@entity7222 decarboxylase (ODC) is a @entity2707 dependent enzyme that catalyzes the first committed step in the biosynthesis of @entity4663 . ODC is a proven drug target for the treatment of @entity7247 . The enzyme is an obligate homodimer, and the two identical active sites are formed at the dimer interface. @entity493 scanning mutagenesis of dimer interface residues in @entity3177 ODC was undertaken to determine the energetic contribution of these residues to subunit association. Twenty-three mutant enzymes were analyzed by analytical ultracentrifugation, and none of the mutations were found to cause a greater than 1 kcal/mol decrease in dimer stability. These data suggest that the energetics of the interaction may be distributed across the interface. Most significantly, many of the mutations had large effects (DeltaDeltaG kcat/Km > 2.5 kcal/mol) on the catalytic efficiency of the enzyme. Residues that affected activity included those in or near the substrate binding site but also a number of residues that are distant (15-20 A) from this site. These data provide evidence that long-range energetic coupling of interface residues to the active site is essential for enzyme function, even though structural changes upon ligand binding to wild-type ODC are limited to local conformational changes in the active site. The ODC dimer interface appears to be optimized for catalytic function and not for dimer stability. Thus, small molecules directed to the ODC interfaces could impact biological function without having to overcome the difficult energetic barrier of dissociating the interacting partners.

Long-range interactions in the dimer interface of XXXX decarboxylase are important for enzyme function.

@entity7247 :: ('MESH:D014353', 'Disease') :: ['African sleeping sickness'] @entity2707 :: ('MESH:D011732', 'Chemical') :: ["pyridoxal 5'-phosphate"] @entity7222 :: ('CHEBI:18257', 'Chemical') :: ['Ornithine'] @entity3177 :: ('5691', 'Species') :: ['Trypanosoma brucei'] @entity4663 :: ('MESH:D011073', 'Chemical') :: ['polyamines'] @entity493 :: ('CHEBI:16449', 'Chemical') :: ['Alanine']
@entity7222 :: (CHEBI:18257,Chemical) :: ['ornithine']
