Genetic, structural and biochemical basis of carbamoyl phosphate synthetase 1 deficiency

Mol Genet Metab. 2010 Dec;101(4):311-23. doi: 10.1016/j.ymgme.2010.08.002. Epub 2010 Aug 6.

Abstract

Carbamoyl phosphate synthetase 1 (CPS1) plays a paramount role in liver ureagenesis since it catalyzes the first and rate-limiting step of the urea cycle, the major pathway for nitrogen disposal in humans. CPS1 deficiency (CPS1D) is an autosomal recessive inborn error which leads to hyperammonemia due to mutations in the CPS1 gene, or is caused secondarily by lack of its allosteric activator NAG. Proteolytic, immunological and structural data indicate that human CPS1 resembles Escherichia coli CPS in structure, and a 3D model of CPS1 has been presented for elucidating the pathogenic role of missense mutations. Recent availability of CPS1 expression systems also can provide valuable tools for structure-function analysis and pathogenicity-testing of mutations in CPS1. In this paper, we provide a comprehensive compilation of clinical CPS1 mutations, and discuss how structural knowledge of CPS enzymes in combination with in vitro analyses can be a useful tool for diagnosis of CPS1D.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carbamoyl-Phosphate Synthase (Ammonia) / chemistry*
  • Carbamoyl-Phosphate Synthase (Ammonia) / deficiency
  • Carbamoyl-Phosphate Synthase (Ammonia) / genetics
  • Carbamoyl-Phosphate Synthase (Ammonia) / metabolism*
  • Carbamoyl-Phosphate Synthase I Deficiency Disease
  • Humans
  • Protein Structure, Tertiary
  • Urea Cycle Disorders, Inborn / enzymology
  • Urea Cycle Disorders, Inborn / genetics
  • Urea Cycle Disorders, Inborn / pathology

Substances

  • Carbamoyl-Phosphate Synthase (Ammonia)