Choline kinase

As of late 2007, six structures have been solved for this class of enzymes, with PDB accession codes 1NW1, 2CKO, 2CKP, 2CKQ, 2I7Q, and 2IG7.

CKα-2 originating from C. elegans, is a dimeric enzyme with each monomer being composed of two domains. The active site is located between the two domains (see figure below). Its overall structure is similar to members of the eukaryotic protein kinase family. Mammalian choline kinases exists in either dimeric or tetrameric forms in solution.[4][5] Structural studies carried out on CKα-2 have implied that the conserved residues in the CK family of enzymes could possibly play a vital role in substrate binding as well as in the stabilization of catalytically important residues.[6]

An enlarged view of the residues involved in the dimer interface between the S-shaped loop of the yellow subunit and the loop following helix A and strand 4 of the cyan subunit. Only residues that are involved in direct salt bridges, hydrogen bonds, or van der Waals interactions are shown. Salt bridges and hydrogen bonds, dashed lines; labels of residues from the yellow subunit, red; labels of residues from the cyan subunit, blue.[6]

Although not much is known about the mechanism by which choline kinase reacts, the recent advancement in the elucidation of the structure of the enzyme has provided scientists with much more insight than they had previously. Since the structure of CK is very similar to that of the eukaryotic protein kinase family, the location of ATP and choline binding pockets have been proposed. These are shown in the figures below.

After closely studying the structurally similar enzymes, CKα-2, APH(3′)-IIIa, and PKA, researchers observed that PKA had less insertions to its structural core compared to the other enzymes. Against this background, it is believed that CKα-2 have evolved from PKA to have more structural elements attached to it.[8]

Choline kinase catalyzes the formation of phoshocholine, the committed step in phosphatidylcholine biosynthesis. Phosphatidylcholine is the major phospholipid in eukaryotic membranes. Phosphatidylcholine is important for a variety of function in eukaryotes such as facilitating the transport of cholesterol through the organism, acting as a substrate for the production of second messengers and as a cofactor for the activity of several membrane-related enzymes.[9] CK also plays a vital role in the production of sphingomyelin, another important membrane phospholipid and in the regulation of cell growth.[10]

The production of phosphocholine from CK is necessary for the signal transduction pathways related to mitogenesis. It has also been found that CK plays a critical role in the proliferation of human mammary epithelial cells.[11]

Choline kinase α can act as a protein chaperone.[12] Kinase can function as chaperone and there may be other kinases that may function as chaperone that are yet to be identified. Choline kinase α (CKα) is overexpressed in prostate cancer where it physically interacts with the androgen receptor (AR), a major driver of prostate cancer. By disabling the function of CHKA researchers were able to inhibit AR function and prostate cancer growth.

In vivo studies carried out using CKα-1 and CKβ isoforms suggest that each isoform might be involved in different biochemical pathways. CKβ plays a major role in the catalysis of the phosphorylation of ethanolamine while CKα-1 catalyzes the phosphorylation of both choline and ethanolamine.[13] ShRNA mediated in vivo depletion of CKα has been shown to decrease the growth of prostate tumor xenografts[12]