Kennedy pathway enzymes for phosphatidylcholine synthesis (CDP-choline pathway) (CDP-choline pathway)

The Kennedy pathway, or CDP-choline pathway, is the primary metabolic route for the de novo synthesis of phosphatidylcholine (PC), the most abundant phospholipid in eukaryotic cell membranes (Gibellini & Smith, 2010, PMID: 20406453). This pathway consists of three sequential enzymatic steps: the phosphorylation of choline to phosphocholine by choline kinase (CHK), the activation of phosphocholine to CDP-choline by CTP:phosphocholine cytidylyltransferase (CCT), and the final transfer of the phosphocholine headgroup to diacylglycerol by cholinephosphotransferase (CPT) or choline/ethanolamine phosphotransferase (CEPT) (Fagone & Jackowski, 2013, PMID: 23541160). CCT is the rate-limiting enzyme and is tightly regulated by membrane lipid composition to maintain phospholipid homeostasis. In many cancers, the pathway is upregulated, particularly through the overexpression of the choline kinase alpha (CHKA) isoform, which leads to elevated phosphocholine levels that support rapid membrane biogenesis and mitogenic signaling (Arlauckas et al., 2016, PMID: 27107435). Consequently, CHKA has emerged as a significant therapeutic target, with small-molecule inhibitors like TCD-717 undergoing clinical evaluation. Additionally, the pathway is implicated in neurodegenerative diseases and metabolic disorders, where precursors like citicoline are used to support membrane repair and cognitive function (Payne et al., 2014, PMID: 24658110).

Other names

CDP-choline pathwayCytidine diphosphate-choline pathwayDe novo phosphatidylcholine synthesis pathwayCholine kinase (CHK)CTP:phosphocholine cytidylyltransferase (CCT)Cholinephosphotransferase (CPT)Choline/ethanolamine phosphotransferase (CEPT)

Inhibition of rate-limiting enzymes such as choline kinase alpha or CTP:phosphocholine cytidylyltransferase to disrupt membrane synthesis and signaling in cancer cells (Arlauckas et al., 2016, PMID: 27107435).