Suppressor mutations in Saccharomyces cerevisiae that block Ca(2+)-induced death of csg2 mutant cells were investigated. These mutants, called scs mutants (suppressor of Ca2+ sensitivity), fall into seven complementation groups (scs1-scs7). All mutant strains in two of the complementation groups (scs1 and scs2) simultaneously acquire a requirement for 10 mM Ca2+, whereas wild type grow with only trace amounts of Ca2+. SCS1 was cloned by complementation of its Ca(2+)-requiring phenotype and found to be homologous to a family of pyridoxal phosphate enzymes that catalyze acyltransfer reactions. Secondary phenotypes of the scs1 mutants indicate that SCS1 is required for serine palmitoyltransferase activity which catalyzes the first committed step in sphingolipid biosynthesis (palmitoyl-CoA + serine-->3-ketosphinganine+CoASH+CO2). Other scs mutants as well as the csg2 null mutant have altered sphingolipid metabolism. The data suggest that sphingolipid metabolism in yeast is either regulated by Ca2+ and/or is required for Ca2+ homeostasis.