{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTALDO1 encodes transaldolase, a pivotal enzyme of the non‐oxidative branch of the pentose phosphate pathway that catalyzes reversible three‐carbon transfers among sugar phosphates, thereby sustaining NADPH production and ribose 5‐phosphate recycling essential for redox balance and biosynthesis. Its expression is tightly regulated at the transcriptional level by factors such as ZNF143, ensuring both basal and tissue‐specific activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, transaldolase associates with other key enzymes like glucose-6-phosphate dehydrogenase as part of supramolecular complexes that facilitate substrate channeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, alternative translational initiation produces two isoforms with differential subcellular localizations—one predominantly nuclear and the other cytoplasmic—suggesting functional roles that extend beyond classical carbon flux regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Structural studies have further highlighted the critical importance of residues like Ser171, whose deletion leads to catalytic inactivation by disrupting ligand access, as well as other key active site features that underpin its enzymatic mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDisruption of TALDO1 activity—whether by mutation or deficiency—leads to perturbations in pentose phosphate pathway flux, resulting in the accumulation of intermediates (e.g., sedoheptulose and related polyols) and a consequential depletion of NADPH. This redox imbalance can trigger mitochondrial dysfunction, aberrant calcium handling, and increased susceptibility to both spontaneous and oxidative stress-induced apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " Clinically, individuals with TALDO1 deficiency present with a heterogeneous spectrum of multisystem manifestations—including liver failure, dysmorphic features, hematological abnormalities, and immune dysfunction—with diagnostic evaluations often revealing elevated urinary polyols and sugar phosphates."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in inherited metabolic disorders, TALDO1 has emerged as a significant player in cancer and immune regulation. In HER2-amplified breast cancer, TALDO1 supports cell survival following HER2 inhibition by maintaining NADPH levels and thus mitigating oxidative stress—a finding that points to its potential as a synthetic lethal target for combination therapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In addition, genetic variations in TALDO1 have been linked with squamous cell carcinoma of the head and neck"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", while aberrant processing by granzyme B can generate immunogenic fragments that may contribute to autoimmunity, as observed in multiple sclerosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, TALDO1 activity influences measurements of gluconeogenesis, underscoring its broader impact on metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Craig E Grossman, Yueming Qian, Katalin Banki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF143 mediates basal and tissue-specific expression of human transaldolase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M307039200"}], "href": "https://doi.org/10.1074/jbc.M307039200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14702349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14702349"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ji-Biao Huang, Jimmy Espinoza, Roberto Romero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase is part of a supramolecular complex containing glucose-6-phosphate dehydrogenase in human neutrophils that undergoes retrograde trafficking during pregnancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Metabolism (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.metabol.2005.03.005"}], "href": "https://doi.org/10.1016/j.metabol.2005.03.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16092052"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16092052"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tetsuji Moriyama, Shu Tanaka, Yasumune Nakayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two isoforms of TALDO1 generated by alternative translational initiation show differential nucleocytoplasmic distribution to regulate the global metabolic network."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep34648"}], "href": "https://doi.org/10.1038/srep34648"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27703206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27703206"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Michael Silberstein, Melissa R Landon, Yaoyu E Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Computational methods for functional site identification suggest a substrate access channel in transaldolase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genome Inform (2006)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17503352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17503352"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sarah Schneider, Tatyana Sandalova, Gunter Schneider, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Replacement of a phenylalanine by a tyrosine in the active site confers fructose-6-phosphate aldolase activity to the transaldolase of Escherichia coli and human origin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M803184200"}], "href": "https://doi.org/10.1074/jbc.M803184200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18687684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18687684"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Vassili Valayannopoulos, Nanda M Verhoeven, Karine Mention, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pediatr (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jpeds.2006.08.016"}], "href": "https://doi.org/10.1016/j.jpeds.2006.08.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17095351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17095351"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "M M Wamelink, D E Smith, E E Jansen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Detection of transaldolase deficiency by quantification of novel seven-carbon chain carbohydrate biomarkers in urine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10545-007-0590-2"}], "href": "https://doi.org/10.1007/s10545-007-0590-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17603756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17603756"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mirjam M Wamelink, Eduard A Struys, Gajja S Salomons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase deficiency in a two-year-old boy with cirrhosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2008.01.011"}], "href": "https://doi.org/10.1016/j.ymgme.2008.01.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18331807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18331807"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Udo F H Engelke, Fokje S M Zijlstra, Fanny Mochel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2010.06.007"}], "href": "https://doi.org/10.1016/j.bbadis.2010.06.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20600873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20600873"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Aisha M Al-Shamsi, Salma Ben-Salem, Jozef Hertecant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pediatr (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00431-014-2449-5"}], "href": "https://doi.org/10.1007/s00431-014-2449-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25388407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25388407"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Wafaa Eyaid, Talal Al Harbi, Shamsa Anazi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10545-012-9577-8"}], "href": "https://doi.org/10.1007/s10545-012-9577-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23315216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23315216"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yi Ding, Chang Gong, De Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-06651-x"}], "href": "https://doi.org/10.1038/s41467-018-06651-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30323337"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30323337"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Patricia V Basta, Jeannette T Bensen, Chiu-Kit Tse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic variation in Transaldolase 1 and risk of squamous cell carcinoma of the head and neck."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Detect Prev (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cdp.2008.08.008"}], "href": "https://doi.org/10.1016/j.cdp.2008.08.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18805652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18805652"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yueming Qian, Sanjay Banerjee, Craig E Grossman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20080722"}], "href": "https://doi.org/10.1042/BJ20080722"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18498245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18498245"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Brian Niland, Gabriella Miklossy, Katalin Banki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0804174"}], "href": "https://doi.org/10.4049/jimmunol.0804174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20194725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20194725"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Rita Basu, Cristina Barosa, Ananda Basu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transaldolase exchange and its effects on measurements of gluconeogenesis in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Endocrinol Metab (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpendo.00403.2010"}], "href": "https://doi.org/10.1152/ajpendo.00403.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21062960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21062960"}]}]}]}