| De novo nucleotide metabolism is highly regulated
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| Because nucleotides are required for mammalian cells to proliferate, the de novo pathways of nucleotide metabolism are inducible both transcriptionally and post-transcriptionally. Genes encoding a number of nucleotide biosynthetic enzymes for both purines and pyrimidines are transcriptionally upregulated following growth factor treatment. Post-transcriptional regulation also plays an important role in nucleotide synthesis. The multimeric protein, CAD is activated by phosphorylation by both mitogen-activated protein kinase (MAPK) and protein kinase A (PKA). MAPK phosphorylation increases the binding of PRPP by CAD and decreases the inhibition of UTP. Both of these allosteric regulatory changes favor biosynthesis of pyrimidines for growth. PKA phosphorylation reduces the response to both allosteric effectors on the CAD enzyme activity. The phosphorylation of CAD is also regulated during in the cell cycle, with phosphorylated forms accumulating just before the onset of S-phase, and these changes are reversed when cells emerge from S-phase (see Chapter 41). Recently, this enzyme has also been shown to be degraded by capsase-3 proteolysis during the initial stages of apoptosis. Thus, the pyrimidine biosynthetic pathway is selectively and efficiently inactivated during the process of apoptosis.
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| PLASMA NUCLEOTIDASE ACTIVITY INCREASES IN HEPATOBILIARY DISEASE |
| The enzyme, 5'-nucleotidase, catalyzes the conversion of nucleotide monophosphates to nucleosides and inorganic phosphate. This enzyme is distributed in the membranes of liver cells, as well as in other tissues. Serum levels of nucleotidase are low in children, rise gradually during adolescence and reach a plateau at ∼50 years of age. Serum levels of nucleotidase increase during hepatobiliary disease, along with other liver enzymes such as alkaline phosphatase. The elevation of both of these enzymes is specific for hepatobiliary disease. Nucleotidase is also elevated in women during the third trimester of pregnancy. |
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