Abstract
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities. Thereby, the comparison of their high-resolution structures defines the mechanistic and structural details of a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity of eukaryotic IMPDHs. Remarkably, retinopathy-associated mutations lie within the mechanical hinges of the conformational change, highlighting its physiological relevance. Our results expand the mechanistic repertoire of Bateman domains and pave the road to new approaches targeting IMPDHs.
Highlights
Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) catalyzes the oxidative reaction of IMP to xanthosine 5′-monophosphate (XMP), the rate-limiting step in the de novo synthesis of guanine nucleotides
We have recently reported that GTP/GDP bind to the regulatory Bateman domain of human and fungal IMPDHs and allosterically inhibit their catalytic activity
Given that multiple examples of Bateman domains that bind adenine nucleotides have been reported[10,11,12,13] and following recent results showing the binding of ATP to prokaryotic IMPDHs4, 24, 26, we tested whether this was the case for eukaryotic IMPDHs
Summary
Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) catalyzes the oxidative reaction of IMP to xanthosine 5′-monophosphate (XMP), the rate-limiting step in the de novo synthesis of guanine nucleotides. The Bateman domain is dispensable for the catalytic activity of IMPDHs4, 15–19, but is essential in a number of functions associated to IMDPH. GTP and GDP binding to the Bateman domain of eukaryotic IMPDHs induces a tail-to-tail dimerization of tetramers, forcing the finger domains of both tetramers to interact, resulting in octamers with compromised catalytic activity. According to a recent classification, class-I bacterial IMPDHs are auto-inhibited in vitro in the absence of nucleotides and require ATP to achieve full catalytic activity[24]. Class-II bacterial IMDPHs are active in the absence of nucleotides and, thereby, do not need ATP to achieve full activity[5, 24] These data demonstrate that eukaryotic and prokaryotic IMPDHs have evolved different allosteric regulatory mechanisms that allow adapting to the metabolic requirements of each particular organism
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