CDP-choline pathway (Kennedy pathway) (CDP-choline pathway)

The CDP-choline pathway, also known as the Kennedy pathway, is the essential metabolic route for the de novo synthesis of phosphatidylcholine (PC), the primary structural phospholipid in eukaryotic cell membranes (PMID: 27538968). This pathway involves three sequential enzymatic reactions: the phosphorylation of choline by choline kinase (CK), the activation of phosphocholine to CDP-choline by CTP:phosphocholine cytidylyltransferase (CCT), and the final transfer of the phosphocholine group to diacylglycerol by cholinephosphotransferase (CPT) (UniProt P35790, P49585, Q8WUD6). Choline kinase alpha (CHKA), the first enzyme in the pathway, is frequently overexpressed in a wide range of human malignancies, including breast, lung, and prostate cancers, where it supports rapid cell proliferation and membrane remodeling (PMID: 21854306). Inhibition of CHKA has been shown to reduce phosphocholine levels, impair oncogenic signaling, and trigger apoptosis, making it a high-priority target for anticancer drug development (PMID: 25100378). CTP:phosphocholine cytidylyltransferase acts as the rate-limiting step of the pathway and is regulated by membrane lipid composition, serving as a sensor for cellular lipid requirements (PMID: 10551025). Beyond oncology, the pathway is a target for antiprotozoal agents, as parasites like Plasmodium falciparum rely on it for membrane biogenesis during their intraerythrocytic life cycle (PMID: 15681343). Clinical evaluation of small-molecule inhibitors like TCD-717 has demonstrated the feasibility of targeting this pathway in patients with advanced solid tumors (NCT01215864).

Other names

Choline kinase / CTP:phosphocholine cytidylyltransferase / cholinephosphotransferaseKennedy pathwayCDP-choline pathwayPhosphatidylcholine biosynthetic pathwayCholine kinase alpha (CHKA)CTP:phosphocholine cytidylyltransferase alpha (PCYT1A)Cholinephosphotransferase 1 (CHPT1)

Inhibition of Choline kinase alpha (CHKA) prevents the conversion of choline to phosphocholine, thereby depleting the essential precursor for phosphatidylcholine synthesis and inducing apoptosis in cancer cells (PMID: 21854306). Miltefosine acts by inhibiting CTP:phosphocholine cytidylyltransferase (PMID: 11033318).