Role of the redox state of the Pirin-bound cofactor on interaction with the master regulators of inflammation and other pathways

Abstract

Persistent cellular stress induced perpetuation and uncontrolled amplification of inflammatory response results in a shift from tissue repair toward collateral damage, significant alterations of tissue functions, and derangements of homeostasis which in turn can lead to a large number of acute and chronic pathological conditions, such as chronic heart failure, atherosclerosis, myocardial infarction, neurodegenerative diseases, diabetes, rheumatoid arthritis, and cancer. Keeping the vital role of balanced inflammation in maintaining tissue integrity in mind, the way to combating inflammatory diseases may be through identification and characterization of mediators of inflammation that can be targeted without hampering normal body function. Pirin (PIR) is a non-heme iron containing protein having two different conformations depending on the oxidation state of the iron. Through exploration of the Pirin interactome and using molecular docking approaches, we identified that the Fe2+-bound Pirin directly interacts with BCL3, NFKBIA, NFIX and SMAD9 with more resemblance to the native binding pose and higher affinity than the Fe3+-bound form. In addition, Pirin appears to have a function in the regulation of inflammation, the transition between the canonical and non-canonical NF-κB pathways, and the remodeling of the actin cytoskeleton. Moreover, Pirin signaling appears to have a critical role in tumor invasion and metastasis, as well as metabolic and neuro-pathological complications. There are regulatory variants in PIR that can influence expression of not only PIR but also other genes, including VEGFD and ACE2. Disparity exists between South Asian and European populations in the frequencies of variant alleles at some of these regulatory loci that may lead to differential occurrence of Pirin-mediated pathogenic conditions.

Novel roles for pirin proteins and a 2-ketoglutarate: ferredoxin oxidoreductase ortholog inBacteroides fragiliscentral metabolism and comparison of metabolic mutants susceptibility to metronidazole and amixicile

“…These findings agree with reports demonstrating a role for pirin in the control of TCA cycle switching to fermentation metabolism or to aerobic respiration in aerobic and facultatively anaerobic bacteria (Soo et al, 2007; Hansen et al, 2012; Tala et al, 2018; Young et al, 2023). It remains to be defined if B. fragilis pirins undergo Fe(II) to Fe(III) redox changes during oxygen exposure or iron-limiting conditions to modulate protein-protein interactions and conformational dynamics (Ahsan et al, 2023); Barman & Hamelberg, 2016; Liu et al, 2013). It is in the pirin active Fe(III)-form, but not in the inactive Fe(II)-form that human pirin coordinates binding to and regulates the nuclear factor NF-κB function (Liu et al, 2013).…”