Trehalose-6-phosphate phosphatase (TPP)

Trehalose-6-phosphate phosphatase (TPP) is a critical enzyme in the trehalose biosynthesis pathway, responsible for the dephosphorylation of trehalose-6-phosphate (T6P) to produce trehalose [1, 4]. This enzyme is essential for the survival, virulence, and stress adaptation of various pathogenic bacteria (e.g., Mycobacterium tuberculosis), fungi (e.g., Candida albicans), and parasitic nematodes, but is notably absent in humans and other vertebrates [1, 7, 17]. Inhibition of TPP is particularly lethal to pathogens because it not only depletes trehalose—a vital osmoprotectant and cell wall component—but also leads to the toxic accumulation of its substrate, T6P, which acts as a metabolic poison [4, 17]. Consequently, TPP is a highly attractive target for the development of novel, narrow-spectrum antimicrobial, antifungal, and anthelmintic agents with potentially low host toxicity [8, 11]. Current research focuses on developing small-molecule inhibitors, such as substrate analogs and aryl glucoside sulfates, to disrupt this metabolic node and combat drug-resistant infections [3, 6]. Despite its promise, therapeutic challenges include ensuring high specificity over other human enzymes in the haloacid dehalogenase (HAD) superfamily and achieving effective delivery to intracellular pathogens [11, 15].

Other names

OtsBOtsB2Tps2Trehalose-phosphataseTrehalose-6-phosphate phosphohydrolaseT6PP

Inhibition of trehalose-6-phosphate phosphatase leads to the depletion of trehalose and the toxic accumulation of trehalose-6-phosphate, resulting in pathogen cell death.