Spermidine is involved in growth and cell division by regulating RNA metabolism in an as yet unknown manner. Direct correlations have been observed between cancer growth and increases in spermidine concentration and the activities of those enzymes responsible for spermidine biosynthesis. This suggests the possibility of controlling cancer growth by controlling spermidine biosynthesis. This application proposes to continue our research to elucidate the mechanisms of the spermidine biosynthetic enzymes by studying the stereochemistry of these reactions using chirally-labeled substrates. The results will indicate the presence and relative positions of the catalytic and binding regions, and the juxtapositions and conformations of the substrates and cofactors. Such a picture could suggest the constitution of potential specific inhibitors for these enzymes. Our approach is to prepare the chirally-labeled substrates, determine the absolute stereochemistry of each, convert each to a labeled spermidine, and determine the absolute stereochemistry of the spermidine label. Key substrates, S-adenosyl-4R-3H-L-methionine and S-adenosyl-4S-3H-L-methionine, are to be synthesized by a series of enzymatic steps beginning with 4R-3H-L-homoserine and 4S-3H-L-homoserine which we have already synthesized enzymatically as the first phase of our program.