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From Proteopedia

Structure

Function(s) and Biological Relevance

IMP (Inosin-5’-monophosphate) dehydrogenase is an enzyme that catalyzes rate limiting step in the de novo guanine nucleotide biosynthetic pathway. It comes from a fungus known as Ashbya gossip and it is particularly interesting because of the major affect cations, like potassium have on it ^[1]. IMPDH facilitates these conformational changes. It represents a therapeutic mechanism for managing several diseases including microbial infections and cancer. Furthermore, dinucleotide polyphosphates play important physiological roles in the allosteric regulation, which may have important implications for the design of therapeutic strategies to inhibit IMPDH’s as well ^[2].

Broader Implications

Dinucleoside polyphosphates have been found to participate in many different cellular processes such as DNA replication and repair, cell division, neurotransmission, apoptosis, vasoconstriction, and platelet aggregation. It is also essential in the regulation of cell growth ^[3]. In a recent study done by Lizbeth Hedstrom, she mentioned how "pacemaker" enzymes, such as IMPDH are linked to neoplastic transformation and progression. Researchers discovered that if there were a way for these enzymes to become inhibited, then the growth of the tumors could be regulated and the rate of being metastasized could be controlled ^[4].

Structural highlights and structure-function relationships

An N to C terminus view of the protein is shown here. Next, a . Within a space filling view of a molecule, we are able to see the proportional arrangements of the atoms as well as the van Der Waals interactions. IMPDH has a two-domain structure that can be easily visualized within this model. The catalytic domain as well as the CBS domain. Both of these domains are an important part of the protein. The catalytic domain is where the ligands, catalytic triad, and the active site are located. The active site is located near the C-terminal and is shown in loops which is important for the protein's conformational flexibility ^[5].

Also, the view to show the location of IMPDH's hydrophobicity. Hydrophobicity has a lot to do with a protein's environmental safety and how it interacts with different molecules around it. IMPDH has a hydrophobic core. This has a major impact on the enzyme's substrate and how it binds to its active site.

A is shown as well (ligand shown in bright green). Because IMPDH has a variety of ligand occupancy binding sites, there are different options as to how each impacts the enzyme. IMPDH can undergo different reorganizations depending on which binding site is occupied.

The is shown here as well. This is also known as the . The core domain in IMPDH is made up of alpha helices and beta sheets. Within these helices and sheets, is the enzyme's active site. This view shows the whole IMPDH molecule which contains 30% alpha helices and 30% beta sheets. The core within this protein resides in a similar conformation as its core. This core is structurally intact and enzymatically active, which is a source of research in biochemistry ^[6].

The view of this protein does not show much because of the lack of charge within the molecule. The parts of the molecule that are highlighted in blue show the histidine side chains. Another view shown is that of the for this protein (shown in red).

The catalytic triad for this protein is Arg - Asn - Asp, 272, 302, 320 which is shown here in this .

Energy Transformation

As IMPDH has three nucleotide-binding sites, which aid in modulating and regulating catalytic activity, there is a large increase in affinity in this molecule. This more than likely comes from the simultaneous reduction of the entropic penalty of binding due to molecularity change ^[7].

References

1. ↑ Fernandez-Justel D, Pelaez R, Revuelta JL, Buey RM. The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates. J Biol Chem. 2019 Aug 15. pii: AC119.010055. doi: 10.1074/jbc.AC119.010055. PMID:31416831 doi:http://dx.doi.org/10.1074/jbc.AC119.010055
2. ↑ Hedstrom L. IMP dehydrogenase: structure, mechanism, and inhibition. Chem Rev. 2009 Jul;109(7):2903-28. doi: 10.1021/cr900021w. PMID:19480389 doi:http://dx.doi.org/10.1021/cr900021w
3. ↑ Fernandez-Justel D, Pelaez R, Revuelta JL, Buey RM. The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates. J Biol Chem. 2019 Aug 15. pii: AC119.010055. doi: 10.1074/jbc.AC119.010055. PMID:31416831 doi:http://dx.doi.org/10.1074/jbc.AC119.010055
4. ↑ Hedstrom L. IMP dehydrogenase: structure, mechanism, and inhibition. Chem Rev. 2009 Jul;109(7):2903-28. doi: 10.1021/cr900021w. PMID:19480389 doi:http://dx.doi.org/10.1021/cr900021w
5. ↑ Makowska-Grzyska M, Kim Y, Wu R, Wilton R, Gollapalli DR, Wang XK, Zhang R, Jedrzejczak R, Mack JC, Maltseva N, Mulligan R, Binkowski TA, Gornicki P, Kuhn ML, Anderson WF, Hedstrom L, Joachimiak A. Bacillus anthracis inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes. Biochemistry. 2012 Aug 7;51(31):6148-63. Epub 2012 Jul 25. PMID:22788966 doi:10.1021/bi300511w
6. ↑ Makowska-Grzyska M, Kim Y, Wu R, Wilton R, Gollapalli DR, Wang XK, Zhang R, Jedrzejczak R, Mack JC, Maltseva N, Mulligan R, Binkowski TA, Gornicki P, Kuhn ML, Anderson WF, Hedstrom L, Joachimiak A. Bacillus anthracis inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes. Biochemistry. 2012 Aug 7;51(31):6148-63. Epub 2012 Jul 25. PMID:22788966 doi:10.1021/bi300511w
7. ↑ Fernandez-Justel D, Pelaez R, Revuelta JL, Buey RM. The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates. J Biol Chem. 2019 Aug 15. pii: AC119.010055. doi: 10.1074/jbc.AC119.010055. PMID:31416831 doi:http://dx.doi.org/10.1074/jbc.AC119.010055