Triosephosphate isomerase deficiency: Facts and doubts

Abstract

SummaryMany glycolytic enzymopathies have been described that manifest clinically as chronic hemolytic anemia. One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates. The TPI gene is well characterized; structure and function studies suggest that instability of the isomerase due to different mutations of the enzyme may underlie the observed reduced catalytic activity. Patients with various inherited mutations have been identified. The most abundant mutation is a Glu104Asp missense mutation that is found in homozygotes and compound heterozygotes. Two germ-line identical Hungarian compound heterozygote brothers with distinct phenotypes question the exclusive role of the inherited mutations in the etiology of neurodegeneration. This paper: (i) reviews our present understanding of TPI mutation-induced structural alterations and their pathological consequences, (ii) summarizes the consequences of TPI impairment in the Hungarian case at local and system levels, and (iii) raises critical questions regarding the exclusive role of TPI mutations in the development of this human disease.

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

“…Indeed, data are not consistent from existing reports to establish whether reduced protein levels, instability of the protein homodimer, aberrant protein complexes, and/or a decrease in isomerase activity contribute to pathogenesis of the disease (Olah et al 2002;Orosz et al 2006). In part, the difficulty arises from the fact that the disease has a strong neurological component, yet patients' erythrocytes are often used for studies due to their accessibility.…”

“…The TPI sugarkill mutation, also known as sugarkill, TPI sgk , or TPI sgk1 , results from a missense mutation predicted to cause an M80T. This numbering uses the established nomenclature for TPI mutations, where the start methionine is assumed to be removed following translation (see the recent review by Orosz et al 2006). TPI transgenic strains were previously published (Celotto et al 2006).…”

“…Studies have also documented markedly elevated DHAP levels, suggesting that the anemia may be caused by toxicity of DHAP or one of its catabolites (Zanella et al 1985;Eber et al 1991;Hollan et al 1997;Karg et al 2000;Olah et al 2002Olah et al , 2005. Interestingly, DHAP levels in nonerythrocytes are only modestly increased, presumably owing to it being a substrate for phospholipid biosynthesis in other cell types, and a yeast model of TPI deficiency reports that proteins bearing the human disease mutations maintain catalytic activity (Orosz et al 2001(Orosz et al , 2006Ralser et al 2006).…”

“…2006; Gnerer et al 2006;Orosz et al 2006). The TPI sugarkill locomotor impairment is conditional with mechanical stress or elevated temperatures inducing acute paralysis.…”

How a host cell signalling molecule modifies carbon metabolism in symbionts of the coral Plesiastrea versipora

“…2A). We suggest that HRF inhibits a step in the triose phosphate pathway leading to starch and lipid synthesis, shunting carbon (via dihydroxyacetone phosphate) towards glycerol synthesis [22]; this would explain the high levels of both released and intracellular glycerol in algae incubated in HRF [3], as well as the lower amounts of newly synthesized TAG and starch [3,16,18] (this study, Fig. 2B,C).…”