The pathogenesis of transaldolase deficiency

Abstract

SummaryThe signaling networks that mediate cell growth, differentiation, and survival are dependent on complex metabolic and redox pathways. Metabolism of glucose through the pentose phosphate pathway (PPP) fulfills two unique functions: formation of ribose 5-phosphate for the synthesis of nucleotides, RNA, and DNA in support cell growth and formation of NADPH for biosynthetic reactions and neutralization of reactive oxygen intermediates (ROI). Balancing of NADPH and ROI levels by the PPP enzyme transaldolase (TAL) regulates the mitochondrial trans-membrane potential (Dw m ), a critical checkpoint of ATP synthesis and cell survival. While complete deficiency of glucose 6-phosphate dehydrogenase (G6PD) or transketolase (TK) is lethal, TAL-deficient mice developed normally with the exception of male sterility due to structural and functional damage of sperm cell mitochondria. Recently, two cases of complete TAL deficiency have been reported in patients with liver cirrhosis which results from increased cell death of hepatocytes. Delineation of the cell type-specific role that TAL plays in the PPP and cell death signal processing will be critical for understanding the pathogenesis of TAL deficiency.

Genome-wide analysis of transcriptional changes in the thoracic muscle of the migratory locust, Locusta migratoria, exposed to hypobaric hypoxia

“…The activation of glycosylation in ER likely helped stabilize and fold the newly synthesized proteins correctly (Parodi, 2000). Besides ER rescue of dysfunctional proteins, PPP in cytosol, working cooperatively, was activated to enhance the production of reductive NADPH, which helps regenerate GSH from GSSG to mitigate the oxidative damages (Perl, 2007).…”

Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum

“…As known, TALDO is a key enzyme in the pentose phosphate pathway, responsible of exchanging a three-carbon moiety between different carbohydrates, enabling either the production of more nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate, or by being inhibited, enabling production of more nucleic acids. Therefore, TALDO function is essential for cell survival (Wamelink et al 2008b;Perl 2007;Perl et al 2011). …”

“…It is crucial in the nonoxidative part, immediately after transketolase (EC 2.2.1.1). These two enzymes enable an important connection between the PPP and glycolysis (Perl 2007). TALDO interconverts a three-carbon moiety between different sugars; thus, it enables the production of fructose-6-phosphate and erythrose-4-phosphate from glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate.…”

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

“…The metabolism of glucose through the pentose phosphate pathway (PPP) provides ribose 5-phosphate (R5P) for the synthesis of nucleotides and NADPH, a reducing equivalent for biosynthetic reactions and for maintenance of GSH in its reduced state (23,24). To assess the consequences of TAL deficiency on the PPP, we determined the levels of PPP sugars and nucleotides by liquid chromatography coupled to tandem mass spectroscopy (LC-MS/ MS) (25).…”