The evolutionary history of the first three enzymes in pyrimidine biosynthesis

  title={The evolutionary history of the first three enzymes in pyrimidine biosynthesis},
  author={Jeffrey N. Davidson and Kuey Chu Chen and Robert S. Jamison and Lisa Musmanno and Christine B Kern},
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… 

Structural and transcriptional analysis of the pyrABCN, pyrD and pyrF genes in Aspergillus nidulans and the evolutionary origin of fungal dihydroorotases

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.

CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis.

Some of the most significant efforts to decipher the architecture of CAD and to understand its catalytic and regulatory mechanisms are retrace.

Phylogenetic analysis of carbamoylphosphate synthetase genes: complex evolutionary history includes an internal duplication within a gene which can root the tree of life.

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.

Half of Saccharomyces cerevisiae Carbamoyl Phosphate Synthetase Produces and Channels Carbamoyl Phosphate to the Fused Aspartate Transcarbamoylase Domain*

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.

Molecular evolution of the histidine biosynthetic pathway

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.

Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

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.

De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways

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.

As in Saccharomyces cerevisiae, aspartate transcarbamoylase is assembled on a multifunctional protein including a dihydroorotase-like cryptic domain in Schizosaccharomyces pombe

Genetic investigations confirmed that both GLNase/CPSase and ATCase activities are carried out by the same polypeptide and are also both feedback-inhibited by UTP (uridine triphosphate).



Pyrimidine biosynthesis in Saccharomyces cerevisiae: the ura2 cluster gene, its multifunctional enzyme product, and other structural or regulatory genes involved in de novo UMP synthesis.

  • M. Denis-Duphil
  • Biology
    Biochemistry and cell biology = Biochimie et biologie cellulaire
  • 1989
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.

Complete hamster CAD protein and the carbamylphosphate synthetase domain of CAD complement mammalian cell mutants defective in de novo pyrimidine biosynthesis

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.

Controlled proteolysis of the multifunctional protein that initiates pyrimidine biosynthesis in mammalian cells: evidence for discrete structural domains.

  • M. MallyD. GraysonD. Evans
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1981
Kinetic studies of the controlled proteolysis of the molecule by elastase showed that the protein was not attacked at random by the protease but rather was successively cleaved into at least six well-defined proteolytic fragments, showing that this multifunctional protein is organized as discrete structural domains in which regions of the polypeptide chain are autonomously folded into separate functional units.

Studies on channeling of carbamoyl-phosphate in the multienzyme complex that initiates pyrimidine biosynthesis in rat ascites hepatoma cells.

Results indicate that carbamoyl-phosphate can be channeled in the multienzyme complex of AH 13 cells, but the extent of channeling is very small, contrary to expectation.

Alteration in structure of multifunctional protein from Chinese hamster ovary cells defective in pyrimidine biosynthesis.

  • J. DavidsonD. Patterson
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1979
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.