Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease.
aspartate transcarbamoylase
carbamoyl phosphate synthetase
de novo pyrimidine biosynthesis
dihydroorotase
multienzymatic protein
nucleotide metabolism
rare diseases
Journal
Protein science : a publication of the Protein Society
ISSN: 1469-896X
Titre abrégé: Protein Sci
Pays: United States
ID NLM: 9211750
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
12
07
2021
received:
01
07
2021
accepted:
13
07
2021
pubmed:
22
7
2021
medline:
25
12
2021
entrez:
21
7
2021
Statut:
ppublish
Résumé
CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein divided into different enzymatic domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutaminase-dependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase. The pathway for de novo pyrimidine synthesis is essential for cell proliferation and is conserved in all living organisms, but the covalent linkage of the first enzymatic activities into a multienzymatic CAD particle is unique to animals. In other organisms, these enzymatic activities are encoded as monofunctional proteins for which there is abundant structural and biochemical information. However, the knowledge about CAD is scarce and fragmented. Understanding CAD requires not only to determine the three-dimensional structures and define the catalytic and regulatory mechanisms of the different enzymatic domains, but also to comprehend how these domains entangle and work in a coordinated and regulated manner. This review summarizes significant progress over the past 10 years toward 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.
Identifiants
pubmed: 34288185
doi: 10.1002/pro.4158
pmc: PMC8442968
doi:
Substances chimiques
CAD trifunctional enzyme
0
Aspartate Carbamoyltransferase
EC 2.1.3.2
Dihydroorotase
EC 3.5.2.3
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
EC 6.3.5.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1995-2008Informations de copyright
© 2021 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
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