Carbamoyl phosphate synthetase: an amazing biochemical odyssey from substrate to product

@article{Holden1999CarbamoylPS,
  title={Carbamoyl phosphate synthetase: an amazing biochemical odyssey from substrate to product},
  author={Hazel M. Holden and James B. Thoden and Frank M. Raushel},
  journal={Cellular and Molecular Life Sciences CMLS},
  year={1999},
  volume={56},
  pages={507-522}
}
Abstract. Carbamoyl phosphate synthetase (CPS) catalyzes one of the most remarkable reactions ever described in biological chemistry, in which carbamoyl phosphate is produced from one molecule of bicarbonate, two molecules of Mg2+ATP, and one molecule of either glutamine or ammonia. The carbamoyl phosphate so produced is utilized in the synthesis of arginine and pyrimidine nucleotides. It is also employed in the urea cycle in most terrestrial vertebrates. Due to its large size, its important… 
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References

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TLDR
This structural analysis reveals, for the first time, the detailed manner in which CPS accommodates nucleotide monophosphate effector molecules within the allosteric domain.
Structure of carbamoyl phosphate synthetase: a journey of 96 A from substrate to product.
TLDR
The two halves of the large subunit are related by a nearly exact 2-fold rotational axis, thus suggesting that this polypeptide chain evolved from a homodimeric precursor.
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TLDR
The X-ray crystallographic structure of carbamoyl phosphate synthetase from E. coli in which His 353 has been replaced with an asparagine residue is described, providing the first direct structural observation of an enzyme intermediate in the amidotransferase family.
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TLDR
The structure of CPS from E. coli is described where, indeed, a domain movement has occurred in response to nucleotide binding, and the two active sites contained within the large subunit of CPS are described.
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TLDR
The three-dimensional structure of carbamoyl phosphate synthetase from E. coli refined to 2.1 A resolution with an R factor of 17.9% is described and it is shown that the enzyme is an alpha,beta-heterodimer consisting of a small sub unit that hydrolyzes glutamine and a large subunit that catalyzes the two required phosphorylation events.
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TLDR
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TLDR
Results are consistent with His-353 functioning as a general acid/base catalyst for proton transfers while His-312 serves a critical role for the binding of glutamine to the active site.
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TLDR
The results indicate that the catalytic activity of this enzyme is not directly linked to oligomer formation and the theoretical properties and possible significance of a generalized model of enzyme association-dissociation in which the active monomeric form is specifically subject to self-association but the different states of association have the same specific activity.
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TLDR
The findings suggest that glutamine-dependent carbamyl phosphate synthetase (and perhaps other glutamine amidotransferases) arose in the course of evolution by a combination of a primitive ammonia-dependent synthetic enzyme and a glutaminase; this combination may have been associated with a change from ammonia to glutamine as the principal source of nitrogen.
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