Dynamic Allosteric Regulation of Mycobacterial IMPDH: Beyond Simple Feedback Mechanism

Kód výsledku v 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>

Výsledek na webu

—

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Dynamic Allosteric Regulation of Mycobacterial IMPDH: Beyond Simple Feedback Mechanism

Popis výsledku v původním jazyce

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

Název v anglickém jazyce

Dynamic Allosteric Regulation of Mycobacterial IMPDH: Beyond Simple Feedback Mechanism

Popis výsledku anglicky

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

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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