PIF

Last update 08 May 2025

Basic Info

Synonyms

AIDD, DCD, DCD-1

+ [6]

Introduction

Found in sweat, has an antimicrobial activity during early bacterial colonization (PubMed:11694882, PubMed:23426625). The secreted peptide assembles into homohexameric complexes that can associate with and also insert into pathogen membranes (PubMed:23426625). Once inserted in bacteria membranes forms anion channels probably altering the transmembrane potential essential for bacterial survival (PubMed:23426625). Highly effective against E.coli, E.faecalis, S.aureus and C.albicans (PubMed:11694882). Optimal pH and salt concentration resemble the conditions in sweat (PubMed:11694882). Also exhibits proteolytic activity, cleaving on the C-terminal side of Arg and, to a lesser extent, Lys residues (PubMed:17448443). Promotes survival of neurons and displays phosphatase activity (PubMed:9736629). It may bind IgG (PubMed:9736629).

100 Clinical Results associated with PIF

100 Translational Medicine associated with PIF

0 Patents (Medical) associated with PIF

928

Literatures (Medical) associated with PIF

24 Apr 2025·Blood

Targeting Enterobacter cloacae attenuates osteolysis by reducing ammonium in multiple myeloma

Article

Author: Xu, Yajing ; An, Gang ; Jian, Xingxing ; Zhou, Wen ; Qiu, Yi ; Abudumijiti, Huerxidan ; Yang, Qin ; Li, Xin ; Chen, Xun ; Hu, Cong ; Liu, Jing ; Huang, Siqing ; He, Yanjuan ; Zhao, Lia ; Feng, Xiangling ; Zhu, Yan ; Qiu, Lugui ; Zhu, Yinghong ; Guo, Jiaojiao ; He, Nihan

AbstractMultiple myeloma (MM)-induced bone disease affects not only patients’ quality of life but also their overall survival. Our previous work demonstrated that the gut microbiome plays a crucial role in MM progression and drug resistance. However, the role of altered gut microbiota in MM bone disease remains unclear. In this study, we show that intestinal Enterobacter cloacae is significantly enriched in patients with MM with osteolysis. Through fecal microbial transplantation and single bacterial colonization experiments in a 5TGM1 MM mouse model, we found that intestinal colonization of E cloacae promotes osteolysis by increasing circulating ammonium levels. Elevated ammonium promotes osteoclastogenesis by increasing Trap protein levels in osteoclast precursors and by acetylating and stabilizing chemokine ligand 3 protein in MM cells. Inhibition of ammonium synthesis, using E cloacae with a deleted dcd gene, along with probiotic supplementation, alleviated osteolysis in MM. Overall, our work suggests that E cloacae promotes osteolysis in MM by synthesizing ammonium. This establishes a novel mechanism and potential intervention strategy for managing MM with osteolysis.

16 Apr 2025·ACS Bio & Med Chem Au

Uncovering the Role of Distal Regions in PDK1 Allosteric Activation

Article

Author: Mulpuri, Nagaraju ; Yao, Xin-Qiu ; Hamelberg, Donald

Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase's ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.

09 Apr 2025·mBio

Noncanonical amino acids as prophage inducers for protein regulation in bacteria-based delivery systems

Article

Author: Lu, Bowen ; Tang, Bing ; Xu, Qi ; Wang, Yuyang ; Qi, Kejing ; Gan, Fei ; Liu, Hongfang ; Wu, Min ; Shen, Sijia

ABSTRACT Genetically engineered bacteria represent a promising drug delivery tool for disease treatment. The development of new strategies for specific and independent protein regulation is necessary, especially for combination protein drug therapy. Using the well-studied Escherichia coli phage λ as a model system, we applied n on c anonical a mino a cid s (ncAAs) as novel inducers for protein regulation in a bacteria-based delivery system. Screening the permissive sites of the Cro protein revealed that incorporation of AlocK at the K8 site with the Mb PylRS-349F/tRNA Pyl system produced a functional Cro-K8AlocK variant. Using an engineered λ lysogen expressing the Mb PylRS-349F/tRNA Pyl pair, Cro-8X, and the reporter mNeonGreen, in vitro and in vivo experiments showed that AlocK led to bacterial lysis through prophage activation and the release of mNeonGreen. If mNeonGreen was integrated into the λ prophage genome, λ phages released due to AlocK induction delivered the reporter gene into the recipient E. coli strain, enabling mNeonGreen expression. Furthermore, insertion of pIF at the F14 site with the Af pIFRS/tRNA Tyr pair produced a functional Cro-F14pIF variant. Importantly, Af pIFRS/tRNA Tyr and Mb PylRS-349F/tRNA Pyl pairs were confirmed to be mutually orthogonal. In a mixture of two engineered λ lysogens expressing different aaRS/tRNAs, Cro-ncAAs, and reporter proteins, AlocK and pIF independently induced bacterial lysis and activated the expression of mNeonGreen and mCherry in the recipient E. coli strain. Collectively, the proposed bacteria-based delivery system provides two options for protein delivery and enables independent regulation of multiple proteins with ncAAs, offering a novel approach for in situ protein regulation and combination therapy. IMPORTANCE The use of genetically engineered bacteria as drug delivery vectors has attracted more and more attention in recent years. A key issue with bacteria-based delivery systems is how to regulate multiple protein drugs. Based on genetic code expansion technology, we developed a new strategy of using ncAAs as small molecular inducers for in situ protein regulation and engineered λ phage lysogen into a bacteria-based delivery system that can function in two delivery modes. Furthermore, this strategy enables independent regulation of multiple proteins by different ncAAs, offering important implications for combination therapy. This approach requires minimal genetic engineering efforts, and similar strategies can be applied to engineer other prophage-bacteria systems or study phage biology. This work expands the therapeutic applications of ncAAs and lysogenic phages.

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