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T1 - Cell cycle-dependent regulation of pyrimidine biosynthesis

Pyrimidine Biosynthesis

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Biosynthesis of pyrimidines leading to formation of UMP.

De novo pyrimidine biosynthesis is activated in proliferating cells in response to an increased demand for nucleotides needed for DNA synthesis. The pyrimidine biosynthetic pathway in baby hamster kidney cells, synchronized by serum deprivation, was found to be upregulated 1.9-fold during S phase and subsequently down-regulated as the cells progressed through the cycle. The nucleotide pools were depleted by serum starvation and were not replenished during the first round of cell division, suggesting that the rate of utilization of the newly synthesized nucleotides closely matched their rate of formation. The activation and subsequent down-regulation of the pathway can be attributed to altered allosteric regulation of the carbamoyl-phosphate synthetase activity of CAD (carbamoyl-phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase), a multifunctional protein that initiates mammalian pyrimidine biosynthesis. As the culture approached S-phase there was an increased sensitivity to the allosteric activator, 5-phosphoribosyl-1-pyrophosphate, and a loss of UTP inhibition, changes that were reversed when cells emerged from S phase. The allosteric regulation of CAD is known to be modulated by MAP kinase (MAPK) and protein kinase A (PKA)-mediated phosphorylations as well as by autophosphorylation. CAD was found to be fully autophosphorylated in the synchronized cells, but the level remained invariant throughout the cycle. Although the MAPK activity increased early in G1, the phosphorylation of the CAD MAPK site was delayed until just before the onset of S phase, probably due to antagonistic phosphorylation by PKA that persisted until late G1. Once activated, pyrimidine biosynthesis remained elevated until rephosphorylation of CAD by PKA and dephosphorylation of the CAD MAPK site late in S phase. Thus, the cell cycle-dependent regulation of pyrimidine biosynthesis results from the sequential phosphorylation and dephosphorylation of CAD under the control of two important signaling cascades.

Biosynthesis of the pyrimidine ring. Precursors of the ring and numbering of the ring atoms.

Nucleotides are so essential to metabolism that genetic defects generally are lethal, and for humans only a few gene defects are observed, at a low frequency.

Regulation of Pyrimidine Synthesis

Many of the enzymatic reactions in the biosynthesis of nucleotides are combined as two or more reactions catalysed by a single multidomain protein. This has made nucleotide biosynthesis more efficient.

FIGURE 16–3 Regulatory mechanisms in the biosynthesis of adenine andguanine nucleotides in E. coli. Regulation of these pathways differs in otherorganisms.

Conclusions: Regulation of pyrimidine biosynthesis in Ps.

FIGURE 16–4 (a) De novo synthesis of pyrimidine nucleotides: biosynthesisof UTP and CTP via orotidylate. The pyrimidine is constructed from carbamoylphosphate and aspartate. The ribose 5-phosphate is then added to the completedpyrimidine ring by orotate phosphoribosyltransferase. The first step in thispathway (not shown here; is the synthesis of carbamoyl phosphate from CO2and NH4+, catalyzed in eukaryotes by carbamoyl phosphate synthetase II. (b)Channeling of intermediates in bacterial carbamoyl phosphate synthetase.(Derived from PDB ID 1M6V.) The large and small subunits are shown in gray andblue, respectively; the channel between active sites (almost 100 Å long) isshown as a yellow mesh. A glutamine molecule (green) binds to the small subunit,donating its amido nitrogen as NH4+ in a glutamine amidotransferase–typereaction. The NH4+ enters the channel, which takes it to a second active site,where it combines with bicarbonate in a reaction requiring ATP (bound ADP inblue). The carbamate then reenters the channel to reach the third active site,where it is phosphorylated to carbamoyl phosphate (bound ADP in red).

Regulation of the rate of pyrimidine nucleotide synthesis in bacteria occurs inlarge part through aspartate transcarbamoylase (ATCase), which catalyzes thefirst reaction in the sequence and is inhibited by CTP, the end product of thesequence (Fig. 16–4a). The bacterial ATCase molecule consists of six catalyticsubunits and six regulatory subunits. The catalytic subunits bind the substratemolecules, and the allosteric subunits bind the allosteric inhibitor, CTP. Theentire ATCase molecule, as well as its subunits, exists in two conformations,active and inactive. When CTP is not bound to the regulatory subunits, theenzyme is maximally active. As CTP accumulates and binds to the regulatorysubunits, they undergo a change in conformation. This change is transmitted tothe catalytic subunits, which then also shift to an inactive conformation. ATPprevents the changes induced by CTP.

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  • Regulation of pyrimidine nucleotide biosynthesis ..

