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

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Macromolecular Protein Complexes II: Structure and Function

Part of the book series: Subcellular Biochemistry ((SCBI,volume 93))

Abstract

CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein that carries the enzymatic activities for the first three steps in the de novo biosynthesis of pyrimidine nucleotides: glutamine-dependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase and Dihydroorotase. This metabolic pathway is essential for cell growth and proliferation and is conserved in all living organisms. However, the fusion of the first three enzymatic activities of the pathway into a single multienzymatic protein only occurs in animals. In prokaryotes, by contrast, these activities are encoded as distinct monofunctional enzymes that function independently or by forming more or less transient complexes. Whereas the structural information about these enzymes in bacteria is abundant, the large size and instability of CAD has only allowed a fragmented characterization of its structure. Here we retrace some of the most significant efforts to decipher the architecture of CAD and to understand its catalytic and regulatory mechanisms.

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Notes

  1. 1.

    There is yet a CPS-3 in some invertebrates and fish that combines properties of CPS-1 and CPS-2 [Anderson PM (1989) Biochem J 261(2): 523–529]. It consists of a single polypeptide with GLN and SYN domains, requires acetylglutamate as co-factor, is not regulated by nucleotides and hydrolyzes glutamine.

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Authors and Affiliations

  1. Department of Genome Dynamics and Function, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolas Cabrera 1, 28049, Madrid, Spain

    Francisco del Caño-Ochoa, María Moreno-Morcillo & Santiago Ramón-Maiques

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  1. Francisco del Caño-Ochoa
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  2. María Moreno-Morcillo
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  3. Santiago Ramón-Maiques
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Correspondence to Santiago Ramón-Maiques .

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  1. Institute of Zoology, University of Mainz, Mainz, Germany

    J. Robin Harris

  2. School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK

    Jon Marles-Wright

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del Caño-Ochoa, F., Moreno-Morcillo, M., Ramón-Maiques, S. (2019). CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis. In: Harris, J., Marles-Wright, J. (eds) Macromolecular Protein Complexes II: Structure and Function . Subcellular Biochemistry, vol 93. Springer, Cham. https://doi.org/10.1007/978-3-030-28151-9_17

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