Salicylic acid dehydrogenases

Mammalian XO is a homodimer of around 1330 amino acids which binds a number of electron transfer centres — an FAD, two spectroscopically distinct [2Fe-2S] clusters, and the Mo-cofactor. The structure of the bovine xanthine dehydrogenase (XDH), bound to the competitive inhibitor salicylic acid, and presented in Figure 17.3(a), consists of four domains, two Fe/S domains (1 and 11) in the N-terminal portion of the molecule, followed by the central FAD domain and the molybdenum-binding domain in the C-terminal part of the molecule. 

Salicylic acid inhibitor binding dehydrogenases, 1016 Sandwich complexes nickel, 35 Schiff bases... 

This inhibitor can even discriminate between isoenzymes. Thus, whereas it irreversibly inhibits the lactic dehydrogenase of skeletal muscle, it does not affect that of the heart. A related compound, 5-(phenoxycarbonylamino)salicylic acid, irreverisbly inhibits the heart (but not the skeletal) isoenzyme, whereas its 4-isomer irreversibly inhibits the skeletal (but not the heart) isoenzyme (Baker and Patel, 1964 Baker, 1967). 

Examination of tissues post mortem showed normal acetoacetate oxidation by muscle and normal ketogenesis in liver. The severity of ketosis eliminated non-metabolic causes such as starvation and salicylism, and further investigation of post-mortem tissues for acetoacetyl-CoA thiolase, 3-hydroxybutyrate dehydrogenase and succinyl-CoA 3-keto acid-CoA transferase activities revealed grossly deficient activity of the latter enzyme in brain, kidney, muscle and cultured fibroblasts, in the presence of normal activities of the other enzymes. 

---