The evolutionary history of the first three enzymes in pyrimidine biosynthesis

@article{Davidson1993TheEH,
  title={The evolutionary history of the first three enzymes in pyrimidine biosynthesis},
  author={Jeffrey N. Davidson and K. C. Chen and R S Jamison and L A Musmanno and Christine B Kern},
  journal={BioEssays},
  year={1993},
  volume={15}
}
Some metabolic pathways are nearly ubiquitous among organisms: the genes encoding the enzymes for such pathways must therefore be ancient and essential. De novo pyrimidine biosynthesis is an example of one such metabolic pathway. In animals a single protein called CAD Abbreviations: CAD, trifunctional protein catalyzing the first three steps of de novo pyrimidine biosynthesis in higher eukaryotes; CPS, carbamyl phosphate synthetase domain; CPSase, carbamyl phosphate synthetase activity; ATC… Expand
Evolutionary implications of the mosaic pyrimidine-biosynthetic pathway in eukaryotes.
TLDR
The phylogenetic analyses of DHOD and OMPDC support the implications of the mosaic pyrimidine biosynthetic pathway in eukaryotes and the potential importance of the horizontal gene transfer(s) and endosymbiosis in establishing the mosaic pathway is discussed. Expand
CAD: A Multifunctional Protein Leading De Novo Pyrimidine Biosynthesis
TLDR
A model of CAD is proposed that sets the DHO and ATC domains as the central framework of the hexameric particles and is expected to be similar to the Escherichia coli CPS and human mitochondrial CPS1 crystal structures. Expand
Structural and transcriptional analysis of the pyrABCN, pyrD and pyrF genes in Aspergillus nidulans and the evolutionary origin of fungal dihydroorotases
TLDR
Cl cloning, mapping and transcriptional characterization of some pyrimidine biosynthesis genes in the filamentous fungus Aspergillus nidulans are reported and Comparison of amino acid sequences of active dihydroorotases with related enzymes and with their non‐functional homologues in yeast and As pergillus indicates that the active diHydro orotases from fungi are more similar to ureases and enzymes of the pyridine degradation pathway. Expand
CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis.
TLDR
Some of the most significant efforts to decipher the architecture of CAD and to understand its catalytic and regulatory mechanisms are retrace. Expand
Phylogenetic analysis of carbamoylphosphate synthetase genes: complex evolutionary history includes an internal duplication within a gene which can root the tree of life.
TLDR
It is confirmed that internal similarity within the synthetase domain of CPS is the result of an ancient gene duplication that preceded the divergence of the Bacteria, Archaea, and Eukarya, and used in phylogenetic tree construction to root the tree of life. Expand
Half of Saccharomyces cerevisiae Carbamoyl Phosphate Synthetase Produces and Channels Carbamoyl Phosphate to the Fused Aspartate Transcarbamoylase Domain*
TLDR
The overall CPSase-ATCase reaction is much less sensitive than the parent molecule to the ATCase bisubstrate analogue,N-phosphonacetyl-l-aspartate (PALA), providing evidence that the endogenously produced carbamoyl phosphate is sequestered and channeled to theATCase active site. Expand
Molecular evolution of the histidine biosynthetic pathway
TLDR
Evidence that the hisA and the hisF genes and their homologues are the result of two successive duplication events that apparently took place before the separation of the three cellular lineages is extended supports the idea that during the early stages of metabolic evolution at least parts of the histidine biosynthetic pathway were mediated by enzymes of broader substrate specificities. Expand
Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease
TLDR
This review summarizes significant progress over the past 10 years towards the characterization of CAD's architecture, function, regulatory mechanisms and cellular compartmentalization, as well as the recent finding of a new and rare neurometabolic disorder caused by defects in CAD activities. Expand
Organisation and sequence determination of glutamine-dependent carbamoyl phosphate synthetase II in Toxoplasma gondii.
TLDR
The novel C-terminal regulatory domain may explain the lack of activation of Toxoplasma gondii carbamoyl phosphate synthetase II by the allosteric effector 5-phosphoribosyl 1-pyrophosphate. Expand
De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways
TLDR
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, and point to increasing evidence for cooperation between key cell signaling pathways and basic elements of cellular metabolism. Expand
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References

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Channeling of carbamyl phosphate, the first intermediate in the pathway, has been demonstrated both in vitro and in permeabilized cells, and aTCase activity of both wild-type and protease-deficient strains has been found to be localized in the nucleus. Expand
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TLDR
A 'genetic cassette', containing information for neither the CPSase nor the ATCase domain, can direct the synthesis of a polypeptide with DHOase activity. Expand
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TLDR
Analysis of the nucleotide and amino acid sequence identities among the various carbamyl phosphate synthetases suggests that the gene fusion which joined the GLN and CPS domains was an early event in the evolution of eukaryotic organisms and that the Saccharomyces cerevisiae enzyme consisting of separate subunits arose by defusion from an ancestral multifunctional protein. Expand
Complete hamster CAD protein and the carbamylphosphate synthetase domain of CAD complement mammalian cell mutants defective in de novo pyrimidine biosynthesis
TLDR
A derivative construct of theCAD cDNA was generated that should encode only the CPSase domain and a protein was synthesized that had significant CPSase activity both in vivo and in vitro. Expand
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TLDR
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TLDR
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TLDR
The reaction mechanism of Saccharomyces cerevisiae aspartate transcarbamylase was studied in permeabilized cells of a mutant in which this enzyme is not associated to carbamylphosphate synthetase, which indicates that the association of the two enzymes within the multienzymatic complex alters the apparent kinetic properties of this enzyme. Expand
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TLDR
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TLDR
A 13-amino acid long sequence is proposed to be part of the catalytic domain of this class of enzymes, based on the observed homologies in the primary sequences of the other amidotransferases examined. Expand
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  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1979
TLDR
A combined genetic, biochemical, and immunological approach has clarified structural relationships involving the first three enzymes of de novo pyrimidine biosynthesis and concluded that these three enzymes reside in a single multifunctional 220,000-dalton polypeptide. Expand
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