The ATP-grasp enzymes

Abstract

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 3 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.

The enzymes of biotin dependent CO2 metabolism: What structures reveal about their reaction mechanisms

“…The manner in which the acylphosphate intermediate is stabilized in the active site of an ATP-grasp protein is still not well understood, however. 33 From structural studies, it is now known that all enzymes belonging to the ATP-grasp superfamily adopt similar molecular architectures with three major motifs: the N-terminal, the central, and the Cterminal regions. These motifs are also referred to in the literature as the A-, B-, and C-domains as described previously for biotin carboxylase [ Fig.…”

A peptide ligase and the ribosome cooperate to synthesize the peptide pheganomycin

“…Among the enzymes identified, approximately 20 catalyze an ATP-dependent phosphorylation of a carboxyl group of one substrate and a nucleophilic attack by an amino or imino group nitrogen of another substrate. In these reactions, the first substrate is a protein, a short peptide, an amino acid, or an organic/inorganic acid, but an amino acid, a thiol group (CoA), a biotinylated protein, a ribonucleotide derivative, an inositol derivative, or an ammonium ion is the second substrate 14 . Therefore, PGM1 is the first example in which a peptide is used as the nucleophile and, moreover, of ribosomes and peptide ligases cooperatively synthesizing a single peptide backbone (Fig.…”

“…carboxylate-amine/thiol ligase superfamily 14,15,16,17,18 . We prepared a recombinant C-terminal His-tagged PGM1 protein ( Supplementary Fig.…”

“…2c, and Supplementary Figs. [7][8][9][10][11][12][13][14] by NMR analysis. This result confirmed that PGM1 catalyzed peptide bond formation between a nonproteinogenic amino acid and a core peptide.…”

Crystal structure of the essential biotin‐dependent carboxylase AccA3 from Mycobacterium tuberculosis

“…Here, we present the 1.94 Å structure of a full‐length construct of MTb AccA3. As predicted from sequence, AccA3 adopts the three‐domain ATP‐grasp superfamily fold 25, 26. The protein crystallized as a dimer in the asymmetric unit with the monomers displaying different structural states, showing conformational dynamics between domains.…”