Regulation of Urease for Acid Habitation

Excerpt

H. pylori shows a remarkable acid-resistance response to the gastric environment by a specialized means of utilizing an intracellular, neutral pH optimum urease. Within the urease gene cluster it has a gene encoding an acid-activated urea channel, UreI. Instead of an acidic pH optimum urease suitable only for passage through the stomach, it has a neutral pH optimum urease that allows the cytoplasm to remain relatively neutral while the organism protects itself against acid by enhancing urea access to intrabacterial urease via Urel and achieving buffering of the periplasm. This maintains an adequate PMF for survival and for growth in an otherwise damaging environment.

There are undoubtedly other subtleties involved in the regulation of urease activity inside the organism as well as the NH₃ efflux across the inner membrane to buffer the periplasm. For example, at low rates of intrabacterial urease activity, the NH₃ produced will not result in significant cytoplasmic alkalinization. This is the situation in the absence of acid activation of Urel. However, at a pH where urea transport is fully activated, NH₃ production intracellularly probably increases by more than two orders of magnitude. This rapid production of NH₃ could alkalinize the cytoplasm even in the presence of NH₃ efflux through a bilayer with permeability of 10⁻¹ cm s⁻¹. However, if NH₃ efflux were enabled through the urea channel, the combination of NH₃ efflux across the bilayer and through UreI could maintain intrabacterial pH near neutrality in the face of high intrabacterial urease activity. Further, as soon as the periplasmic pH reaches 6.5, urea entry is switched off, thus inactivating intra-cellular urease.

It would seem possible that this mechanism of H. pylori adaptation to life in the human stomach may form the basis for methods designed to eradicate the organism. Presumably, drugs could be developed targeting the periplasmic domain of UreI and preventing acid activation of urea transport. If the bacterium is exposed, even for a short time, to a pH of less than 4.0, interference with urea uptake at these acidic pH values could prove lethal to the organism.