GO:0106263 1-acylglycerophosphoserine O-acyltransferase activity

Phospholipids are fundamental components of cellular membranes and play critical roles in signaling and metabolism. The diversity of phospholipid species is generated through remodeling pathways, one of which is the Lands cycle. Within this cycle, the enzyme 1-acylglycerophosphoserine O-acyltransferase (GO:0106263) catalyzes the acylation of 1-acyl-sn-glycero-3-phospho-L-serine to form 1,2-diacyl-sn-glycero-3-phospho-L-serine, utilizing acyl-CoA as the acyl donor. This activity is essential for maintaining the acyl chain composition of phosphatidylserine, a phospholipid enriched in the inner leaflet of the plasma membrane and involved in apoptosis, blood coagulation, and synaptic function. Research on this enzymatic activity has gained attention due to its potential role in regulating free arachidonic acid pools and eicosanoid production. Peroxisome proliferators, such as fibrates, have been shown to induce lysophospholipid acyltransferases, including the activity described by GO:0106263, thereby attenuating the free arachidonic acid pool in the kidney. This suggests that the enzyme may modulate inflammatory responses and lipid signaling. Understanding the molecular mechanism, regulation, and disease relevance of this activity is therefore of significant interest to cell biologists, biochemists, and pharmacologists. In this article, we provide a comprehensive overview of GO:0106263, covering its definition, biological context, key genes, regulatory mechanisms, associated diseases, and state-of-the-art research methods. We also highlight how CRISPR-based genome editing can be leveraged to study this activity and its downstream effects, offering insights for both basic research and therapeutic development.

GO:0106263, 1-acylglycerophosphoserine O-acyltransferase activity, is a molecular function defined by the catalytic reaction: a 1-acyl-sn-glycero-3-phospho-L-serine + an acyl-CoA = a 1,2-diacyl-sn-glycero-3-phospho-L-serine + CoA. In other words, it transfers an acyl group from acyl-CoA to the sn-2 position of lysophosphatidylserine, producing phosphatidylserine and free CoA. This activity is part of the phospholipid remodeling pathway and is mediated by enzymes of the lysophospholipid acyltransferase family.

The acylation of lysophosphatidylserine to phosphatidylserine is a critical step in phospholipid remodeling, influencing membrane fluidity, curvature, and the availability of signaling lipids. Phosphatidylserine is uniquely distributed in the plasma membrane and serves as a docking site for signaling proteins, a marker for apoptotic cells, and a cofactor for blood coagulation. By regulating the acyl chain composition of phosphatidylserine, GO:0106263 activity impacts a wide range of physiological processes, from inflammation to neurotransmission. Moreover, peroxisome proliferator-induced upregulation of this activity can reduce free arachidonic acid levels, suggesting a role in controlling eicosanoid production and inflammatory responses. Thus, understanding this enzymatic activity is essential for deciphering lipid-mediated signaling in health and disease.

The following genes encode enzymes with lysophospholipid acyltransferase activity, including the specific activity defined by GO:0106263, or are closely related to phosphatidylserine metabolism.

The activity of 1-acylglycerophosphoserine O-acyltransferase is regulated at multiple levels. Transcriptional regulation occurs through nuclear receptors such as peroxisome proliferator-activated receptors (PPARs), which induce the expression of lysophospholipid acyltransferases in response to peroxisome proliferators like fibrates. This induction enhances the acylation of lysophosphatidylserine, thereby reducing free arachidonic acid pools and modulating inflammatory signaling. Post-translational modifications, including phosphorylation, may also affect enzyme activity, although specific sites remain to be characterized. Additionally, substrate availability, particularly the levels of lysophosphatidylserine and acyl-CoA, can influence the reaction rate. The enzyme's localization in the endoplasmic reticulum membrane places it in proximity to lipid synthesis and remodeling machinery, allowing efficient coupling with upstream phospholipase A2 and downstream phospholipid transport processes.

