The crystal structure of beta-ketoacyl-acyl carrier protein synthase II from Synechocystis sp. at 1.54 angstrom resolution and its relationship to other condensing enzymes

Condensing enzymes, catalyzing the formation of carbon-carbon bonds in seve ral biosynthetic pathways, have lately been recognized as potential drug ta rgets against cancer and tuberculosis, as crucial for combinatorial biosynt hesis of antibiotics and related compounds, and as determinants of plant oi l composition. beta -Ketoacyl-ACP synthases (KAS) are the condensing enzyme s present in the fatty acid biosynthesis pathway and are able to elongate a n acyl chain bound to either co-enzyme A (CoA) or acyl carrier protein (ACP ) with a two-carbon unit derived from malonyl-ACP. Several isoforms of KAS with different substrate specificity are present in most species. We have d etermined the crystal structure of KAS II from Synechocystis sp. PCC 6803 t o 1.54 Angstrom resolution giving a detailed description of the active site geometry. In order to analyze the structure function relationships in this class of enzymes in more detail, we have compared all presently known thre e-dimensional structures of condensing enzymes from different pathways. The comparison reveals that these enzymes can be divided into three structural and functional classes. This classification can be related to variations i n the catalytic mechanism and the set of residues in the catalytic site, e. g. due to differences in the nature of the second substrate providing the t wo-carbon elongation unit. The variation in the acyl-carrier (ACP or CoA) s pecificity might also be connected to this classification and residues invo lved in ACP binding in structure class 2 can be suggested based on the comp arison. Finally, the two subunits in the dimer contribute differently to fo rmation of the substrate binding-pocket in the three structural classes. (C ) 2001 Academic Press.