Isolation of a cDNA encoding human lysophosphatidic acid phosphatase that is involved in the regulation of mitochondrial lipid biosynthesis

In this study, we isolated cDNA encoding lysophosphatidic acid (LPA) phosph atase (LPAP). The amino acid sequence deduced from the cDNA encoding I;PAP had 421 residues including a putative signal peptide and was homologous to acid phosphatase, especially at the active site. Human LPAP had 28.5% amino acid identity to human prostatic acid phosphatase. Northern blot analysis showed a ubiquitous expression of LPAP, which was marked in kidney, heart, small intestine, muscle, and liver. Human chromosome map obtained by fluore scence in situ hybridazation showed that, the gene for LPAP was localized t o chromosome 1 q21. The mutant in which histidine was replaced with alanine at the active site and the putative signal peptide-deleted LPAP had no I;P A phosphatase activity. In addition, the putative signal peptide-deleted LP AP showed no mitochondrial localization. The site of intracellular localiza tion of endogenous LPAP was also mitochondria in MDCK cells and differentia ted C2C12 cells. The LPAP homologous phosphatase, human prostatic acid phos phatase, also has LPA phosphatase activity. LPAP-stable transfected NIH 3T3 cells showed less phosphatidic acid, phosphatidylglycerol, and cardiolipin . These results suggested that LPAP regulates lipid metabolism in mitochond ria via the hydrolysis of LPA to monoacylglycerol.