Histidinol-phosphate phosphatase (HPP)

Histidinol-phosphate phosphatase (EC 3.1.3.15) is an enzyme that catalyzes the ninth step of the histidine biosynthesis pathway, specifically the dephosphorylation of L-histidinol phosphate to L-histidinol (UniProt: P00815). This enzyme is essential for the survival of various bacteria, fungi, and plants, but it is absent in humans, who lack the entire histidine biosynthetic machinery and must obtain the amino acid through diet (PMID: 25613578). Consequently, it is a highly regarded target for the development of novel antibiotics, antifungals, and herbicides, as its inhibition leads to histidine auxotrophy and the cessation of protein synthesis (PMID: 15907911). In some organisms like Escherichia coli, the phosphatase activity is part of a bifunctional enzyme (HisB) that also possesses imidazoleglycerol-phosphate dehydratase activity, whereas in others like Saccharomyces cerevisiae, it is a monofunctional protein (PMID: 2185415). While no drugs targeting this enzyme are currently FDA-approved, research has identified several experimental inhibitors, including substrate analogs and metal-binding compounds, particularly for treating infections like tuberculosis (PMID: 25613578). A significant challenge in targeting this enzyme is the potential for pathogens to bypass the block by scavenging histidine from the host environment (PMID: 10931331).

Other names

L-histidinol-phosphate phosphohydrolaseHIS2HisBHistidinol-phosphatase

Inhibition of the histidine biosynthetic pathway, leading to histidine auxotrophy and cessation of protein synthesis and microbial growth.