Last updated Structures and localization of the enzymes in the CDP-choline pathway.
The CDP-choline pathway, first identified by Eugene P. Kennedy in 1956, is the predominant mechanism by which mammalian cells synthesize phosphatidylcholine (PC) for incorporation into membranes or lipid-derived signalling molecules.[1][2] The CDP-choline pathway represents one half of what is known as the Kennedy pathway. The other half is the CDP-ethanolamine pathway which is responsible for the biosynthesis of the phospholipid phosphatidylethanolamine (PE).[1]
Phosphatidylcholine can be acted upon by phospholipases to form different metabolites.
Choline transport
Mammalian cells are unable to synthesize sufficient quantities of de novo choline to meet physiologic requirements, and therefore must rely on exogenous sources from the diet. The uptake of choline is accomplished predominantly by the high-affinity, sodium dependent choline transporter (CHT) and requires ATP as an energy source. On the other hand, choline may enter the cell through the activation of low-affinity, sodium-independent organic cation transport proteins (OCTs) and/or carnitine/organic cation transporters (OCTNs), and do not require ATP. Lastly, choline may enter the cell through intermediate-affinity transporters, which include the choline transporter-like protein 1 (CTL1).[3]
The fate of internalized choline depends on the cell type. In pre-synaptic neurons the majority of choline will be acetylated by the enzyme choline acetyltransferase to form the neurotransmitter acetylcholine. Most other cells will phosphorylate choline by the enzyme choline kinase, the first committed step of CDP-choline pathway.
In addition to the phosphorylation of choline, CK has also been shown to phosphorylate ethanolamine, a precursor to another important glycerophospholipid, phosphatidylethanolamine. CK functions as a dimer consisting of either α1, α2 or β subunits. Each CK isoform is ubiquitously expressed throughout tissues, however CKα is enriched in the testis and liver, whereas CKβ is enriched in the liver and the heart. Homozygous deletion of CKα is embryonic lethal after about 5 days, whereas deletion of CKβ is not.
Under normal circumstances, choline kinase is not the rate-limiting step of the CDP-choline pathway. However in rapidly dividing cells, there is increased CK expression and activity as a result of increased demand for PC synthesis.
CCT functions as a dimer of either α and β subunits encoded by Pcyt1a and Pcyt1b, respectively. CCTα has four domains; a Nuclear localization signal (NLS), an α-helical membrane binding domain, a catalytic domain, and a phosphorylation domain. The major difference between the α and β isoforms is that CCTβ lacks the NLS resulting in a predominantly cytosolic pool of CCTβ. On the other hand, the presence of an NLS results in a predominantly nuclear pool of CCTα. CCTα shuttles between the nucleus (where it is considered inactive) to the cytoplasm where it associates with membranes and is activated in response to lipid activators or during progression through the cell cycle when PC demand is high.
CCTα is an amphitropic enzyme, meaning that it exists as either an inactive soluble form, or an active, membrane bound form. Whether or not CCTα is membrane bound is largely dictated by the relative composition of membranes. If membranes are low in PC, and relatively enriched in anionic lipids, diacylglycerol, or phosphatidylethanolamine, CCT inserts into the membrane bilayer via its membrane binding domain. This binding event relieves an autoinhibitory constraint on the catalytic domain, resulting in a decrease in the Km for phosphocholine.
Choline/ethanolamine phosphotransferase (CEPT)
Choline/ethanolamine phosphotransferase (CEPT), or Choline Phosphotransferase (CPT) the last enzymatic reaction in the CDP-choline pathway, catalyzes the following reaction:[1]:423
The last step in the CDP-choline pathway is catalyzed by either CPT or CEPT and are localized to the Golgi or endoplasmic reticulum, respectively. CPT and CEPT are encoded by separate genes that share 60% sequence similarity. Both isoforms contain 7 transmembrane segments, and an α-helix near the catalytic domain that is required for CDP-alcohol binding.
CPT recognizes only CDP-choline, whereas CEPT recognizes both CDP-choline and CDP-ethanolamine. The reason for this dual specificity is not exclusively known. CEPT is largely considered to be the enzyme responsible for the bulk of PC synthesis, with CPT having an exclusive role in the Golgi, where it may control the levels of the precursor DAG, an important second messenger.
Neither CPT or CEPT are considered to be rate-limiting, but can be if DAG is restricted.
Related Research Articles
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.
Choline ( KOH-leen) is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4). It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoylphosphatidylcholine (lecithin) is a major component of the pulmonary surfactant, and is often used in the lecithin–sphingomyelin ratio to calculate fetal lung maturity. While phosphatidylcholines are found in all plant and animal cells, they are absent in the membranes of most bacteria, including Escherichia coli. Purified phosphatidylcholine is produced commercially.
Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.
Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.
Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction
Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine can subsequently methylate the amine of phosphatidylethanolamines to yield phosphatidylcholines.
Citicoline (INN), also known as cytidine diphosphate-choline (CDP-choline) or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs.
Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.
The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:
Choline kinase is an enzyme which catalyzes the first reaction in the choline pathway for phosphatidylcholine (PC) biosynthesis. This reaction involves the transfer of a phosphate group from adenosine triphosphate (ATP) to choline in order to form phosphocholine.
Choline-phosphate cytidylyltransferase is an enzyme that catalyzes the chemical reaction
In enzymology, a diacylglycerol cholinephosphotransferase is an enzyme that catalyzes the chemical reaction
In enzymology, an ethanolaminephosphotransferase is an enzyme that catalyzes the chemical reaction
In enzymology, a phosphatidylcholine synthase is an enzyme that catalyzes the chemical reaction
Choline-phosphate cytidylyltransferase A is an enzyme that in humans is encoded by the PCYT1A gene.
Choline kinase beta (CK), also known as Ethanolamine kinase (EK), Choline kinase-like protein , choline/ethanolamine kinase beta (CKEKB), or Choline/ethanolamine kinase is a protein encoded by the CHKB gene. This gene is found on chromosome 22 in humans. The encoded protein plays a key role in phospholipid biosynthesis. Choline kinase (CK) and ethanolamine kinase (EK) catalyzes the first step in phosphatidylethanolamine biosynthesis. Read-through transcripts are expressed from this locus that include exons from the downstream CPT1B locus.
In molecular biology, the choline/ethanolamine kinase family includes choline kinase(EC 2.7.1.32) and ethanolamine kinase.
1-Lysophosphatidylcholines are a class of phospholipids that are intermediates in the metabolism of lipids. They result from the hydrolysis of an acyl group from the sn-1 position of phosphatidylcholine. They are also called 2-acyl-sn-glycero-3-phosphocholines. The synthesis of phosphatidylcholines with specific fatty acids occurs through the synthesis of 1-lysoPC. The formation of various other lipids generates 1-lysoPC as a by-product.
In enzymology, a ceramide phosphoethanolamine synthase is an enzyme that catalyzes the chemical reaction
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