The ATP-grasp enzymes

• Published in: Bioorganic chemistry Vol. 39; no. 5; pp. 185 - 191
• Main Authors: Fawaz, Maria V., Topper, Melissa E., Firestine, Steven M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2011
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Sequence; ATP-grasp fold; Binding Sites; Binding, Competitive; Biotin carboxylase; Carbamoyl phosphate synthetase; Carbon-Nitrogen Ligases - chemistry; Carbon-Nitrogen Ligases - metabolism; Enzyme Inhibitors - pharmacology; Enzymes - chemistry; Enzymes - metabolism; Inhibitors; Mechanism; Molecular Sequence Data; Protein Conformation; Structure; Biotin carboxylase; Carbamoyl phosphate synthetase; Inhibitors; Structure; ATP-grasp fold; Mechanism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2011.08.004

[Display omitted] ► ATP-grasp enzymes utilize an unique ATP-binding fold. ► These enzymes are found in critical metabolic pathways and are medicinally relevant. ► The basic outlines of the mechanism of these enzymes is known. ► A variety of potent inhibitors of these enzymes have been discovered. The ATP-grasp enzymes consist of a superfamily of 21 proteins that contain an atypical ATP-binding site, called the ATP-grasp fold. The ATP-grasp fold is comprised of two α + β domains that “grasp” a molecule of ATP between them and members of the family typically have an overall structural design containing three common conserved focal domains. The founding members of the family consist of biotin carboxylase, d-ala- d-ala ligase and glutathione synthetase, all of which catalyze the ATP-assisted reaction of a carboxylic acid with a nucleophile via the formation of an acylphosphate intermediate. While most members of the superfamily follow this mechanistic pathway, studies have demonstrated that two enzymes catalyze only the phosphoryl transfer step and thus are kinases instead of ligases. Members of the ATP-grasp superfamily are found in several metabolic pathways including de novo purine biosynthesis, gluconeogenesis, and fatty acid synthesis. Given the critical nature of these enzymes, researchers have actively sought the development of potent inhibitors of several members of the superfamily as antibacterial and anti-obseity agents. In this review, we will discuss the structure, function, mechanism, and inhibition of the ATP-grasp enzymes.