Sandbox Reserved 1563

This Sandbox is Reserved from Aug 26 through Dec 12, 2019 for use in the course CHEM 351 Biochemistry taught by Bonnie_Hall at the Grand View University, Des Moines, USA. This reservation includes Sandbox Reserved 1556 through Sandbox Reserved 1575.

To get started: Click the edit this page tab at the top. Save the page after each step, then edit it again. show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page. Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc. More help: Help:Editing

Inosine-5'-monophosphate dehydrogenase (IMPDH)

spinqualitylabelsall models Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function(s) and Biological Relevance Inosine-5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate limiting step of the de novo guanine nucleotide biosynthetic pathway. NAD is reduced resulting in IMP converting to Xanthosine monophosphate (XMP). Additional ligands include Acetate (ACT) and Guanosine-5'-monophosphate (5GP). IMPDH is found in organisms that go through the purine biosynthetic pathway, this includes humans. IMPDH is used medically to help fight against microbial infections and cancer. Broader Implications If IMPDH is not regulated correctly it could lead to uncontrolled cell division. Without the regulation of cell division this could lead to cancer. Dinucleoside polyphosphates could allosterically regulate inhibition of IMPDH. If inhibition of IMPDH is regulated errors would occur less frequently and thus uncontrolled cell division would become less likely. Dinucleoside polyphosphates used as IMPDH inhibitors may contribute as anticancer and antiviral drugs. Structural highlights and structure-function relationships In the IMPDH secondary structures. Alpha and beta sheets are shown. The active site of the protein is located on the C-terminus end in the TIM barrel. This contains 8 beta sheets and 8 alpha helices. IMPDH quaternary structure. These quaternary structures include tetramers, compacted and extended octamers, and multiunit complexes. These are created through multiple subunits of tertiary structures. They are formed and reinforced through hydrogen bonding, disulfide bonds, and hydrophobic interactions. The IMPDH space filled is important to get a more accurate representation of the amount of space the protein would take up. It better shows the interactions in the structure. In the image the light blue is the amino acid residues. The red dots represent water molecules. The orange is phosphorus. Lastly the blue is nitrogen. IMPDH hydrophobicity view. The hydrophilic residues interact with the outside enviornment. They contain amino acid residues that can hydrogen bond and are used to maintain structure for the active binding site. The hydrophobic region (Gly 361 and Gly 383) interacts with the phosphate chain. This will allow for more movement of the cations. IMPDH ligand view. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. IMPDH triad. The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid black structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding. IMPDH active binding site. The active binding cite is where the binding takes place after the catalytic triad makes cysteine more reactive and binding is induced. In the image the cysteines are in white. This is where binding would occur. So for this image the cysteines that are made more reactive are shown in light green. Asp 259 (shown in red in this image) hydrogen bonds to ribose hydroxyls and Ser 315 (also shown in red) hydrogen bonds to ribose phosphate. Gly 383 (Shown in Light blue) interacts with NAD through hydrophobic interactions. Gly 361 (also light blue) binds to NAD through hydrophobic interactions as well. IMPDH charge. IMPDH has no significant charge since it is found in physiological environments. Positively and negatively charged amino acids play a part in intermediate covalent binding steps. IMPDH composition. G5P and GDP ligands are shown in Pink. The green represents the anions that, during the intermediate step, function as ligands. Cations will travel through an active IMPDH. Energy Transformation There are three binding sites within the Bateman domain that regulate catalytic activity. These three sites bind dinucleoside polyphosphates, and the affinity for those binding sites increases as activity with IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within the Bateman domain. This requires the Bateman domain to make IMPDH more sensitive to inhibition. Covalent bonds are broken later in the reaction that allows the system enough energy to complete the process.