Mannose metabolism pathway

The mannose metabolism pathway refers to a sequence of enzymatic reactions involving the transport and conversion of mannose, a simple sugar, within mammalian cells. Mannose enters cells primarily via GLUT glucose transporters and is quickly phosphorylated to mannose-6-phosphate by hexokinase[1][3][5][7][8]. Mannose-6-phosphate is a central metabolic node, being converted by phosphomannose isomerase (MPI) into fructose-6-phosphate (feeding into glycolysis), or by phosphomannomutase (PMM2) into mannose-1-phosphate for the biosynthesis of GDP-mannose and subsequent glycosylation of proteins and lipids[1][3][5][7][8]. Tight regulation ensures proper flux between energy metabolism and the synthesis of glycoconjugates, and genetic or acquired defects in any enzyme can result in severe disease, including congenital disorders of glycosylation and altered cellular responses in cancer and infection[1][2][4][7][8]. The pathway is increasingly studied for its roles in cancer, immunity, infection, and therapy resistance, but is not itself a singular drug target; instead, individual enzymes within the pathway are considered therapeutic targets[4][8].

Inhibition of key enzymes (e.g., MPI inhibition blocks conversion of mannose-6-phosphate to fructose-6-phosphate, altering glycosylation and sensitizing cancer cells to chemotherapy); Modulation of protein glycosylation leading to ER stress, UPR activation, and cell death; Sensitization of cancer cells to apoptosis or ferroptosis (especially in AML and other select cancers); Reduction of pathogenic glycosylation on viral and host proteins (mechanisms under investigation); Inhibition of bacterial adhesion in urinary tract infection, via competitive inhibition at cellular glycan binding sites.