Tktl1-KO Mouse

Tktl1, or transketolase-like 1, is a crucial regulatory enzyme in the pentose phosphate pathway (PPP), playing a significant role in energy synthesis [4]. It is also associated with anaerobic glucose metabolism (Warburg effect) [3]. Three transketolase genes, including Tktl1, have been identified in the human genome, and homology modelling suggests Tktl1 is a functional transketolase, potentially a novel therapeutic target for diabetes and cancer [7].

In modern humans, Tktl1 differs from Neanderthal Tktl1 by a lysine-to-arginine amino acid substitution. Overexpression in developing mouse neocortex and knockout in fetal human neocortical tissue, along with experiments in genome-edited cerebral organoids, show that the modern human variant of Tktl1 increases the abundance of basal radial glia (bRG), which generate more neocortical neurons, suggesting differences in neocortical neurogenesis between modern humans and Neanderthals [1]. In THP-1 AML cells, knockdown of Tktl1 impairs hypoxia-induced overexpression of glucose-6-phosphate dehydrogenase (G6PD) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), affecting the cell's redox capacity and its ability to adapt to hypoxia [2]. In paclitaxel-resistant human ovarian cancer cells, inhibition of Tktl1 re-sensitizes the cells to paclitaxel, reducing cellular proliferation and increasing apoptosis [5]. In cervical cancer cells, interference of Tktl1 expression inhibits cell proliferation, invasion, migration, and glycolysis [6].

In summary, Tktl1 is essential in the pentose phosphate pathway and glucose metabolism. Studies using gene knockout and knockdown models have revealed its role in various biological processes such as neurogenesis, cell response to hypoxia, and cancer cell behavior, highlighting its significance in understanding human evolution and treating cancer.