Studies on Trypsin-modified Bovine and Human Lens Acylpeptide Hydrolase

Senthilkumar, R.; Reddy, P. Neelakanta; Sharma, K. Krishna

doi:10.1006/exer.2000.0955

Cited by 9 publications

(11 citation statements)

References 36 publications

(41 reference statements)

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“…KKS5 and mutant lines did not show cleavage of APH. It is plausible that the 57-kDa APH fragment possesses hydrolytic activity against crystallins, similar to our previous observation made in vitro with a 55-kDa APH fragment (47). In support of this view, we saw an increased accumulation of crystallin fragments in mouse lens expressing active APH even before the development of cataract.…”

Section: Discussionsupporting

confidence: 91%

“…We previously showed that APH is unable to act on intact crystallins and that cleavage of a 22-kDa N-terminal fragment from the APH generates a 55-kDa active enzyme capable of unblocking and hydrolyzing crystallins (45,47). The 55-kDa fragment is also present in human and bovine lenses, in addition to full-length APH (46).…”

Section: Discussionmentioning

confidence: 99%

“…We have demonstrated in earlier studies proteolytic activity in a 55-kDa truncated fragment generated in vitro by trypsin treatment of the APH. The 55-kDa truncated enzyme is also present in bovine and human lenses, and its generation is mediated through proteolytic processing (45)(46)(47). Interestingly, the 55-kDa active fragment generated in vitro unblocked ␣A-crystallin and exhibited ␣A-, ␣B-, and ␤-crystallin hydrolyzing activity (46,47).…”

mentioning

confidence: 99%

“…The 55-kDa truncated enzyme is also present in bovine and human lenses, and its generation is mediated through proteolytic processing (45)(46)(47). Interestingly, the 55-kDa active fragment generated in vitro unblocked ␣A-crystallin and exhibited ␣A-, ␣B-, and ␤-crystallin hydrolyzing activity (46,47). Native APH exhibits endopeptidase activity toward glycated and oxidatively damaged proteins in animal (48) and plant cells (49).…”

mentioning

confidence: 99%

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Lens Crystallin Modifications and Cataract in Transgenic Mice Overexpressing Acylpeptide Hydrolase

Santhoshkumar¹,

Xie

Raju

et al. 2014

Journal of Biological Chemistry

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Background: Acylpeptide hydrolase (APH) in the lens may have an integral role in cataract formation. Results: Transgenic overexpression of APH results in crystallin cleavage, impaired lens development, and cataract. Conclusion: APH may be involved in the generation of peptides that have the potential to induce protein aggregation. Significance: The transgenic APH mouse model could help us understand the role of crystallin fragments in cataractogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Lens Crystallin Modifications and Cataract in Transgenic Mice Overexpressing Acylpeptide Hydrolase

Santhoshkumar¹,

Xie

Raju

et al. 2014

Journal of Biological Chemistry

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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%

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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