Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency
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 identifie...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-05-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/15/5/dmm049261 |
| _version_ | 1818470815721586688 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Andrew P. VanDemark |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T21:42:38Z |
| format | Article |
| id | doaj.art-6e587810fc2644ddac6db38219dae764 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T21:42:38Z |
| publishDate | 2022-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-6e587810fc2644ddac6db38219dae7642022-12-22T02:28:42ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-05-0115510.1242/dmm.049261049261Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiencyAndrew P. VanDemark0Stacy L. Hrizo1Samantha L. Eicher2Jules Kowalski3Tracey D. Myers4Megan R. Pfeifer5Kacie N. Riley6Dwight D. Koeberl7Michael J. Palladino8 Biological Sciences and Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Biological Sciences and Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA Biological Sciences and Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA 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.http://dmm.biologists.org/content/15/5/dmm049261biochemistryglycolytic dysfunctionstructural biologytriosephosphate isomerase |
| spellingShingle | 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 Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency Disease Models & Mechanisms biochemistry glycolytic dysfunction structural biology triosephosphate isomerase |
| title | Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency |
| title_full | Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency |
| title_fullStr | Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency |
| title_full_unstemmed | Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency |
| title_short | Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency |
| title_sort | itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of tpi deficiency |
| topic | biochemistry glycolytic dysfunction structural biology triosephosphate isomerase |
| url | http://dmm.biologists.org/content/15/5/dmm049261 |
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