Last update 19 Sep 2024

PITRM1

Last update 19 Sep 2024

Basic Info

Synonyms

hMP1, hPreP, KIAA1104

+ [7]

Introduction

Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing (PubMed:10360838, PubMed:16849325, PubMed:19196155, PubMed:24931469). Has an ATP-independent activity (PubMed:16849325). Specifically cleaves peptides in the range of 5 to 65 residues (PubMed:19196155). Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference (PubMed:10360838, PubMed:19196155, PubMed:24931469). Degrades the transit peptides of mitochondrial proteins after their cleavage (PubMed:19196155). Also degrades other unstructured peptides (PubMed:19196155). It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion (PubMed:16849325, PubMed:24931469, PubMed:26697887). It is a highly efficient protease, at least toward amyloid-beta protein 40 (PubMed:24931469, PubMed:29764912, PubMed:29383861). Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently (PubMed:24931469). It is also able to degrade amyloid-beta protein 42 (PubMed:29764912).

Drugs associated with PITRM1

B05/CD3

Target

CD3 x HLA-A 24 x PITRM1

Mechanism

CD3 modulators [+2]

Active Org.-

Originator Org.

Affimed GmbH

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PITRM1

100 Translational Medicine associated with PITRM1

0 Patents (Medical) associated with PITRM1

211

Literatures (Medical) associated with PITRM1

20 Aug 2024·mSystems

Transcriptome and proteome analyses reveal genes and signaling pathways involved in the response to two insect hormones in the insect-fungal pathogen Hirsutella satumaensis

Article

Author: Zhou, Yeming ; Zou, Xiao ; Qu, Jiaojiao ; Cao, Wei ; Feng, Yongli

ABSTRACT The insect hormones ecdysone (20E) and juvenile hormone III (JH) have been demonstrated to stimulate the secretion of conidia mucilage and pigments in Hirsutella satumaensis . However, the underlying mechanisms remain elusive. Here, comparative transcriptome and proteome analyses were performed to identify the fungal genes and proteins of H. satumaensis that are up- or downregulated in response to insect hormones. A total of 17,407 unigenes and 1,016 proteins in conidia mucilage were identified. The genes involved in response to the hormones were classified into four functional groups: ( 1 ) stress response-related genes that are required for the removal of reactive oxygen species (glutathione synthetase, c7144) and genes involved in the response to osmotic stress in the hemocoel, such as those encoding proteins involved in the G, mTOR, and MAPK signaling pathways ( 2 ); insect hormone metabolic genes, including genes encoding ecdysteroid UDP-glucosyltransferase, ecdysteroid-22-kinase, and a key aldehyde dehydrogenase in a juvenile hormone synthesis pathway ( 3 ); secretory proteins that share homology with those of the host Bombyx mori , including fibrohexamerin, sericin 1, metalloprotease 1 protein, and silk gum protein, which were revealed by the omics data; and ( 4 ) proteins related to amino sugar metabolism and oxidative phosphorylation that were specifically expressed in mucilage in response to 20E and JH, respectively. These findings revealed that H. satumaensis can mount effective responses by modulating the expression of genes involved in the detoxification, adaptation, and evasion of insect hormone-mediated immune responses, providing fresh insights into fungal pathogen-host insect interactions. IMPORTANCE Insect hormones are highly important for the regulation of insect growth, development, and immune system function. Thus, the expansion of entomopathogenic fungi (EPF) could be affected by these hormones when they inhabit the host hemocoel. However, the molecular basis of EPF in response to insect hormones has yet to be determined. Our results revealed that EPF are impacted by 20E and JH, both of which act as signals, as these hormones lead to changes in metabolic pathways of the fungus, thus demonstrating a direct relationship between the fungus and the hormones. Furthermore, adaptive strategies, such as the use of ecdysone-inactivating enzymes and secreted filamentous proteins in H. satumaensis , which strongly resemble those of the host insect, have been discovered, thus illustrating the importance of adaptation to insect hormones for a better understanding of the interaction between insects and EPF.

