2026-08-29T16:26:21Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/258992025-12-18T12:56:53Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Del Caño-Ochoa, Francisco
author
Ramadane-Morchadi, Lobna
author
Eixerés, Lluís
author
Moreno-Morcillo, María
author
Fernández-Leiro, Rafael
author
Ramón-Maiques, Santiago
funder
Fundacion Ramon Areces
funder
Ministerio de Ciencia y Universidades (España)
2024-12-18T11:39:27Z
2024-12-18T11:39:27Z
2024-12-01
J Mol Biol . 2024 Dec 1;436(23):168832.
Journal of Molecular Biology
39447673
https://hdl.handle.net/20.500.12105/25899
CAD, the multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD's dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD's stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic.
eng
aspartate transcarbamoylase
dihydroorotase
inborn errors of metabolisms
pathogenic variant
pyrimidine nucleotide biosynthesis
Disruption of CAD Oligomerization by Pathogenic Variants.
research article
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URL
https://repisalud.isciii.es/bitstreams/c01122d7-1262-477c-96c1-ee0e912ad398/download
File
MD5
e345d4ef6b8f017c9f4cc67e897d9104
5711785
application/pdf
DisruptionofCADOligomerization-2024.pdf