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Function(s) and Biological Relevance

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^[1].

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^[2].

Structural highlights and structure-function relationships

In the . 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.

. These quaternary structures include tetramers, compacted and extended octamers, and multiunit complexes. These are created through multiple subunits of . They are formed and reinforced through hydrogen bonding, disulfide bonds, and hydrophobic interactions.

The 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.

. 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.

. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein.

. 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.

. 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 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^[3].

. 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^[4]. Covalent bonds are broken later in the reaction that allows the system enough energy to complete the process.