Molecular structure and differential function of choline kinases CHKα and CHKβ in musculoskeletal system and cancer

Abstract

Choline, a hydrophilic cation, has versatile physiological roles throughout the body, including cholinergic neurotransmission, memory consolidation and membrane biosynthesis and metabolism. Choline kinases possess enzyme activity that catalyses the conversion of choline to phosphocholine, which is further converted to cytidine diphosphate-coline (CDP-choline) in the biosynthesis of phosphatidylcholine (PC). PC is a major constituent of the phospholipid bilayer which constitutes the eukaryotic cell membrane, and regulates cell signal transduction. Choline Kinase consists of three isoforms, CHKα1, CHKα2 and CHKβ, encoded by two separate genes (CHKA(Human)/Chka(Mouse) and CHKB(Human)/Chkb(Mouse)). Both isoforms have similar structures and enzyme activity, but display some distinct molecular structural domains and differential tissue expression patterns. Whilst Choline Kinase was discovered in early 1950, its pivotal role in the development of muscular dystrophy, bone deformities, and cancer has only recently been identified. CHKα has been proposed as a cancer biomarker and its inhibition as an anti-cancer therapy. In contrast, restoration of CHKβ deficiency through CDP-choline supplements like citicoline may be beneficial for the treatment of muscular dystrophy, bone metabolic diseases, and cognitive conditions. The molecular structure and expression pattern of Choline Kinase, the differential roles of Choline Kinase isoforms and their potential as novel therapeutic targets for muscular dystrophy, bone deformities, cognitive conditions and cancer are discussed.

Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition

“…23,24 hChoKα is overexpressed in some of the most common cancers and has oncogenic activity when overexpressed in human cells, yet most studies claim that hChoKβ does not contribute to oncogenic transformation. [25][26][27][28][29][30] As a result of the relevance of hChoKα in human carcinogenesis, many hChoKα inhibitors have been synthesized by means of different chemical approaches. The inhibition of hChoKα leads to an indirect decrease of PtdCho and in turn, to cell proliferation arrest through apoptosis, which is an efficient antitumor strategy.…”

“…Despite the high grade of identity (56%) at the amino acid level between hChoKα and hChoKβ, both enzymes have proven differences in the lipid metabolism and their role in carcinogenesis 23,24 . hChoKα is overexpressed in some of the most common cancers and has oncogenic activity when overexpressed in human cells, yet most studies claim that hChoKβ does not contribute to oncogenic transformation 25–30 …”

Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth

“…Many cancers overexpress CHKα to increase phosphocholine, which is also increased in tumor cells. Therefore, CHKα is a cancer biomarker and can be a target for anticancer therapy [ 52 ]. We think that metformin elevates the level of choline (a conditional vitamin) to inhibit pancreatic cancer growth, possibly by targeting several choline regulators such as CHKα.…”

ChoK-Full of Potential: Choline Kinase in B Cell and T Cell Malignancies

“…Choline kinase is a cytosolic enzyme that catalyzes the phosphorylation of choline to generate P-Cho in the presence of ATP and magnesium, the first step in de novo PC biosynthesis termed the Kennedy pathway [ 9 , 10 , 11 ]. This enzyme exists in mammalian cells as three isoforms, CHKα1, CHKα2 and CHKβ, which form active hetero- or homo-dimers and are encoded by two separate genes, CHKA and CHKB in human [ 9 , 10 , 12 , 13 ]. CHKα1 and CHKα2 isoforms are generated by alternative splicing of the CHKA gene and share the same catalytic activity [ 10 , 13 ].…”

“…This enzyme exists in mammalian cells as three isoforms, CHKα1, CHKα2 and CHKβ, which form active hetero- or homo-dimers and are encoded by two separate genes, CHKA and CHKB in human [ 9 , 10 , 12 , 13 ]. CHKα1 and CHKα2 isoforms are generated by alternative splicing of the CHKA gene and share the same catalytic activity [ 10 , 13 ]. CHKα and CHKβ display differential tissue expression patterns [ 9 , 12 , 13 ].…”