Study of transaldolase deficiency in urine samples by capillary LC‐MS/MS

Vas, György; Conkrite, Karina L.; Amidon, Wendy; Qian, Yueming; Bánki, Katalin; Perl, András

doi:10.1002/jms.1004

Cited by 22 publications

(18 citation statements)

References 20 publications

(35 reference statements)

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“…All samples were analyzed after methanol/water extraction by LC-MS/MS (25). Sugar phosphates and nucleotides were detected in the same sample.…”

Section: Methodsmentioning

confidence: 99%

“…NADH and NADPH were separately analyzed after extraction with KOH (25,71). This method allowed parallel detection of NADH (m/z 665), NADP (m/z 743), and NADPH (m/z 744) by CapLC/Q-TOF detection (25). ATP levels were also determined using the luciferin-luciferase kit (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…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). The unique TAL substrate sedoheptulose 7-phosphate (S7P) accumulated 17-fold in Taldo1 -/-livers ( Figure 3).…”

Section: Spontaneous Development Of Steatosis Steatohepatitis Cirrhmentioning

confidence: 99%

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

Hanczko¹,

Fernández²,

Doherty³

et al. 2009

J. Clin. Invest.

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125

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Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1 -/-and Taldo1 +/-mice spontaneously developed HCC, and Taldo1 -/-mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1 -/-livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1 -/-livers reflected adaptation to oxidative stress. Taldo1 -/-hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1 -/-mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.

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“…All samples were analyzed after methanol/water extraction by LC-MS/MS (25). Sugar phosphates and nucleotides were detected in the same sample.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Spontaneous Development Of Steatosis Steatohepatitis Cirrhmentioning

confidence: 99%

See 1 more Smart Citation

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

Hanczko¹,

Fernández²,

Doherty³

et al. 2009

J. Clin. Invest.

Self Cite

125

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show abstract

“…We developed a negative ion electrospray LC-MS/ MS method using a Waters capillary liquid chromatograph (CapLC) coupled with a Q-TOF micro mass spectrometer equipped with tandem quadrupole and time-of-flight analyzers (80). The extraction and separation protocols were optimized to detect 5-thio-D-glucose-6-phosphate internal standard (IS).…”

Section: Metabolic Consequences Of Tal Deficiency Are Cell Type-specificmentioning

confidence: 99%

The pathogenesis of transaldolase deficiency

Perl¹

2007

IUBMB Life

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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.

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“…The use of LC–MS/MS, LC–MS, and GC–MS for this purpose has been reported [7–9]. 1 H-NMR spectroscopy can be used for identification and quantification of proton-containing metabolites in body fluids [10].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency

Engelke

Zijlstra

Mochel

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Background Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency. Method Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using 1H-NMR spectroscopy and GC–mass spectrometry. Results Our data confirm the known metabolic characteristics in TALDO-deficient patients. The β-furanose form was the major sedoheptulose anomer in TALDO-deficient patients. Erythronic acid was identified as a major abnormal metabolite in all patients and in knock-out TALDO mice implicating an as yet unknown biochemical pathway in this disease. A putative sequence of enzymatic reactions leading to the formation of erythronic acid is presented. The urinary concentration of the citric acid cycle intermediates 2-oxoglutaric acid and fumaric acid was increased in the majority of TALDO-deficient patients but not in the knock-out mice. Conclusion Erythronic acid is a novel and major hallmark in TALDO deficiency. The pathway leading to its production may play a role in healthy humans as well. In TALDO-deficient patients, there is an increased flux through this pathway. The finding of increased citric acid cycle intermediates hints toward a disturbed mitochondrial metabolism in TALDO deficiency.

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Study of transaldolase deficiency in urine samples by capillary LC‐MS/MS

Cited by 22 publications

References 20 publications

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

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

The pathogenesis of transaldolase deficiency

Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency

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