Tktl1-KO Mouse

Tktl1, or transketolase-like 1, is a key enzyme in the pentose phosphate pathway (PPP), a metabolic pathway crucial for energy synthesis, nucleotide production, and redox balance [2,4,6]. It plays a significant role in various biological processes, especially those related to glucose metabolism. Given its role in metabolism, genetic models such as knockout or over-expression models can be valuable for studying its functions.

In terms of core findings, modern human Tktl1, with a lysine-to-arginine amino acid substitution compared to Neanderthal Tktl1, increases the abundance of basal radial glia (bRG) in the developing neocortex through the pentose phosphate pathway and fatty acid synthesis, suggesting differences in neocortical neurogenesis between modern humans and Neanderthals [1]. In cancer research, TKTL1 knockdown in THP-1 AML cells impairs hypoxia-induced overexpression of glucose-6-phosphate dehydrogenase (G6PD) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and affects metabolic reprogramming under hypoxia [2]. In pancreatic ductal adenocarcinoma, TKTL1 may serve as a prognostic marker in elderly patients and those with advanced disease [3]. In cervical cancer cells, interfering with TKTL1 expression inhibits cell proliferation, invasion, migration, and glycolysis [5].

In conclusion, Tktl1 is essential for metabolic processes, especially those related to the pentose phosphate pathway. Model-based research, such as the use of gene knockout models, has revealed its role in neocortical neurogenesis, as well as its significance in cancer-related metabolic reprogramming, prognosis, and malignant progression. These findings contribute to our understanding of biological development and disease mechanisms, potentially guiding future research and therapeutic strategies in neuroscience and oncology.

References:

1. Pinson, Anneline, Xing, Lei, Namba, Takashi, Pääbo, Svante, Huttner, Wieland B. 2022. Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals. In Science (New York, N.Y.), 377, eabl6422. doi:10.1126/science.abl6422. https://pubmed.ncbi.nlm.nih.gov/36074851/

2. Baptista, Inês, Karakitsou, Effrosyni, Cazier, Jean-Baptiste, Marin, Silvia, Cascante, Marta. 2022. TKTL1 Knockdown Impairs Hypoxia-Induced Glucose-6-phosphate Dehydrogenase and Glyceraldehyde-3-phosphate Dehydrogenase Overexpression. In International journal of molecular sciences, 23, . doi:10.3390/ijms23073574. https://pubmed.ncbi.nlm.nih.gov/35408935/

3. Ahopelto, Kaisa, Saukkonen, Kapo, Hagström, Jaana, Böckelman, Camilla, Haglund, Caj. 2020. TKTL1 as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma and Its Correlation with FDG-PET-CT. In Oncology, 99, 177-185. doi:10.1159/000510862. https://pubmed.ncbi.nlm.nih.gov/33120381/

4. Yuan, Xiaole, Kang, Huaiyan, Liu, Bo, Chen, Shenghui, Du, Xiaomin. . Molecular Characteristics and Expression of TKTL1 in Germ Cells: Implications for Nontumour Cell Research. In Reproduction in domestic animals = Zuchthygiene, 59, e14723. doi:10.1111/rda.14723. https://pubmed.ncbi.nlm.nih.gov/39311634/

5. Zhu, Yingping, Qiu, Yu, Zhang, Xueqin. 2021. TKTL1 participated in malignant progression of cervical cancer cells via regulating AKT signal mediated PFKFB3 and thus regulating glycolysis. In Cancer cell international, 21, 678. doi:10.1186/s12935-021-02383-z. https://pubmed.ncbi.nlm.nih.gov/34922556/

6. Deshpande, Gaurang P, Patterton, Hugh-George, Faadiel Essop, M. 2019. The human transketolase-like proteins TKTL1 and TKTL2 are bona fide transketolases. In BMC structural biology, 19, 2. doi:10.1186/s12900-018-0099-y. https://pubmed.ncbi.nlm.nih.gov/30646877/