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Structural insights into regulation of vertebrate homolog N‐acetylglutamate synthase/kinase from Maricaulis maris
Author(s) -
Shi Dashuang,
Li Yongdong,
Cabrera-Luque Juan,
Jin Zhongming,
Yu Xiaolin,
Zhao Genxiang,
Allewell Norma M,
Tuchman Mendel
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.558.1
Subject(s) - biology , biochemistry , phosphofructokinase 2 , arginine , atp synthase , enzyme , lyase , active site , tetramer , protein subunit , amino acid , gene
Novel bifunctional N ‐acetylglutamate synthase/kinases (NAGS/K) that catalyze the first two steps of arginine biosynthesis and are homologous to vertebrate N ‐acetylglutamate synthase (NAGS), an essential cofactor‐producing enzyme in the urea cycle, were identified in Maricaulis maris and several other bacteria. The crystal structures of M. maris NAGS/K (mmNAGS/K) with and without L‐arginine bound indicate that mmNAGS/K functions as a tetramer, in contrast to the hexameric structure of Neisseria gonorrhoeae NAGS. Each subunit has an amino acid kinase (AAK) domain, which is likely responsible for N ‐acetylglutamate kinase (NAGK) activity and has a arginine binding site, and an N‐ acetyltransferase (NAT) domain that contains the putative NAGS active site. The angle of rotation between AAK and NAT domains varies among crystal forms and subunits within the tetramer. A rotation of 26° is sufficient to close the predicted AcCoA binding site, thus reducing enzymatic activity. Since mmNAGS/K has the highest degree of sequence homology to vertebrate NAGS of NAGS and NAGK enzymes whose structures have been determined, the mmNAGS/K structure was used to develop a structural model of human NAGS that is fully consistent with the functional effects of the 14 missense mutations that were identified in NAGS‐deficient patients.