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.

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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. IMPDH space filled. In the space filled view we can see a better representation of how much space the protein would actually take up. In the image the white is the protein as a whole and the red dots represent hydrogen bonds. IMPDH hydrophobicity view. For this image purple represent polar molecules and grey represents hydrophobic molecules. 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 cystine 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 cystine more reactive and binding is induced. In the image the cystines are in white. This is where binding would occur. 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. Brown represents a protein. Red represents a RNA. Green represents ligands. 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.