A diverse superfamily of enzymes with ATP-dependent carboxylate-amine/thiol ligase activity

Protein Sci. 1997 Dec;6(12):2639-43. doi: 10.1002/pro.5560061218.


The recently developed PSI-BLAST method for sequence database search and methods for motif analysis were used to define and expand a superfamily of enzymes with an unusual nucleotide-binding fold, referred to as palmate, or ATP-grasp fold. In addition to D-alanine-D-alanine ligase, glutathione synthetase, biotin carboxylase, and carbamoyl phosphate synthetase, enzymes with known three-dimensional structures, the ATP-grasp domain is predicted in the ribosomal protein S6 modification enzyme (RimK), urea amidolyase, tubulin-tyrosine ligase, and three enzymes of purine biosynthesis. All these enzymes possess ATP-dependent carboxylate-amine ligase activity, and their catalytic mechanisms are likely to include acylphosphate intermediates. The ATP-grasp superfamily also includes succinate-CoA ligase (both ADP-forming and GDP-forming variants), malate-CoA ligase, and ATP-citrate lyase, enzymes with a carboxylate-thiol ligase activity, and several uncharacterized proteins. These findings significantly extend the variety of the substrates of ATP-grasp enzymes and the range of biochemical pathways in which they are involved, and demonstrate the complementarity between structural comparison and powerful methods for sequence analysis.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology*
  • Amino Acid Sequence
  • Binding Sites
  • Carbon-Nitrogen Ligases / chemistry*
  • Carbon-Nitrogen Ligases / metabolism*
  • Conserved Sequence
  • Molecular Sequence Data
  • Sequence Alignment
  • Sequence Analysis
  • Structure-Activity Relationship


  • Adenosine Triphosphate
  • Carbon-Nitrogen Ligases
  • biotin carboxylase