TY - JOUR

T1 - Structure, cooperativity and inhibition of the inosine 5′-monophosphate-specific phosphatase from Saccharomyces cerevisiae

AU - Byun, Sujeong

AU - Park, Changkon

AU - Suh, Jeong Yong

AU - Witte, Claus Peter

AU - Rhee, Sangkee

N1 - Funding Information: We would like to thank Dr Eunyoung Park and Prof Jeong‐Han Kim for HPLC measurements at the early stage of a project. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2021R1A2C2092118 and RS‐2023‐00207820).

PY - 2024/2/16

Y1 - 2024/2/16

N2 - The nucleoside inosine is a main intermediate of purine nucleotide catabolism in Saccharomyces cerevisiae and is produced via the dephosphorylation of inosine monophosphate (IMP) by IMP-specific 5′-nucleotidase 1 (ISN1), which is present in many eukaryotic organisms. Upon transition of yeast from oxidative to fermentative growth, ISN1 is important for intermediate inosine accumulation as purine storage, but details of ISN1 regulation are unknown. We characterized structural and kinetic behavior of ISN1 from S. cerevisiae (ScISN1) and showed that tetrameric ScISN1 is negatively regulated by inosine and adenosine triphosphate (ATP). Regulation involves an inosine-binding allosteric site along with IMP-induced local and global conformational changes in the monomer and a tetrameric re-arrangement, respectively. A proposed interaction network propagates local conformational changes in the active site to the intersubunit interface, modulating the allosteric features of ScISN1. Via ATP and inosine, ScISN1 activity is likely fine-tuned to regulate IMP and inosine homeostasis. These regulatory and catalytic features of ScISN1 contrast with those of the structurally homologous ISN1 from Plasmodium falciparum, indicating that ISN1 enzymes may serve different biological purposes in different organisms.

AB - The nucleoside inosine is a main intermediate of purine nucleotide catabolism in Saccharomyces cerevisiae and is produced via the dephosphorylation of inosine monophosphate (IMP) by IMP-specific 5′-nucleotidase 1 (ISN1), which is present in many eukaryotic organisms. Upon transition of yeast from oxidative to fermentative growth, ISN1 is important for intermediate inosine accumulation as purine storage, but details of ISN1 regulation are unknown. We characterized structural and kinetic behavior of ISN1 from S. cerevisiae (ScISN1) and showed that tetrameric ScISN1 is negatively regulated by inosine and adenosine triphosphate (ATP). Regulation involves an inosine-binding allosteric site along with IMP-induced local and global conformational changes in the monomer and a tetrameric re-arrangement, respectively. A proposed interaction network propagates local conformational changes in the active site to the intersubunit interface, modulating the allosteric features of ScISN1. Via ATP and inosine, ScISN1 activity is likely fine-tuned to regulate IMP and inosine homeostasis. These regulatory and catalytic features of ScISN1 contrast with those of the structurally homologous ISN1 from Plasmodium falciparum, indicating that ISN1 enzymes may serve different biological purposes in different organisms.

KW - allosteric site

KW - ATP

KW - inosine

KW - negative regulation

KW - purine metabolism

UR - http://www.scopus.com/inward/record.url?scp=85185258276&partnerID=8YFLogxK

U2 - 10.1111/febs.17093

DO - 10.1111/febs.17093

M3 - Article

C2 - 38362806

AN - SCOPUS:85185258276

VL - 291

SP - 1992

EP - 2008

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 9

ER -