Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.

Abstract

Triosephosphate isomerase (TPI) deficiency (TPI Df) is an untreatable glycolytic enzymopathy that results in hemolytic anemia, progressive muscular impairment and irreversible brain damage. Although there is a 'common' mutation (TPIE105D), other pathogenic mutations have been described. We identified patients who were compound heterozygous for a newly described mutation, TPIQ181P, and the common TPIE105D mutation. Intriguingly, these patients lacked neuropathy or cognitive impairment. We then initiated biochemical and structural studies of TPIQ181P. Surprisingly, we found that purified TPIQ181P protein had markedly impaired catalytic properties whereas crystallographic studies demonstrated that the TPIQ181P mutation resulted in a highly disordered catalytic lid. We propose that genetic complementation occurs between the two alleles, one with little activity (TPIQ181P) and one with low stability (TPIE105D). Consistent with this, TPIQ181P/E105D fibroblasts exhibit a significant reduction in the TPI protein. These data suggest that impaired stability, and not catalytic activity, is a better predictor of TPI Df severity. Lastly, we tested two recently discovered chemical modulators of mutant TPI stability, itavastatin and resveratrol, and observed a significant increase in TPI in TPIQ181P/E105D patient cells.

• Authors: Andrew P VanDemark, Stacy L Hrizo, Samantha L Eicher, Jules Kowalski, Tracey D Myers, Megan R Pfeifer, Kacie N Riley, Dwight D Koeberl, Michael J Palladino
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 15 Issue 5 (05 01 2022) ISSN: 1754-8411 [Electronic] England
• PMID: 35315486 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. Published by The Company of Biologists Ltd.

Chemical References

• Quinolines
• Triose-Phosphate Isomerase
• pitavastatin
• Resveratrol

Topics

• Anemia, Hemolytic, Congenital Nonspherocytic (genetics)
• Carbohydrate Metabolism, Inborn Errors
• Humans
• Quinolines
• Resveratrol (pharmacology)
• Triose-Phosphate Isomerase (deficiency, genetics)