Molecular Illustration: Effect of SAICAR on Protein Kinase Activity for PKM2
The basis for this project was built on recent research published on the effects of SAICAR on pyruvate kinase M2 (PKM2). PKM2 is a metabolic enzyme that is involved in the abnormal metabolism and overactive proliferation of cancer. It is an isoform of pyruvate kinase that is mostly found in fetal and cancer cells, while the other three isoforms of pyruvate kinase reside in normal somatic tissue. The protein kinase activity of PKM2 has been shown to increase cancer cell proliferation, and if PKM2 is replaced or reduced, then cancer cell survival rate lowers significantly during hypoxia and glucose-limited conditions.
Succinyl-5-aminomidazole-4-carboxamide-1-ribose-5'-phosphate (SAICAR) is a metabolite found in proliferating cells that is an intermediate of the de novo purine nucleotide synthesis pathway. In vitro and in cells it has been shown to increase PKM2's protein kinase activity when SAICAR binds to PKM2. After the two bind, PKM2-SAICAR phosphorylates Erk1/2 for activation. Erk1/2 then goes on to sensitize other PKM2 molecules for SAICAR binding.
Additionally, SAICAR has been found to increase cancer cell survival rates even in glucose-limited conditions. When glucose is scarce, SAICAR increases in number and induces PKM2 activity. However in normal cells, SAICAR does not accumulate no matter what the glucose conditions are.
This project focuses on the research published by Keller et. al. titled 'SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells.' The goals included creating a 3-panel storyboard illustrating the mechanism-of-action between SAICAR, Erk1/2, and PKM2, as well as an illustration of a chosen panel from the storyboard.
Since the binding mechanism-of-action between SAICAR and PKM2 is still unknown, the storyboard needed to show the mechanism-of-action either without showing the binding or finding an alternative representation of the binding. Due to the interaction between SAICAR, PKM2, and Erk1/2 behaving in a positive feedback loop, we focused on the activity of PKM2 and SAICAR after the two have bound. Therefore the final chosen illustration was the panel in which PKM2-SAICAR phosphorylates Erk1/2.
Date Started: 11/13/2014
Date Completed: 12/02/2014
Audience: Scientific professionals
Final Deliverable: 1920 x 1080 pixel HDTV illustration
- Visual Molecular Dynamics (VMD)
- Autodesk 3ds Max
- Adobe Photoshop
- Adobe Illustrator
These are progress shots of the molecular assets for the final illustration. The first image shows an example of the Erk 1 molecule after being exported from the VMD. The second image contains the molecules after being taken from the VMD and into 3ds Max. A surface model representation was chosen for PKM2 afterward in order to better show its recognizable dimer formation. The thurd image is of the protein models after being rendered and brought into Photoshop for compositing.