Lipase I (enzyme name LIPI or LPDL) (gene name LIPI [human] or Lipi [mouse]) is a phos- pholipase which generates 2-acyl lysophos- phatidic acid (LPA), a lipid mediator required for maintaining homeostasis of diverse biological functions and in activating cell surface recep- tors. Bioinformatic methods were used to pre- dict the amino acid sequences, secondary and tertiary structures and gene locations for LIPI genes and encoded proteins using data from several mammalian genome projects. LIPI is located on human chromosome 21 and is dis- tinct from other phospholipase A1-like genes (LIPH and PS-PLA1). Mammalian LIPI genes contained 10 (human) or 11 (mouse) coding ex- ons transcribed predominantly on the negative DNA strand. Mammalian LIPI protein subunits shared 61% - 99% sequence identities and ex- hibited sequence alignments and identities for key LIPI amino acid residues as well as exten- sive conservation of predicted secondary and tertiary structures with those previously re- ported for pancreatic lipase (PL), with "N-signal peptide", "lipase" and "plat" structural domains. Comparative studies of mammalian LIPI se- quences with LIPH, PS-PLA1 and pancreatic lipase (PL) confirmed predictions for LIPI N- terminal signal peptides (residues 1 - 15); pre- dominantly conserved mammalian LIPI N-gly- cosylation sites (63NNSL and 396NISS for hu- man LIPI); active site "triad" residues (Ser159; Asp183; His253); disulfide bond residues (238 - 251; 275 - 286; 289 - 297; 436 - 455); and a 12 residue "active site lid", which is shorter than for other lipases examined. Phylogenetic analyses supported a hypothesis that LIPI arose from a vertebrate LIPH gene duplication event within a mammalian common ancestral genome. In addi-tion, LIPI, LIPH and PL-PLA1 genes were distinct from the vascular lipase (LIPG, LIPC and LPL) and pancreatic lipase (PL) gene families.