Hydrogenase nickel incorporation protein HypB (HypB)

Hydrogenase nickel incorporation protein HypB is a prokaryotic metallochaperone and GTPase essential for the maturation of [NiFe]-hydrogenases and, in specific pathogens like Helicobacter pylori, the nickel-dependent enzyme urease (PubMed: 24389922). The protein functions by sequestering nickel ions and facilitating their insertion into hydrogenase precursors, a process that is energetically driven by GTP binding and hydrolysis at its conserved G-domain (UniProt: O31139). In the human stomach, these nickel-containing enzymes are vital for bacterial survival, as urease neutralizes gastric acid and hydrogenase supports energy metabolism during colonization. Bismuth-based therapeutic agents, such as bismuth subcitrate, are known to target HypB by having bismuth ions (Bi3+) displace nickel at the protein's high-affinity binding sites (Chem Commun: 2014, 50, 1611-1614). This displacement induces abnormal protein oligomerization and inhibits the GTPase cycle, effectively starving the pathogen of functional nickel enzymes and leading to bacterial eradication. Because HypB lacks a human ortholog, it serves as a highly selective target for antimicrobial drug development, particularly in the context of antibiotic-resistant infections. Current clinical applications involve bismuth-containing quadruple therapies to manage persistent gastric infections and prevent downstream complications like peptic ulcers and gastric cancer (MDPI: 2014, 7, 452-473).

Other names

Nickel-binding protein HypBHydrogenase accessory protein HypBGTP-binding protein HypBHydrogenase-expression protein HypBNi-dependent GTPase HypB

Bismuth ions (Bi3+) act as competitive inhibitors by binding to the conserved nickel-binding site of HypB with high affinity, subsequently inducing protein oligomerization and dysfunction of the GTPase activity required for nickel delivery to hydrogenases.