Lens Crystallin Modifications and Cataract in Transgenic Mice Overexpressing Acylpeptide Hydrolase

Santhoshkumar, Puttur; Xie, Leike; Raju, Murugesan; Reneker, Lixing W.; Sharma, K. Krishna

doi:10.1074/jbc.m113.510677

Cited by 10 publications

(10 citation statements)

References 59 publications

(63 reference statements)

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“…In mammals, APEH acts in coordination with the proteasome to clear cytotoxic denatured proteins from cells (Fujino et al, 2000b; Shimizu et al, 2004; Palmieri et al, 2011) and it has also been described that a truncated form of the enzyme displays endopeptidase activity in bovine and human lenses (Senthilkumar et al, 2001; Santhoshkumar et al, 2014). At present, there is little information about the role of APEH in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…Acylpeptide hydrolase (APEH) is a homomeric tetramer that belongs to the prolyl oligopeptidase family of serine hydrolases ( Rosenblum and Kozarich, 2003 ) and catalyzes the hydrolysis of several peptides that possess an acylated N -terminal amino acid to generate an acylated amino acid and a free N -terminal peptide ( Scaloni et al, 1992 ; Polgar, 2002 ). In mammals, APEH acts in coordination with the proteasome to clear cytotoxic denatured proteins from cells ( Fujino et al, 2000b ; Shimizu et al, 2004 ; Palmieri et al, 2011 ) and it has also been described that a truncated form of the enzyme displays endopeptidase activity in bovine and human lenses ( Senthilkumar et al, 2001 ; Santhoshkumar et al, 2014 ). At present, there is little information about the role of APEH in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

et al. 2017

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Acylpeptide hydrolase (APEH) is a serine hydrolase that displays two catalytic activities, acting both as an exopeptidase toward short N-acylated peptides and as an endopeptidase toward oxidized peptides or proteins. It has been demonstrated that this enzyme can degrade monomers, dimers, and trimers of the Aβ1-40 peptide in the conditioned media of neuroblastoma cells. In a previous report, we showed that the specific inhibition of this enzyme by the organophosphate molecule dichlorvos (DDVP) triggers an enhancement of long-term potentiation in rat hippocampal slices. In this study, we demonstrate that the same effect can be accomplished in vivo by sub-chronic treatment of young rats with a low dose of DDVP (0.1 mg/kg). Besides exhibiting a significant enhancement of LTP, the treated animals also showed improvements in parameters of spatial learning and memory. Interestingly, higher doses of DDVP such as 2 mg/kg did not prove to be beneficial for synaptic plasticity or behavior. Due to the fact that at 2 mg/kg we observed inhibition of both APEH and acetylcholinesterase, we interpret that in order to achieve positive effects on the measured parameters only APEH inhibition should be obtained. The treatment with both DDVP doses produced an increase in the endogenous concentration of Aβ1-40, although this was statistically significant only at the dose of 0.1 mg/kg. We propose that APEH represents an interesting pharmacological target for cognitive enhancement, acting through the modulation of the endogenous concentration of Aβ1-40.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

et al. 2017

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“…Several members of this family, including prolyl oligopeptidase (the POP enzyme, namesake of the family), dipeptidyl peptidase IV, and oligopeptidase B (OPB), are important drug targets for diseases like celiac sprue and diabetes (1)(2)(3)(4). Another member of this family, acylaminoacyl peptidase (AAP), is associated with Alzheimer's disease, cataract formation, and cancer and has been implicated in the DNA damage response (5)(6)(7)(8). Given the immense pharmacological relevance of this family, proper annotation and knowledge of substrate specificity mechanisms used by various members of the family are highly valuable.…”

mentioning

confidence: 99%

Carboxypeptidase in prolyl oligopeptidase family: Unique enzyme activation and substrate-screening mechanisms

Yadav

Goyal

Gaur

et al. 2019

Journal of Biological Chemistry

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Edited by Wolfgang PetiSerine peptidases of the prolyl oligopeptidase (POP) family are of substantial therapeutic importance because of their involvement in diseases such as diabetes, cancer, neurological diseases, and autoimmune disorders. Proper annotation and knowledge of substrate specificity mechanisms in this family are highly valuable. Although endopeptidase, dipeptidyl peptidase, tripeptidyl peptidase, and acylaminoacyl peptidase activities have been reported previously, here we report the first instance of carboxypeptidase activity in a POP family member. We determined the crystal structures of this carboxypeptidase, an S9C subfamily member from Deinococcus radiodurans, in its active and inactive states at 2.3-Å resolution, providing an unprecedented view of assembly and disassembly of the active site mediated by an arginine residue. We observed that this residue is poised to bind substrate in the active structure and disrupts the catalytic triad in the inactive structure. The assembly of the active site is accompanied by the ordering of gating loops, which reduces the effective size of the oligomeric pore. This prevents the entry of larger peptides and constitutes a novel mechanism for substrate screening. Furthermore, we observed structural adaptations that enable its carboxypeptidase activity, with a unique loop and two arginine residues in the active site cavity orienting the peptide substrate for catalysis. Using these structural features, we identified homologs of this enzyme in the POP family and confirmed the presence of carboxypeptidase activity in one of them. In conclusion, we have identified a new type within POP enzymes that exhibits not only unique activity but also a novel substrate-screening mechanism.

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“…Although this post‐translational modification occurs in 50–90 % of eukaryotic proteins and N‐acetylated proteins show higher stability in vivo as compared to their non‐acetylated counterparts, [5–7] the precise function of this process has not been fully understood. APH also displays a peptidase activity on oxidized and glycated proteins, [8,9] it participates in the cellular response to DNA damage, [10] cleaves amyloid β‐peptide, [11,12] while its overexpression results in crystallin degradation facilitating cataract development and it regulates the activity of proteasome [13,14] . Since APH is involved in the protein degradation cycle, its cellular communication with proteasome allows the cell to discard cytotoxic denatured proteins [15] .…”

Section: Introductionmentioning

confidence: 99%

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

Sieńczyk

Walczak

Chryplewicz

et al. 2021

Chemistry & Biodiversity

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Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N‐acetylated amino acid residues from proteins and peptides. Although the N‐acylation occurs in 50–90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β‐peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross‐talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down‐regulation of the ubiquitin‐proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1‐aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N‐terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV‐4‐11 tumor cell lines.

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Lens Crystallin Modifications and Cataract in Transgenic Mice Overexpressing Acylpeptide Hydrolase

Cited by 10 publications

References 59 publications

In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

Carboxypeptidase in prolyl oligopeptidase family: Unique enzyme activation and substrate-screening mechanisms

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

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