LNPEP

更新于：2025-01-23

基本信息

别名

angiotensin IV receptor、CAP、cystinyl aminopeptidase

+ [13]

简介

Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.

关联

100 项与 LNPEP 相关的临床结果

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100 项与 LNPEP 相关的转化医学

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0 项与 LNPEP 相关的专利（医药）

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658

项与 LNPEP 相关的文献（医药）

2024-12-01·Alzheimer's & Dementia

Unveiling Proteomic Signatures of Tau Pathogenesis through Label‐Free Mass Spectrometry Analysis

Article

作者: Ikonomovic, Milos D ; Paljug, William R ; Sehrawat, Anuradha ; Karikari, Thomas K ; Abrahamson, Eric E ; Chen, Yijun ; Zeng, Xuemei ; Kofler, Julia

AbstractBackgroundNeurofibrillary tangles (NFT), consisting of hyperphosphorylated tau aggregates, are one of the major pathological hallmarks of Alzheimer’s disease (AD). The burden of NFTs correlates with cognitive decline, and in vivo detection of NFT may help predict the clinical progression of AD. Mass spectrometry‐based proteomic analysis of brain regions affected by NFTs holds the potential to unveil the molecular mechanisms underlying tau pathogenesis and uncover novel diagnostic/prognostic biomarkers and therapeutic targets.MethodPost‐mortem frozen samples of inferior temporal and middle frontal cortex were collected from 9 cases with different severity of tau pathology assessed by Braak NFT stage. Proteins were fractionated into three fractions using sequential extraction with lysis buffers with different solubility strengths (TBS, Na2CO3, and Urea), trypsin‐digested, and analyzed using label‐free nano‐flow liquid chromatography‐tandem mass spectrometry (nano LC‐MS/MS). Linear mixed models were employed to assess the significance of proteins showing a differential abundance in tissues with Braak NFT stages 0‐III and IV‐VI or displaying Braak stage‐dependent solubility changes.ResultA total of 64908 peptides originating from 5475 protein groups were identified through the analysis of 18 brain tissue samples. Differential proteomic analysis revealed several proteins with significantly varied abundance in tissues with different severity of tau pathology. The most significant proteins among these include COL25A1, SNRNP70, MDK, ASPRV1, CLMN, DOCK5, HTRA1, LNPEP, SQSTM1 and Aβ peptides. Additionally, a number of proteins exhibited Braak‐stage dependent solubility change; a significant subset of these proteins, including SNRNP70, SNRPGP15, PRPF6, SNRPE, SNRPD1, SNRPB, and SNRPD3, is involved in the spliceosome‐mediated mRNA splicing.ConclusionOur study reveals numerous proteins exhibiting a significant association with tau pathology. These results align well with published findings that suggest the involvement of alternative splicing in reprogramming gene expression in the pathogenesis of AD. Further validation will be needed to assess their potential as therapeutic targets and/or diagnostic/prognostic biomarkers for AD pathologies.

2024-11-01·Autophagy

Signal-Sustained Imaging of Mitophagy with an Enzyme-Activatable Metabolic Lipid Labeling Probe

Article

作者: Wang, Xunxiang ; Han, Jiahuai ; Han, Shoufa ; Zou, Xiaoxue ; Xu, Lichun ; Gao, Lei ; Wen, Shixiong ; Hu, Xiao

Imaging of mitophagy is of significance as aberrant mitophagy is engaged in multiple diseases. Mitophagy has been imaged with synthetic or biotic pH sensors by reporting pH acidification en route delivery into lysosomes. To circumvent uncertainty of acidity-dependent signals, we herein report an enzyme-activatable probe covalently attached on mitochondrial inner membrane (ECAM) for signal-persist mitophagy imaging. ECAM is operated via ΔΨm-driven accumulation of Mito-proGreen in mitochondria and covalent linking of the trapped probe with azidophospholipids metabolically incorporated into the mitochondrial inner membrane. Upon mitophagy, ECAM is delivered into lysosomes and hydrolyzed by LNPEP/leucyl aminopeptidase, yielding turn-on green fluorescence that is immune to lysosomal acidity changes and stably retained in fixed cells. With ECAM, phorbol-12-myristate-13-acetate (PMA) was identified as a highly potent inducer of mitophagy. Overcoming signal susceptibility of pH probes and liability of ΔΨm probes to dissipation from stressed mitochondria, ECAM offers an attractive tool to study mitophagy and mitophagy-inducing therapeutic agents.Abbreviations: Baf-A1, bafilomycin A₁; CCCP, carbonyl cyanide m-chlorophenylhydrazone; DBCO, dibenzocyclooctyne; ECAM, enzyme-activated probe covalently attached on mitochondrial inner membrane; GFP, green fluorescent protein; LAMP2, lysosomal associated membrane protein 2; LNPEP/LAP, leucyl and cystinyl aminopeptidase; PMA, phorbol-12-myristate-13-acetate; ΔΨm, mitochondrial transmembrane potential; RFP, red fluorescent protein; TPP, triphenylphosphonium.

2024-09-01·Protein Science

Stabilization of the open conformation οf insulin‐regulated aminopeptidase by a novel substrate‐selective small‐molecule inhibitor

Article

作者: Hamprecht, Dieter W. ; Georgaki, Galateia ; Stratikos, Efstratios ; Findlay, Alison D. ; Mpakali, Anastasia ; van Endert, Peter ; Foot, Jonathan S. ; Buson, Alberto ; Mauvais, Francois‐Xavier ; Giastas, Petros

AbstractInsulin‐regulated aminopeptidase (IRAP) is an enzyme with important biological functions and the target of drug‐discovery efforts. We combined in silico screening with a medicinal chemistry optimization campaign to discover a nanomolar inhibitor of IRAP based on a pyrazolylpyrimidine scaffold. This compound displays an excellent selectivity profile versus homologous aminopeptidases, and kinetic analysis suggests it utilizes an uncompetitive mechanism of action when inhibiting the cleavage of a typical dipeptidic substrate. Surprisingly, the compound is a poor inhibitor of the processing of the physiological cyclic peptide substrate oxytocin and a 10mer antigenic epitope precursor but displays a biphasic inhibition profile for the trimming of a 9mer antigenic peptide. While the compound reduces IRAP‐dependent cross‐presentation of an 8mer epitope in a cellular assay, it fails to block in vitro trimming of select epitope precursors. To gain insight into the mechanism and basis of this unusual selectivity for this inhibitor, we solved the crystal structure of its complex with IRAP. The structure indicated direct zinc(II) engagement by the pyrazolylpyrimidine scaffold and revealed that the compound binds to an open conformation of the enzyme in a pose that should block the conformational transition to the enzymatically active closed conformation previously observed for other low‐molecular‐weight inhibitors. This compound constitutes the first IRAP inhibitor targeting the active site that utilizes a conformation‐specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements.

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