Human Lysophosphatidic Acid Acyltransferase

Abstract

Lysophosphatidic acid (1-acyl-sn-glycero-3-phosphate (LPA)) is a phospholipid with diverse biological activities. The mediator serves as an intermediate in membrane phospholipid metabolism but is also produced in acute settings by activated platelets. LPA is converted to phosphatidic acid, itself a lipid mediator, by an LPA acyltransferase (LPAAT). A human expressed sequence tag was identified by homology with a coconut LPAAT and used to isolate a full-length human cDNA from a heart muscle library. The predicted amino acid sequence bears 33% identity with a Caenorhabditis elegans LPAAT homologue and 23-28% identity with plant and prokaryotic LPAATs. Recombinant protein produced in COS 7 cells exhibited LPAAT activity with a preference for LPA as the acceptor phosphoglycerol and arachidonyl coenzyme A as the acyl donor. Northern blotting demonstrated that the mRNA is expressed in most human tissues including a panel of brain subregions; expression is highest in liver and pancreas and lowest in placenta. The human LPAAT gene is contained on six exons that map to chromosome 9, region q34.3.

Acyl-CoA:Lysophospholipid Acyltransferases

“…Human LPAAT2 mRNA is found in most tissues, with the highest expression seen in the heart, liver, and adipocytes (21,24,27). LPAAT2 prefers 20:4-CoA rather than 16:0-or 18:0-CoA (24,26).…”

“…LPAAT2 prefers 20:4-CoA rather than 16:0-or 18:0-CoA (24,26). Mutations in LPAAT2 have been linked to congenital generalized lipodystrophy (also known as BerardinelliSeip syndrome) (27), indicating that LPAAT2 is involved in TAG synthesis and storage in adipocytes.…”

“…To date, two LPAATs (LPAAT1 and LPAAT2) have been cloned and characterized (21)(22)(23)(24), and three additional LPAAT candidates (AGPAT3-5) have been reported but have not been analyzed in any detail (25). They are all members of the AGPAT family and have four LPLAT motifs.…”

“…They are all members of the AGPAT family and have four LPLAT motifs. Human LPAAT1 (called AGPAT1 or LPAAT␣) and human LPAAT2 (called AGPAT2 or LPAAT␤) were cloned based on their homologies to yeast, Escherichia coli, and coconut AGPATs (21,22,24). Human LPAAT1 is expressed ubiquitously (21,22).…”

AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34

“…Recombination mapping in pedigrees CG7000 and CG600 reduced the critical region to approximately 0.86 Mb between rs1747838 and DPP7 (see Table A online). Sequencing of the exons and splice-site junctions of AGPAT2 located in this interval 3,4 revealed homozygous or compound heterozygous mutations in CGL-affected individuals of 11 pedigrees showing linkage to 9q34 (see Table 1 and Web Fig. A online).…”