Role of Salt Bridge Dynamics in Inter Domain Recognition of Human IMPDH Isoforms: An Insight to Inhibitor Topology for Isoform-II

Abstract

Inosine monophosphate dehydrogenase (IMPDH) enzyme involves in the biosynthesis pathway of guanosine nucleotide. Type II isoform of the enzyme is selectively upregulated in neoplastic fast replicating lymphocytes and CML cancer cells. The hIMPDH-II is an excellent target for antileukemic agent. The detailed investigation during MD-Simulation (15 ns) of three different unliganded structures (1B3O, 1JCN and 1JR1) have clearly explored the salt bridge mediated stabilization of inter or intra domain (catalytic domains I(N), I(C) with res. Id. 28-111 and 233-504, whereas two CBS domains C₁, C₂ are 112-171 and 172-232) in IMPDH enzyme which are mostly inaccessible in their X-rays structures. The salt bridge interaction in I(N)---C₁ inter-domain of hIMPDH-I, I(N)---C₂ of IMPDH-II and C₁---I(C) of nhIMPDH-II are discriminative features among the isoforms. The I(N)---C₂ recognition in hIMPDH-II (1B3O) is missing in type-I isoform (1JCN). The salt bridge interaction D232---K238 at the surface of protein and the involvement of three conserved water molecules or the hydrophilic centers (WA²³²(OD1), WB ²³²(OD2) and W²³⁸(NZ)) to those acidic and basic residues seem to be unique in hIMPDH-II. The hydrophilic susceptibility, geometrical and electronic consequences of this salt bridge interaction could be useful to design the topology of specific inhibitor for hIMPDH-II which may not be effective for hIMPDH-I. Possibly, the aliphatic ligand containing carboxyl, amide or hydrophilic groups with flexible structure may be implicated for hIMPDH-II inhibitor design using the conserved water mimic drug design protocol.

Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

“…(C)]. Lastly we investigated plausible salt bridges formed at the interface of ARID and PHD1 domains, because salt bridges are frequently observed at transient domain‐domain interfaces . Since we had previously performed 5 parallel runs, we only selected the salt‐bridges observed in no less than two runs.…”

Emerging Cytotoxic Alkaloids in the Battle against Cancer: Overview of Molecular Mechanisms

“…For example, it is capable of inhibiting the epidermal growth factor receptor (EGFR) in gastric cancer cells which is involved in DNA synthesis and cell proliferation [ 87 ]. On the other hand, in cervical cancer cells, oxymatrine has the ability to constrain the activity of IMPDH2 enzyme [ 88 ] which is required for guanosine 5′-triphosphate (GTP) formation and thus DNA and RNA synthesis [ 95 ]. Oxymatrine exerts its anti-angiogenic effect in pancreatic cancer cells via targeting the NF-κB pathway and hindering the activity of the vascular endothelial growth factor (VEGF) involved in stimulating vasculogenesis and angiogenesis [ 89 ].…”

Assembly of IMPDH2-Based, CTPS-Based, and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

“…Interestingly, the catalysis of inosine-5 0 -monophosphate into xanthine-5 0 -monophosphate is done by IMPDH2, followed by a subsequent conversion into guanosine-5 0 -monophosphate. IMPDH2 is also involved in the control of the cellular pool of nucleotide guanine, necessary for DNA and RNA synthesis (Natsumeda et al, 1990;Bairagya et al, 2011). The formation of RR structures usually happens when the GTP/CTP pathways are inhibited, either by specific drug targeting of their enzymes or by lack of nutrients that would fuel these pathways.…”