The structure and functions of human lysophosphatidic acid acyltransferases

Abstract

Lysophosphatidic acid (LPA) and phosphatidic acid (PA) are two phospholipids involved in signal transduction and in lipid biosynthesis in cells. LPA acyltransferase (LPAAT), also known as 1-acyl sn-glycerol-3-phosphate acyltransferase (1-AGPAT) (EC 2.3.1.51), catalyzes the conversion of LPA to PA. Two human isoforms of LPAAT, designated as LPAAT-alpha (AGPAT1) and LPAAT-beta (AGPAT2), have been extensively characterized. These two proteins contain extensive sequence similarities to microbial, plant and animal LPAAT sequences. LPAAT-alpha mRNA is uniformly expressed throughout most tissues with the highest level found in skeletal muscle; whereas LPAAT-beta is differentially expressed, with the highest level found in heart and liver, and negligible level in brain and placenta. The LPAAT-alpha gene is located on chromosome 6p21.3, an area within the class III region of the major hiscompatibility complex (MHC) and the LPAAT-beta gene is mapped to chromosome 9q34.3. Enhanced transcription of LPAAT-beta is suggested for neoplasm of the female genital tract. Additionally, ectopic LPAAT expression in certain cytokine-responsive cell lines can effect amplification of cellular signaling processes, such as those leading to enhancement of synthesis of tumor necrosis factor-alpha and interleukin-6 from cells following stimulation with interleukin-1beta; this suggests that the LPAAT genes represent candidates for affecting the development of certain cancers or inflammation-associated diseases.

Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes

“…Previous attempts for its isolation suggested that protein(s) of an apparent molecular mass of 50-60 kDa could be labeled with a photoreactive azido-lysoPC derivative in a partially purified microsomal fraction containing a LPCAT activity (10). To identify candidate LPCATs in RBCs, we searched databases for proteins carrying the E. coli plsC domain, which is characteristic of all known 1-acyl-sn-glycerol-3-phosphate acyltransferases (11)(12)(13), and excluded all known enzymes that have been described as lysophosphatidic acid acyltransferases (LPAATs). We focused particularly on two gene products of unknown function with a predicted molecular mass of 60 kDa, annotated in human as AYTL1 and AYTL2 and as Aytl1 and Aytl2 in mouse (Fig.…”

Genetic basis of congenital generalized lipodystrophy

“…10 Further mutagenesis analysis of bacterial glycerol-3-phosphate acyltransferase (GPAT) revealed that two motifs, NHX 4 D and EGTR, are involved in the catalytic function of these enzymes. 11 The role of conserved motif NHX 4 D is further substantiated by the X-ray crystallographic analysis of highly conserved squash GPAT, showing that the phosphate group lies in the positively charged pocket created by histidine and aspartate. 12 The nature of the interaction between the various species of lysophosphatidic acid (LPA) and acyl-CoAs is unclear partly because the binary complex has not been studied.…”

“…11 Previous Northern blot analysis showed that AGPAT1 message is ubiquitously expressed in human tissues with the highest levels of expression in the skeletal muscle, whereas AGPAT2 expression is more tissue restricted with high levels in the liver and heart but almost undetectable in the brain. 9,11 Our data reveal that AGPAT2 expression is at least two-fold higher than AGPAT1 in the normal human omental adipose tissue (Figure 1c). 5 Furthermore, AGPAT2 is expressed at lower level in the liver and much less in the skeletal muscle compared to adipose tissue.…”

Cloning and identification of the human LPAAT-zeta gene, a novel member of the lysophosphatidic acid acyltransferase family

“…Previous sequence alignment of LPAAT proteins from various species shows that the regions around the amino acid sequences NHQSxxD and PEGTR, which occur at amino acids 103-109 and 177-181 of human LPAAT-a respectively, are the most conserved sequences (Leung 2001). Site-directed mutagenesis has shown that the conserved His and Asp residues within the motif NHQSxxD and the Glu and Gly residues within the motif PEGTR are essential for catalytic (Lewin et al 1999;Heath and Rock 1998).…”

“…Although the other three members (LPAAT-c, d, and ) have been cited in a review (Leung 2001) and deposited in public sequence databases, confirmation is lacking whether they have enzymatic activity or not. This is also the case with our LPAAT-f; we will report this elsewhere, after completion of characterization.…”