CDP-Diacylglycerol Synthases (CDS): Gateway to Phosphatidylinositol and Cardiolipin Synthesis

Abstract

Cytidine diphosphate diacylglycerol (CDP-DAG) is a key intermediate in the synthesis of phosphatidylinositol (PI) and cardiolipin (CL). Both PI and CL have highly specialized roles in cells. PI can be phosphorylated and these phosphorylated derivatives play major roles in signal transduction, membrane traffic, and maintenance of the actin cytoskeletal network. CL is the signature lipid of mitochondria and has a plethora of functions including maintenance of cristae morphology, mitochondrial fission, and fusion and for electron transport chain super complex formation. Both lipids are synthesized in different organelles although they share the common intermediate, CDP-DAG. CDP-DAG is synthesized from phosphatidic acid (PA) and CTP by enzymes that display CDP-DAG synthase activities. Two families of enzymes, CDS and TAMM41, which bear no sequence or structural relationship, have now been identified. TAMM41 is a peripheral membrane protein localized in the inner mitochondrial membrane required for CL synthesis. CDS enzymes are ancient integral membrane proteins found in all three domains of life. In mammals, they provide CDP-DAG for PI synthesis and for phosphatidylglycerol (PG) and CL synthesis in prokaryotes. CDS enzymes are critical for maintaining phosphoinositide levels during phospholipase C (PLC) signaling. Hydrolysis of PI (4,5) bisphosphate by PLC requires the resynthesis of PI and CDS enzymes catalyze the rate-limiting step in the process. In mammals, the protein products of two CDS genes (CDS1 and CDS2) localize to the ER and it is suggested that CDS2 is the major CDS for this process. Expression of CDS enzymes are regulated by transcription factors and CDS enzymes may also contribute to CL synthesis in mitochondria. Studies of CDS enzymes in protozoa reveal spatial segregation of CDS enzymes from the rest of the machinery required for both PI and CL synthesis identifying a key gap in our understanding of how CDP-DAG can cross the different membrane compartments in protozoa and in mammals.

Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

“…PI synthesis is a two-step process, the conversion of PA (phosphatidic acid) into the intermediate, cytidine diphosphate DAG (CDP-DAG) by CDP-DAG synthase (CDS) enzymes followed by its conversion into PI by PI synthase (PIS) ( Figure 2). There are two CDS enzymes, CDS1 and CDS2, and one PIS enzyme, both localised at the ER; all three enzymes are integral membrane proteins [6,22]. The first step requires CTP and the second-step requires inositol.…”

Mammalian PITPs at the Golgi and ER-Golgi Membrane Contact Sites

“…DAG can be phosphorylated by DAGKα to PA at the Golgi. Similarly, DAG can be phosphorylated by ER-specific DAGKs (δ, η and κ (Xie et al., 2015)) to produce PA in the ER, which can be further converted into CDP-DAG by CDS (CDP-DAG synthase) and subsequently to PI by PIS (PI synthase) (Blunsom and Cockcroft, 2020a), to be transport by Nir2, PITPNC1 and/or PITPβ back to the Golgi. DAG can be consumed by the CDP-choline pathway for PC synthesis at the Golgi, and together these metabolic pathways highlight the central role of DAG in regulating the production of PI, PC, PA at the ER-Golgi interface.…”

Cloning, characterization, and expression features of chicken CDS2 splicing variants

“…CDS cDNA sequences were subsequently cloned from yeast [5], human [6][7][8][9], rat [10], mouse [11,12], and pig [13]. All eukaryotic genomes have been shown to contain CDS homologs [7,14,15] and the number of CDS genes varies in different organisms [16]. There is one CDS gene in yeast and y [17], and two CDS genes (CDS1 and CDS2) in vertebrates [7], including rat, mice, human, and zebra sh [16].…”

“…Human CDS1 and CDS2 can create different CDP-DAG pools; CDS2 is selective for acyl chains at the sn-1 and sn-2 positions [22]. The importance of CDS enzymes stems from the need for cells to maintain their phosphoinositide levels, in particular, those of PIP2 [7,16].…”