation appear to operate in vivo. The evidence indicates that these two regulatory mechanisms act synergistically. Thus, phosphorylation of the enzyme by cAMP-dependent protein kinase is stimulated by phenylalanine, especially in the presence of BH4, (which by itself inhibits), whereas phosphorylation sensitizes the enzyme to activation by phenylalanine. One of the consequences of these interlocking control mechanisms is to enhance the responsiveness of the activity of the hydroxylase to alterations in tissue levels of phenylalanine. As a result, elevated concentrations of phenylalanine can be rapidly metabolized, thereby protecting the fetal and neonatal brain from possible damage by excess phenylalanine.
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PMID:Regulation of the activity of hepatic phenylalanine hydroxylase. 302 51

Activation of rat striatal tyrosine hydroxylase [TyrOHase; tyrosine monooxygenase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] by ATP/Mg2+ and endogenous protein kinase can be produced without the addition of cAMP. This activation is not due to endogenous free catalytic subunit derived from cAMP-dependent protein kinase. In the presence of amounts of protein kinase inhibitor sufficient for complete inhibition of striatal cAMP-dependent protein kinase and the cAMP-mediated activation of TyrOHase, addition of ATP/Mg2+ results in an enhancement of TyrOHase activity. Enzyme activation does not occur when the nonhydrolyzable form of ATP, adenylyl imidodiphosphate, is substituted for ATP. When TyrOHase is assayed in the presence of ATP/Mg2+ and different concentrations of either tyrosine or 6-methyltetrahydropterin co-factor, a 2-fold increase in enzyme Vmax is demonstrable, with no change in the Km for either substrate or cofactor. In contrast, in the presence of cAMP and ATP/Mg2+, both an increase in Vmax and an enhanced affinity for pterin cofactor are demonstrable. In the latter circumstance, the 2-fold increase in Vmax can be attributed entirely to the action of cAMP-independent protein kinase. The addition of either EGTA or CaCl2 does not modify the effect seen in the presence of ATP, suggesting that the effect of ATP/Mg2+ is not mediated by a Ca2+-dependent protein kinase. These data support the existence of a cAMP-independent striatal protein kinase that can catalyze the activation of TyrOHase.
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PMID:Evidence for the involvement of a cyclic AMP-independent protein kinase in the activation of soluble tyrosine hydroxylase from rat striatum. 613 85

The effects of substrate and cofactors on the phosphorylation of hepatic phenylalanine hydroxylase by cAMP-dependent protein kinase and on dephosphorylation by phosphoprotein phosphatase have been examined. The presence of the natural cofactor (6R)-tetrahydrobiopterin strongly inhibits the activation observed under phosphorylating conditions; in contrast, this activation is enhanced approximately 20 to 50% by phenylalanine. The phosphorylation of the hydroxylase is strongly inhibited (approximately 80%) by (6R)-tetrahydrobiopterin, while phosphorylation is modestly stimulated by phenylalanine. High concentrations of phenylalanine (1 mM), however, can substantially reverse the inhibition of phosphorylation by (6R)-tetrahydrobiopterin. Neither (6R)-tetrahydrobiopterin nor phenylalanine affect the phosphorylation of a synthetic peptide substrate of cAMP-dependent protein kinase. The inhibition is specific for (6R)-tetrahydrobiopterin; the diastereoisomer (6S)-tetrahydrobiopterin has a much smaller effect, and 6-methyltetrahydropterin and 6,7-dimethyltetrahydropterin have no effect. Both phenylalanine and (6R)-tetrahydrobiopterin inhibit to a small extent the dephosphorylation of phosphorylated phenylalanine hydroxylase catalyzed by phosphoprotein phosphatase. Neither phenylalanine nor (6R)-tetrahydrobiopterin inhibit the dephosphorylation of phosphorylated histones by phosphoprotein phosphatase. These results suggest that the phosphorylation state, and thus the activation state, of phenylalanine hydroxylase in vivo may be modulated, in part, by the availability of substrate.
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PMID:Ligand effects on the phosphorylation state of hepatic phenylalanine hydroxylase. 669 76