Abstract
Glucose is a fundamental energy source for both prokaryotes and eukaryotes. The balance between glucose utilization and storage is integral for proper energy homeostasis, and defects are associated with several diseases, e.g. type II diabetes. In vertebrates, the transcription factor ChREBP is a major component in glucose metabolism, while its ortholog MondoA is involved in glucose uptake. Both MondoA and ChREBP contain five Mondo conserved regions (MCRI-V) that affect their cellular localization and transactivation ability. While phosphorylation has been shown to affect ChREBP function, the mechanisms controlling glucose response of both ChREBP and MondoA remain elusive. By incorporating sequence analysis techniques, structure predictions, and functional annotations, we synthesized data surrounding Mondo family proteins into a cohesive, accurate, and general model involving the MCRs and two additional domains that determine ChREBP and MondoA glucose response. Paramount, we identified a conserved motif within the transactivation region of Mondo family proteins and propose that this motif interacts with the phosphorylated form of glucose. In addition, we discovered a putative nuclear receptor box in non-vertebrate Mondo and vertebrate ChREBP sequences that reveals a potentially novel interaction with nuclear receptors. These interactions are likely involved in altering ChREBP and MondoA conformation to form an active complex and induce transcription of genes involved in glucose metabolism and lipogenesis.
Highlights
Glucose is a carbohydrate in the form of a simple sugar that is an important source of energy for both eukaryotes and prokaryotes
MCRI-V, basic Helix-Loop-Helix-Leucine Zipper (bHLHZ), and DCD domains are conserved among Mondo protein sequences
We propose G6P binds to Mondo proteins within the highly conserved Mondo Conserved Region 6 (MCR6) region, which contains an Sx[ST]xx[ST] motif similar to that found in glucose phosphate isomerase (GPI) and Gfat1
Summary
Glucose is a carbohydrate in the form of a simple sugar that is an important source of energy for both eukaryotes and prokaryotes. SREBF1 and ChREBP promote glucose storage in mammals. The liver is the primary organ that controls energy homeostasis by processing glucose for energy or storage. The liver produces glucose via de novo synthesis (gluconeogenesis) or decomposition of glycogen (glycogeneolysis). Glucose can be converted to pyruvate through glycolysis and subsequently enter the citric acid (TCA) cycle within mitochondria to produce energy. When excess carbohydrates are consumed, glucose can be stored according to two major pathways. Insulin induced enzymes trigger the glycogen synthase pathway to store glucose as glycogen. Glucose can be converted to triglycerides through the de novo lipogenesis pathway for a more compact form of storage. Triglycerides within the liver can be further packaged into lipoproteins (i.e. VLDL, LDL, HDL) and transported into the blood stream and other tissues
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