Crystal structure of human spermidine/spermine N1-acetyltransferase (hSSAT): the first structure of a new sequence family of transferase homologous superfamily

Introduction. Polyamines including putrescine, spermidine, and spermine are important polycationic small molecules for life. They are involved in protein synthesis, cell growth, and regulation of several metabolic processes in a cell. Overaccumulation of the polyamines is toxic to cells. The intracellular concentration of polyamines is carefully controlled by a combination of regulated enzymatic steps, including biosynthetic enzymes such as ornithine decarboxylase, and catabolic enzymes such as spermidine/spermine N-acetyltransferase (SSAT). SSAT is one of the diamine N-acetyltransferases and a rate-limiting enzyme, which has a key role in polyamine metabolism. It catalyzes the N-acetylation of spermine and spermidine to form less charged derivatives that are either excreted from the cell or undergo further metabolism. It is the turning point of the polyamine metabolism pathway. So far 11 proteins have been identified as belonging to the SSAT homologous family, as shown in Figure 1. Although the function of SSAT is important, the three-dimensional structure as well as the mechanism of enzyme reaction and actual activity site of SSAT are still unknown. Human SSAT (hSSAT), containing 171 residues, is related with many serious diseases, such as human colon cancer and infection of human immunodeficiency virus1. Herein, we report the crystal structure of hSSAT, which is the first structure of diamine N-acetyltransferases. The fold of hSSAT belongs to the transferase homologous superfamily. The comparisons of sequence and structure show that the hSSAT structure is the representative of a new sequence family of transferase superfamily. Three-dimensional structure also suggests the potential enzyme activity site of hSSAT.