Evidence of a triosephosphate isomerase non-catalytic function critical to behavior and longevity

Abstract

SummaryTriosephosphate isomerase (TPI) is a glycolytic enzyme that converts dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP). Glycolytic enzyme dysfunction leads to metabolic diseases collectively known as glycolytic enzymopathies. Of these enzymopathies, TPI deficiency is unique in the severity of neurological symptoms. The Drosophila sugarkill mutant closely models TPI deficiency and encodes a protein prematurely degraded by the proteasome. This led us to question whether enzyme catalytic activity was crucial to the pathogenesis of TPI sugarkill neurological phenotypes. To study TPI deficiency in vivo we developed a genomic engineering system for the TPI locus that enables the efficient generation of novel TPI genetic variants. Using this system we demonstrate that TPI sugarkill can be genetically complemented by TPI encoding a catalytically inactive enzyme. Furthermore, our results demonstrate a non-metabolic function for TPI, the loss of which contributes significantly to the neurological dysfunction in this animal model.

Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency

“…TPI Deficiency is unique among all other glycolytic enzymopathies in the presentation of severe neurologic deficits and the lack of ATP depletion [2]. It is not currently understood why mutations in a non-linear glycolytic enzyme elicit far greater pathology than other central glycolytic enzymes, though recent work has suggested that these neurologic differentiae are derived from a source other than general metabolic stress [3]. To date, only one of eleven physically distinct disease-associated TPI mutations has been structurally characterized [4, 5].…”

In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: Towards a predictive framework for TPI deficiency

“…diet, environment, quality of medical care), play a role in the development of this enigmatic disease. Indeed data from a Drosophila study has indicated the existence of an isomerase-independent function of TPI which opens up new avenues of investigation that may prove crucial in developing our understanding of this enzyme in the conservation of normal neuronal function and, therefore, in TPI deficiency pathogenesis (Roland et al, 2015;Roland et al, 2013). Other non-metabolic functions of TPI have also been reported in a number of organisms, mostly pathogens.…”

“…Structural studies were based on the crystal structure of human TPI (PDB: 4POC; (Roland et al, 2015;Roland et al, 2013)) obtained from the RCSB protein data bank (http://www.rcsb.org/pdb/home/home.do) (Berman et al, 2002;Berman et al, 2000). Secondary structural elements were defined according to Supplementary Table S2.…”

“…Thus, TPI ensures that the three carbon atoms in DHAP can be utilised in glycolysis and subsequent pathways. In addition to this metabolic role it has been proposed that TPI also functions in sperm-egg recognition in mammals and may have non-metabolic roles in nerve cells (Auer et al, 2004;Petit et al, 2014;Roland et al, 2013;Roland et al, 2016).…”

Molecular identification, immunolocalization, and characterization of Clonorchis sinensis triosephosphate isomerase

“…The loss of enzymatic activity most likely results from misfolding of the enzyme or its failure to dimerize (Daar et al 1986;Seigle et al 2008 andRalser et al 2006). Furthermore, the TIM knockout can lead to metabolic diseases and neurological dysfunction (Velur Selvamani et al 2014;Roland et al 2013;Eanes et al 2006) Giardia depends on glycolysis as its major ATP source (Adam 2001). TIM from Schistosoma species was considered as a potential drug and vaccine target Wen 2011 andZinsser et al 2013a, b).…”