Dynamic Allosteric Regulation of Mycobacterial IMPDH: Beyond Simple Feedback Mechanism

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00604151" target="_blank" >RIV/61388963:_____/24:00604151 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Dynamic Allosteric Regulation of Mycobacterial IMPDH: Beyond Simple Feedback Mechanism

Original language description

Mycobacterial inosine-5′-monophosphate dehydrogenase (IMPDH) is a key enzyme in purine metabolism that integrates signals of multiple allosteric effectors. Its activity is tightly regulated by ATP, in combination with effectors GTP and the universal bacterial alarmone, ppGpp. The specific concentration ratios of these effectors are essential for effective regulation. These allosteric signals act as sensitive indicators of the metabolic state of the purine pathway and, more broadly, of cellular energy metabolism. This allows for a fine-tuning of the enzyme activity during the exponential growth as well as a complete shutdown of the enzyme during stress conditions or stalled growth. Furthermore, the molecular mechanism of how the ligands affect the activity of IMPDH challenges traditional models of allosteric regulation, where an effector simply induces a structural change in the enzyme, leading to altered catalytic function. In contrast, IMPDH exhibits dynamic allostery, where the effector alters the intrinsic dynamics of the enzyme complex, effectively locking the enzyme in its inactive conformation. Interestingly, distinct effectors bind to different sites, but use a common regulatory mechanism, illustrating how evolution can repurpose a common strategy to integrate multiple regulatory signals. IMPDH provides an example of a complex enzyme regulatory system that extends beyond the conventional view of simple feedback regulation. Understanding the mechanistic details of this regulation may guide the development of novel IMPDH-targeting allosteric inhibitors.nn

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů