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Function(s) and Biological Relevance

Inosine-5'-monophosphate dehydrogenase (IMPDH) is the enzyme that catalyzes the rate-limiting step in the de novo guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus Ashbya gossypii ^[1]. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to tumor cell proliferation and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of Ashbya gossypii IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides^[2].

Broader Implications

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair^[3]. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs^[4], with antibacterial and chemotherapeutic strategies feasibility^[5].

Structural Highlights and Structure-Function Relationships

Energy Transformation

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