Genetics and biochemistry of carbamoyl phosphate biosynthesis and its utilization in the pyrimidine biosynthetic pathway

Makoff, Andrew; Radford, Alan

doi:10.1128/mr.42.2.307-328.1978

Cited by 49 publications

(3 citation statements)

References 150 publications

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“…Uridine-monophosphate (UMP) is synthesized de novo from glycine/ammonia-donating substrates via the orotate pathway , with the liver being the major site of synthesis. The first and most important regulatory step in de novo synthesis of pyrimidines is production of carbamoyl phosphate (CP) from ammonia/glutamine, ATP, and carbonate, catalyzed by carbamoyl phosphate synthetase (CPS). Most eukaryotes have two types of CPS; CPS I is a mitochondrial enzyme which is ammonia-specific and is involved in arginine biosynthesis and the urea cycle.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of Galactosamine Toxicity Revisited; A Metabonomic Study

et al. 2007

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1H NMR spectroscopy was used to investigate the metabolic effects of the hepatotoxin galactosamine (galN) and the mechanism by which glycine protects against such toxicity. Rats were acclimatized to a 0 or 5% glycine diet for 6 days and subsequently administered vehicle, galN (500 mg/kg), glycine (5% via the diet), or both galN and glycine. Urine was collected over 12 days prior to administration of galN and for 24 hours thereafter. Serum and liver tissue were sampled on termination, 24 hours post-dosing. The metabolic profiles of biofluids and tissues were determined using high-field 1H NMR spectroscopy. Orthogonal-projection to latent structures discriminant analysis (O-PLS-DA) was applied to model the spectral data and enabled the hepatic, urinary, and serum metabolites that discriminated between control and treated animals to be determined. Histopathological data and clinical chemistry measurements confirmed the protective effect of glycine. The level of N-acetylglucosamine (glcNAc) in the post-dose urine was found to correlate strongly with the degree of galN-induced liver damage, and the urinary level of glcNAc was not significantly elevated in rats treated with both galN and glycine. Treatment with glycine alone was found to significantly increase hepatic levels of uridine, UDP-glucose, and UDP-galactose, and in view of the known effects of galactosamine, this suggests that the protective role of glycine against galN toxicity might be mediated by changes in the uridine nucleotide pool rather than by preventing Kupffer cell activation. Thus, we present a novel hypothesis: that administration of glycine increases the hepatic uridine nucleotide pool which counteracts the galN-induced depletion of these pools and facilitates complete metabolism of galN. These novel data highlight the applicability of NMR-based metabonomics in elucidating multicompartmental metabolic consequences of toxicity and toxic salvage.

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Section: Discussionmentioning

confidence: 99%

The Mechanism of Galactosamine Toxicity Revisited; A Metabonomic Study

et al. 2007

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“…CPS-II is upregulated in many cancers [24], and mainly in hepatoma [25][26][27] The optimal pH for CPS-II activity is 7.4 [28]. Normal cells have an intracellular pH between 7.1 and 7.2.…”

Section: The Steps In De Novo Pyrimidine Synthesismentioning

confidence: 99%

“…The optimal pH for CPS-II activity is 7.4 [ 28 ]. Normal cells have an intracellular pH between 7.1 and 7.2.…”

Section: The Pyrimidine Synthesis Pathwaymentioning

confidence: 99%

Role of pH in Regulating Cancer Pyrimidine Synthesis

Al‐Qahtani

Koltai²,

Ibrahim

et al. 2022

JoX

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Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.

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Control-mechanisms acting at the transcriptional and post-transcriptional levels are involved in the synthesis of the arginine pathway carbamoylphosphate synthase of yeast.

et al. 1983

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In Saccharomyces cerevisiae, the synthesis of the arginine pathway enzyme carbamoylphosphate synthase (CPSase A) is subject to two control mechanisms. One mechanism, the general control of amino acid biosynthesis, influences the expression of both CPA1 and CPA2 genes, the structural genes for the two subunits of the enzyme. The second mechanism, the specific control of arginine biosynthesis, only affects the expression of CPA1. To study these mechanisms in more detail, we have cloned the CPA1 and CPA2 genes and used their DNA to measure the CPA1 and CPA2 mRNA content of cells grown under various conditions. A close coordination was observed in the variation of the levels of CPA1 and CPA2 mRNAs and polypeptide products under conditions where the general control of amino acid biosynthesis operates. In contrast, little correlation was found between the levels of CPA1 mRNA and the corresponding protein for conditions affecting repression by arginine: the total amplitude of variation was 6‐fold higher for the CPA1 protein than for the CPA1 messenger transcript. Such findings are consistent with the conclusion that the general control operates at the transcriptional level and that the specific arginine control acts primarily at a post‐transcriptional level.

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Genetics and biochemistry of carbamoyl phosphate biosynthesis and its utilization in the pyrimidine biosynthetic pathway

Cited by 49 publications

References 150 publications

The Mechanism of Galactosamine Toxicity Revisited; A Metabonomic Study

The Mechanism of Galactosamine Toxicity Revisited; A Metabonomic Study

Role of pH in Regulating Cancer Pyrimidine Synthesis

Control-mechanisms acting at the transcriptional and post-transcriptional levels are involved in the synthesis of the arginine pathway carbamoylphosphate synthase of yeast.

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