title: De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways.
abstract: The de novo biosynthesis of pyrimidine nucleotides provides essential precursors for multiple growth-related events in higher eukaryotes. Assembled from ATP, bicarbonate and glutamine, the uracil and cytosine nucleotides are fuel for the synthesis of RNA, DNA, phospholipids, UDP sugars and glycogen. Over the past 2 decades considerable progress has been made in elucidating the mechanisms by which cellular pyrimidines are modulated to meet the needs of the cell. Recent studies demonstrate that CAD, a rate-limiting enzyme in the de novo synthesis of pyrimidines, is regulated through reversible phosphorylation, Myc-dependent transcriptional changes and caspase-mediated degradation. These studies point to increasing evidence for cooperation between key cell signaling pathways and basic elements of cellular metabolism, and suggest that these events have the potential to determine distinct cellular fates, including growth, differentiation and death. This review highlights some of the recent advances in the regulation of pyrimidine synthesis by growth-factor-stimulated signaling pathways.
authors.affiliation: University of North Carolina at Chapel Hill, Department of Pharmacology, Manning Drive CB #7365, Chapel Hill, North Carolina 27599, USA.
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: L M
authors.initials: LM
authors.lastname: Graves
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis; D001221:Aspartate Carbamoyltransferase / Q000378:metabolism; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D017868:Cyclic AMP-Dependent Protein Kinases; D004080:Dihydroorotase / Q000378:metabolism; D016259:Genes, myc; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: C033626:CAD trifunctional enzyme; D009097:Multienzyme Complexes; D011742:Pyrimidine Nucleotides; D001221:Aspartate Carbamoyltransferase; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D004080:Dihydroorotase; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)