    Traut TW (1994) Physiological concentrations of purines and pyrimidines. Molecular and Cellular Biochemistry 140: 1–22.

  • Regulation of Pyrimidine Nucleotide Biosynthesis ..

    Involvement of Rho in the regulation of pyrimidine de novo biosynthesis genes has not been reported.

  • Cell Cycle-dependent Regulation of Pyrimidine Biosynthesis

    Methods and Results: The pyrimidine biosynthetic pathway enzymes were assayed in extracts of Ps.

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down-regulation of pyrimidine biosynthesis, ..

Overview of the pathways for the biosynthesis of purine and pyrimidine nucleotides (THF, tetrahydrofolate). Ribonucleoside triphosphates are blue; deoxyribonucleoside triphosphates are green. To emphasise that it is not a building block for deoxyribonucleic acid (DNA) synthesis dUTP is red. Both pathways start from a common set of precursor amino acids and other metabolites. Each arrow represents an enzymatic reaction.

Regulation of Pyrimidine Nucleotide Biosynthesis - …

An S, Kumar R, Sheets ED and Benkovic SJ (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320: 103–106.

Nucleotide Metabolism: Nucleic Acid Synthesis

N2 - De novo pyrimidine biosynthesis is activated in proliferating cells in response to an increased demand for nucleotides needed for DNA synthesis. The pyrimidine biosynthetic pathway in baby hamster kidney cells, synchronized by serum deprivation, was found to be upregulated 1.9-fold during S phase and subsequently down-regulated as the cells progressed through the cycle. The nucleotide pools were depleted by serum starvation and were not replenished during the first round of cell division, suggesting that the rate of utilization of the newly synthesized nucleotides closely matched their rate of formation. The activation and subsequent down-regulation of the pathway can be attributed to altered allosteric regulation of the carbamoyl-phosphate synthetase activity of CAD (carbamoyl-phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase), a multifunctional protein that initiates mammalian pyrimidine biosynthesis. As the culture approached S-phase there was an increased sensitivity to the allosteric activator, 5-phosphoribosyl-1-pyrophosphate, and a loss of UTP inhibition, changes that were reversed when cells emerged from S phase. The allosteric regulation of CAD is known to be modulated by MAP kinase (MAPK) and protein kinase A (PKA)-mediated phosphorylations as well as by autophosphorylation. CAD was found to be fully autophosphorylated in the synchronized cells, but the level remained invariant throughout the cycle. Although the MAPK activity increased early in G1, the phosphorylation of the CAD MAPK site was delayed until just before the onset of S phase, probably due to antagonistic phosphorylation by PKA that persisted until late G1. Once activated, pyrimidine biosynthesis remained elevated until rephosphorylation of CAD by PKA and dephosphorylation of the CAD MAPK site late in S phase. Thus, the cell cycle-dependent regulation of pyrimidine biosynthesis results from the sequential phosphorylation and dephosphorylation of CAD under the control of two important signaling cascades.

The nucleotide metabolism page discusses the ..

AB - De novo pyrimidine biosynthesis is activated in proliferating cells in response to an increased demand for nucleotides needed for DNA synthesis. The pyrimidine biosynthetic pathway in baby hamster kidney cells, synchronized by serum deprivation, was found to be upregulated 1.9-fold during S phase and subsequently down-regulated as the cells progressed through the cycle. The nucleotide pools were depleted by serum starvation and were not replenished during the first round of cell division, suggesting that the rate of utilization of the newly synthesized nucleotides closely matched their rate of formation. The activation and subsequent down-regulation of the pathway can be attributed to altered allosteric regulation of the carbamoyl-phosphate synthetase activity of CAD (carbamoyl-phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase), a multifunctional protein that initiates mammalian pyrimidine biosynthesis. As the culture approached S-phase there was an increased sensitivity to the allosteric activator, 5-phosphoribosyl-1-pyrophosphate, and a loss of UTP inhibition, changes that were reversed when cells emerged from S phase. The allosteric regulation of CAD is known to be modulated by MAP kinase (MAPK) and protein kinase A (PKA)-mediated phosphorylations as well as by autophosphorylation. CAD was found to be fully autophosphorylated in the synchronized cells, but the level remained invariant throughout the cycle. Although the MAPK activity increased early in G1, the phosphorylation of the CAD MAPK site was delayed until just before the onset of S phase, probably due to antagonistic phosphorylation by PKA that persisted until late G1. Once activated, pyrimidine biosynthesis remained elevated until rephosphorylation of CAD by PKA and dephosphorylation of the CAD MAPK site late in S phase. Thus, the cell cycle-dependent regulation of pyrimidine biosynthesis results from the sequential phosphorylation and dephosphorylation of CAD under the control of two important signaling cascades.

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