Four different enzymes share a similar catalytic mechanism which involves the phosphorylation by ATP (or GTP) of a specific histidine residue in the active site. These enzymes are:

• ATP citrate-lyase (EC 2.3.3.8) [1], the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues, catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. ATP-citrate lyase is a tetramer of identical subunits.
• Succinyl-CoA ligase (GDP-forming) (EC 6.2.1.4) [2] is a mitochondrial enzyme that catalyzes the substrate level phosphorylation step of the tricarboxylic acid cycle: the formation of succinyl-CoA from succinate with a concomitant hydrolysis of GTP to GDP and phosphate. This enzyme is a dimer composed of an α and a β subunits.
• Succinyl-CoA ligase (ADP-forming) (EC 6.2.1.5) [3] is a bacterial enzyme that during aerobic metabolism functions in the citric acid cycle, coupling the hydrolysis of succinyl-CoA to the synthesis of ATP. It can also function in the other direction for anabolic purposes. This enzyme is a tetramer composed of two α and two β subunits.
• Malate-CoA ligase (EC 6.2.1.9) (malyl-CoA synthetase) [4], is a bacterial enzyme that forms malyl-CoA from malate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. Malate-CoA ligase is composed of two different subunits.

We developed three signature patterns for these enzymes, the first corresponds to a glycine-rich conserved region, located in the second half of ATP citrate lyase and in the α subunits of succinyl-CoA ligases and malate-CoA ligase. The second pattern, which is located some 50 residues to the C-terminal of the first one, includes the active site phosphorylated histidine residue. The last pattern corresponds to a conserved region located in the first half of ATP citrate lyase and in the β subunits of succinyl-CoA ligases and malate-CoA ligase.