Atomic structures have been determined from a number of acyl transferases related to tafazzin, illustrating a conserved fold for the catalytic core of the enzyme. Structures of four acyl transferases are shown on the right together with their PDB accession codes. The catalytic core consists of a beta sheet (yellow strands) that harbor a conserved catalytic motif of HxxxxD. The beta sheet is sandwiched by alpha helices (purple). Whereas these elements are structurally conserved across the acyltransferase family, additional helices on the N-terminus (blue) are thought to interact with the membrane surface in order to access lipid substrates and products. Despite the similar architecture, the substrates of glycerol-phosphate acyl transferase (GPAT) are substantially different from tafazzin (TAZ). For the former, substrates are glycerol-3-phosphate and lyso-fattyacid-CoA, which require the enzyme to harbor only a single acyl chain during catalysis, which is driven energetically by the CoA moiety. In contrast, tafazzin substrates (MLCL and PC) comprise five acyl chains and the reaction to produce CL and LPC does not driven by CoA or any other known energy source. Although the basis for specificity of tafazzin is uncertain, our collaborator, Dr. Michael Schlame, has obtained evidence that it is driven by the physical chemistry of the lipid bilayer and by thermodynamic favorability of correctly modeled tafazzin to associate with mitochondrial super complexes.