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TitleDisorder-to-order active site capping regulates the rate-limiting step of the inositol pathway.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 34, Page e2400912121, Year 2024
Publish dateAug 20, 2024
AuthorsToni K Träger / Fotis L Kyrilis / Farzad Hamdi / Christian Tüting / Marie Alfes / Tommy Hofmann / Carla Schmidt / Panagiotis L Kastritis /
PubMed AbstractMyo-inositol-1-phosphate synthase (MIPS) catalyzes the NAD-dependent isomerization of glucose-6-phosphate (G6P) into inositol-1-phosphate (IMP), controlling the rate-limiting step of the inositol ...Myo-inositol-1-phosphate synthase (MIPS) catalyzes the NAD-dependent isomerization of glucose-6-phosphate (G6P) into inositol-1-phosphate (IMP), controlling the rate-limiting step of the inositol pathway. Previous structural studies focused on the detailed molecular mechanism, neglecting large-scale conformational changes that drive the function of this 240 kDa homotetrameric complex. In this study, we identified the active, endogenous MIPS in cell extracts from the thermophilic fungus . By resolving the native structure at 2.48 Å (FSC = 0.143), we revealed a fully populated active site. Utilizing 3D variability analysis, we uncovered conformational states of MIPS, enabling us to directly visualize an order-to-disorder transition at its catalytic center. An acyclic intermediate of G6P occupied the active site in two out of the three conformational states, indicating a catalytic mechanism where electrostatic stabilization of high-energy intermediates plays a crucial role. Examination of all isomerases with known structures revealed similar fluctuations in secondary structure within their active sites. Based on these findings, we established a conformational selection model that governs substrate binding and eventually inositol availability. In particular, the ground state of MIPS demonstrates structural configurations regardless of substrate binding, a pattern observed across various isomerases. These findings contribute to the understanding of MIPS structure-based function, serving as a template for future studies targeting regulation and potential therapeutic applications.
External linksProc Natl Acad Sci U S A / PubMed:39145930 / PubMed Central
MethodsEM (single particle)
Resolution2.48 Å
Structure data

50149

9f2k

EMDB-50149, PDB-9f2k:
Myo-inositol-1-phosphate synthase from Thermochaetoides thermophila in complex with NAD
Method: EM (single particle) / Resolution: 2.48 Å

Chemicals

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

Source
  • thermochaetoides thermophila dsm 1495 (fungus)
KeywordsISOMERASE / inositol metabolism / endogenous / conformational selection

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