Altered phosphatidylserine metabolism is a hallmark of many cancers, where it supports tumor cell survival, immune evasion, and angiogenesis. The activity of GO:0106263 may contribute to the generation of specific phosphatidylserine species that promote oncogenic signaling. For example, increased acylation of lysophosphatidylserine could enhance the availability of phosphatidylserine on the outer leaflet of cancer cells, facilitating recognition by immune cells and promoting immunosuppression. Targeting this activity might therefore offer a novel strategy for cancer therapy, although direct evidence linking GO:0106263 to cancer remains to be established.

Neuronal membranes are rich in phosphatidylserine, which is essential for synaptic function and neuroprotection. Dysregulation of phospholipid remodeling enzymes, including those with GO:0106263 activity, has been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's. Peroxisome proliferator-induced upregulation of lysophospholipid acyltransferases may protect against neuroinflammation by reducing free arachidonic acid and its pro-inflammatory metabolites. However, the specific contribution of GO:0106263 to neurodegeneration requires further investigation using appropriate models.

The ability of peroxisome proliferators to attenuate the free arachidonic acid pool through induction of lysophospholipid acyltransferases suggests a role for GO:0106263 in metabolic and inflammatory conditions. By promoting the incorporation of arachidonic acid into phosphatidylserine, this activity may limit the production of eicosanoids, which are key mediators of inflammation. Consequently, modulating this enzyme could have therapeutic potential in diseases characterized by chronic inflammation, such as atherosclerosis and arthritis. Further studies are needed to validate this hypothesis and to identify specific inhibitors or activators.

Lipidomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the gold standard for measuring phosphatidylserine species and other phospholipids. By comparing wild-type and knockout cells, researchers can determine the contribution of GO:0106263 to the cellular lipidome. This method allows quantification of both substrate (lysophosphatidylserine) and product (phosphatidylserine) levels, providing direct evidence of enzyme activity in vivo.

In vitro acyltransferase assays using radiolabeled or fluorescent acyl-CoA and lysophosphatidylserine can directly measure GO:0106263 activity. Membrane fractions from cells or recombinant enzymes expressed in heterologous systems are incubated with substrates, and the formation of phosphatidylserine is monitored by thin-layer chromatography or mass spectrometry. These assays are crucial for kinetic characterization and inhibitor screening.

CRISPR-Cas9 knockout of candidate genes (e.g., MBOAT1, MBOAT2) enables loss-of-function studies to identify which enzyme is responsible for GO:0106263 in a given cell type. Point mutations can be introduced to dissect catalytic residues, while knock-in of tagged versions allows localization and interaction studies. Overexpression models complement these approaches by testing gain-of-function effects.

RNA sequencing (RNA-seq) can reveal changes in gene expression upon modulation of GO:0106263 activity, identifying downstream pathways. Proteomics, including targeted mass spectrometry, can quantify enzyme abundance and post-translational modifications. These global approaches help place GO:0106263 within broader cellular networks and identify regulatory mechanisms.

Researchers studying 1-acylglycerophosphoserine O-acyltransferase activity-related genes often need to determine whether a candidate gene is causally involved in a specific lipid metabolic pathway, disease phenotype, or drug response. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process, from gene knockout to precise point mutations and overexpression, all supported by advanced bioinformatics and screening platforms.

GO:0106263, 1-acylglycerophosphoserine O-acyltransferase activity, represents a key enzymatic step in phospholipid remodeling that impacts membrane composition, lipid signaling, and inflammatory responses. Although the specific enzymes catalyzing this activity in different tissues are still being elucidated, the available evidence links it to peroxisome proliferator signaling and arachidonic acid homeostasis. Future research using CRISPR-based models and advanced lipidomics will be crucial to fully understand its physiological and pathological roles. Targeting this activity may offer new therapeutic opportunities for metabolic and inflammatory diseases.