Inhibition of growth by imadazol(on)e propionic acid: Evidence in vivo for coordination of histidine catabolism with the catabolism of other amino acids

Abstract

Imidazole propionic acid (ipa), a gratuitous inducer of the histidine-utilization (hut) system in Salmonella typhimurium, inhibits the organism's growth on succinate minimal medium. Induction of the hut system is necessary, but not sufficient, to cause inhibition. A study of the ability of single amino acids to relieve ipa-restricted growth suggests that insufficient glutamate is the cause of slow growth. The inhibition of growth by imidazolone propionic acid (iopa), an intermediate in the catabolism of histidine to glutamate, is similar to that by ipa. Studies using 2, 3, 5-triphenyl tetrazolium chloride plates to examine amino acid catabolism suggest that accumulation of ipa or iopa leads to inactivation of aspartate amino-transferase (AAT). This interpretation is supported by studies of an Escherichia coli mutant lacking AAT. The mutant grows poorly on succinate minimal medium, and the poor growth is relieved by the same amino acids that relieve ipa- and iopa-restricted growth. These and other findings are discussed in terms of coordination of the histidine-utilization system with enzymatic activities involved in the catabolism of other amino acids.

Regulation of the Histidine Utilization (Hut) System in Bacteria

“…That would be consistent with the observation that either a very high concentration of exogenous histidine (48) or a large amount of histidase and urocanase activity (14) is required for histidine to inhibit growth effectively. It has also been suggested that both imidazole propionate and IP or products derived in vivo from them may somehow interfere with the aspartate aminotransferase of Salmonella enterica and that this might explain the toxicity of IP (12). However, neither imidazole propionate nor IP inhibits aspartate aminotransferase in vitro (12), so a mechanism for this effect remains unclear.…”

“…It has also been suggested that both imidazole propionate and IP or products derived in vivo from them may somehow interfere with the aspartate aminotransferase of Salmonella enterica and that this might explain the toxicity of IP (12). However, neither imidazole propionate nor IP inhibits aspartate aminotransferase in vitro (12), so a mechanism for this effect remains unclear. In any event, it is clear that accumulation of intermediates of the Hut pathway, their analogs, or their metabolites can have deleterious effects on growth.…”

Crystal structure of a bicupin protein HutD involved in histidine utilization in Pseudomonas

“…All of the available intermediates of the pathway were tested, including histidine, urocanate, FIGLU, FG, formate and glutamate. IP was not tested as it is both unavailable commercially and highly unstable …”

“…Taken together, our DSF and docking analyses suggest that FG is potentially a biologically relevant ligand of PfluHutD. From the perspective of Hut regulation, the prediction that FG binds to HutD is compatible with the role of HutD as a governor protein limiting Hut pathway over‐expression: FG is the last intermediate in the degradation pathway, and stands to be the most information‐rich signal of danger arising from over‐activation of Hut and the resulting harmful effects of surplus of toxic pathway intermediates, in particular ammonia and IP . However, despite considerable efforts involving both co‐crystallization and soaking experiments, we did not observe FG (or any soaked ligand) in any of the structures determined.…”

The origin and ecological significance of multiple branches for histidine utilization in Pseudomonas aeruginosa PAO1

“…All available intermediates of the hut pathway were tested, including histidine, urocanate, FIGLU and formylglutamate. It was not possible to test imidazolone propionate as it is both unstable (Bochner and Savageau, 1979) and unavailable commercially. Histidine, urocanate and FIGLU all induced expression from the P hutR promoter, by approximately 30‐fold (Fig.…”