01 May 2024·Chemico-Biological Interactions

Gelsenicine disrupted the intestinal barrier of Caenorhabditis elegans

Article

Author: Zhu, An ; Wu, Zekai ; Zhang, Jian ; Li, Maodong ; Li, Chutao ; Wu, Yajiao ; Zheng, Lifeng ; Lin, Xiaohuang ; Chen, Li ; Yang, Qiaomei ; Gao, Xinyue ; Chen, Mengting ; Zhang, Youbo ; Hu, Hong ; Chen, Kunqi

Gelsemium elegans Benth. (G. elegans) is a traditional medicinal herb that has anti-inflammatory, analgesic, sedative, and detumescence effects. However, it can also cause intestinal side effects such as abdominal pain and diarrhea. The toxicological mechanisms of gelsenicine are still unclear. The objective of this study was to assess enterotoxicity induced by gelsenicine in the nematodes Caenorhabditis elegans (C. elegans). The nematodes were treated with gelsenicine, and subsequently their growth, development, and locomotion behavior were evaluated. The targets of gelsenicine were predicted using PharmMapper. mRNA-seq was performed to verify the predicted targets. Intestinal permeability, ROS generation, and lipofuscin accumulation were measured. Additionally, the fluorescence intensities of GFP-labeled proteins involved in oxidative stress and unfolded protein response in endoplasmic reticulum (UPR^ER) were quantified. As a result, the treatment of gelsenicine resulted in the inhibition of nematode lifespan, as well as reductions in body length, width, and locomotion behavior. A total of 221 targets were predicted by PharmMapper, and 731 differentially expressed genes were screened out by mRNA-seq. GO and KEGG enrichment analysis revealed involvement in redox process and transmembrane transport. The permeability assay showed leakage of blue dye from the intestinal lumen into the body cavity. Abnormal mRNAs expression of gem-4, hmp-1, fil-2, and pho-1, which regulated intestinal development, absorption and catabolism, transmembrane transport, and apical junctions, was observed. Intestinal lipofuscin and ROS were increased, while sod-2 and isp-1 expressions were decreased. Multiple proteins in SKN-1/DAF-16 pathway were found to bind stably with gelsenicine in a predictive model. There was an up-regulation in the expression of SKN-1:GFP, while the nuclear translocation of DAF-16:GFP exhibited abnormality. The UPR^ER biomarker HSP-4:GFP was down-regulated. In conclusion, the treatment of gelsenicine resulted in the increase of nematode intestinal permeability. The toxicological mechanisms underlying this effect involved the disruption of intestinal barrier integrity, an imbalance between oxidative and antioxidant processes mediated by the SKN-1/DAF-16 pathway, and abnormal unfolded protein reaction.

13 Aug 2023·Journal of Biomolecular Structure and Dynamics

PITRM1 interaction studies with amyloidogenic nonapeptide mutants of familial Alzheimer’s disease

Article

Author: Rajesh Kannan, Rajaretinam ; Wilson Alphonse, Carlton Ranjith ; Nagarajan, Nagasundaram

Amyloid β-protein (ABP) is found to be the major cause for the development of neurodegeneration which leads to Alzheimer's. The Aβ nonapeptide segment, QKLVFFAED (amino acids 15-23) is the highly amyloidogenic central region of Aβ. Familial mutation in Aβ increases the aggregation property of the peptide compared to the Native (Wild) amyloid-beta (Aβ) and these mutations fall on the Aβ nonapeptide segment. The catalytic activity of pitrilysin metallopeptidase 1(PITRM1) with familial mutant Aβ (Flemish, Arctic, Dutch, Italian and Iowa) during interaction is examined using molecular dynamic simulation. The molecular dynamics simulation of PITRM1 and the Aβ nonapeptide segment showed similar RMSD with respect to stability. The active site amino acid (AA) H108, hydrophobic pocket AA residues L111, F123, F124, and L127 and the basic pocket AA residues R888 and H896 showed similar interactions with both wild and familial Aβ. The molecular level interaction between amyloid beta and PITRM1 were similar in the wild and familial mutants except for the Arctic mutant. The hydrophobic interaction was commonly observed between the S1 hydrophobic pocket and the LVFF region, the Arctic mutant showed less hydrogen bond formation consistently when compared to other complexes. This molecular information on catalytic activity suggests that modulating inactive PITRM1 or an increase in expression of PITRM1 can help in eliminating different kinds of familial mutant Aβ in neurodegenerative cells.Communicated by Ramaswamy H. Sarma.

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PITRM1

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