A Summary of Pirin

A Summary of Pirin

I am not, as might become evidently clear a few sentences from now, a biologist. It is not my field of study and much of the nomenclature and visualizations go over my head. I am, however, extraordinarily fascinated by the field, and would be enthralled to be able to apply my mathematical and computational abilities to the area eventually. All this to say: I am still learning; a lot of the information in the databases I accessed were very heady for my understanding of biology, but hopefully I can manage to put together at least a few coherent strings of text with the help of the advanced biochemical technique known as “Right-click; search for definition”. 

On the most basic level Pirin is a nuclear protein encoded by the PIR gene (Wendler, Kremmer, Foerster, et al., 1997). That's all well and good, but what is the function of pirin? The answer to that question is, at the time, not so cut and dry. We currently know that Pirin, most likely, functions as an oxidative stress sensor, meaning that the protein is able to sense when the amount of free radicals in a cell has began to become dangerously large in proportion to antioxidants, which would cause the cell to become extremely reactive, probably leading that cell to a violent death (Perez-Dominguez, Carrillo-Beltrán, Blanco, et al., 2021). However, various experiments using E. Coli expression systems have suggested several other functions of pirin (Pang, Bartlam, Zang, et al., 2004).¹

One of these suggested functions of pirin is that of a transcription coregulator for the NF-κB protein complex via its function as an oxidative stress sensor. (Liu, Rehmani, Esaki, et al., 2013). If this assertion is correct, it would mean that pirin’s interaction with NF-κB is necessary for the activation and/or repression of  transcription of the genetic information that NF-κB is responsible for. The RNA encoding that results from NF-κB transcription is extraordinarily important for the proper regulation of the immune system and cellular growth (Beinke, Robinson, Hugunin, 2004). Specifically, pirin’s property as a transcription coregulator has been linked to myeloid hemopoiesis (The growth of of hematopoietic stem cells in bone marrow) (Licciuli, Cambiaghi, Scafetta, et al., 2010) and the regulation of cancer cell proliferation of breast cancer (Suleman, Chen, Ma, et al., 2019). Conversely, when pirin is displaced from the nucleus and into the cytoplasm in high proportions it has been linked with the progression of melanoma, cervical cancer, and several other cancers, though the mechanisms by which this occurs are still speculative (Licciulli, Luise, Zanardi, 2010) (Perez-Dominguez, Carrillo-Beltrán, Blanco, et al., 2021) . Furthermore, pirin has been noted to have the enzymatic activity of the oxidoreductase quercetin 2,3-dioxygenase, which allows pirin to interact with NF-κB  (Adams & Jia, 2005). Pirin has also been linked to programmed cell death; its role as an oxidative stress sensor might allow high concentrations of pirin in pancreatic cells to mitigate cellular death caused by a form of autophagy-induced cell death known as ferroptosis.² Likewise, a lack of pirin in pancreatic cells should, theoretically, result in more cell death via ferroptosis, thus providing possible future use in cancer treatment (Hu, Bai, Dai, et al., 2020).

Pirin forms a ligand attached to nonheme iron cations³ at its N-terminus (Pang, Bartlam, Zang, et al., 2004).; this iron-binding behavior is extremely important, as research has shown that ferrous iron is the only tested metal that properly functions as a pirin cofactor, without which pirin cannot conduct any of its enzymatic activity or its function as an oxidative stress sensor (Liu, Rehmani, Esaki, et al., 2013). The secondary structure of pirin is composed of beta sheets, which form its tertiary structure by coiling into two sets of beta-barrels (Pang, Bartlam, Zang, et al., 2004).

Footnotes

[1] I performed some moderate research on the use of expression systems in biological research and found the topic profoundly interesting. I might try to write more about this topic at a later date.

[2] Ferroptosis occurs when highly oxidative cells begin to convert fatty acids into far too much hydrogen peroxide.

[3]  Fe(II).

References

Adams M, Jia Z. Structural and biochemical analysis reveal pirins to possess
quercetinase activity. J Biol Chem. 2005 Aug 5;280(31):28675-82. doi:
10.1074/jbc.M501034200. Epub 2005 Jun 11. PMID: 15951572.

Beinke S, Robinson MJ, Hugunin M, Ley SC. Lipopolysaccharide activation of the
TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein
kinase cascade is regulated by IkappaB kinase-induced proteolysis of
NF-kappaB1 p105. Mol Cell Biol. 2004 Nov;24(21):9658-67. doi:
10.1128/MCB.24.21.9658-9667.2004. PMID: 15485931; PMCID: PMC522219.

Hu N, Bai L, Dai E, Han L, Kang R, Li H, Tang D. Pirin is a nuclear redox-sensitive
modulator of autophagy-dependent ferroptosis. Biochem Biophys Res Commun.
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Licciulli S, Cambiaghi V, Scafetta G, Gruszka AM, Alcalay M. Pirin downregulation is a
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Licciulli S, Luise C, Zanardi A, Giorgetti L, Viale G, Lanfrancone L, Carbone R, Alcalay
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Liu F, Rehmani I, Esaki S, Fu R, Chen L, de Serrano V, Liu A. Pirin is an iron-dependent
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Pang H, Bartlam M, Zeng Q, Miyatake H, Hisano T, Miki K, Wong LL, Gao GF, Rao Z.
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Perez-Dominguez F, Carrillo-Beltrán D, Blanco R, Muñoz JP, León-Cruz G,

       Corvalan AH, Urzúa U, Calaf GM, Aguayo F. Role of Pirin, an Oxidative Stress Sensor         

      Protein, in Epithelial Carcinogenesis. Biology (Basel). 2021 Feb 4;10(2):116. doi: 

      0.3390/biology10020116. PMID: 33557375; PMCID: PMC7915911.

Suleman M, Chen A, Ma H, Wen S, Zhao W, Lin D, Wu G, Li Q. PIR promotes
tumorigenesis of breast cancer by upregulating cell cycle activator E2F1. Cell
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Wendler WM, Kremmer E, Förster R, Winnacker EL. Identification of pirin, a novel highly
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