Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

Udechukwu, M. Chinonye; Tsopmo, Apollinaire; Mawhinney, Hannah; He, Rong; Kienesberger, Petra C.; Udenigwe, Chibuike C.

doi:10.1039/c6ra26678a

Cited by 23 publications

(15 citation statements)

References 49 publications

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“…A recent study on rye secalin‐derived tripeptides (QCA and CQV) and its analogues (QVC and QCV) showed the dose‐dependent inhibition of “A disintegrin and metalloproteinase 17” (ADAM17) or TNF‐α converting enzyme (TACE) (Udechukwu et al, ). This catalytic inhibition of ADAM17 was zinc‐chelation dependent as shown by the cysteine‐containing tripeptides which interacted with the zinc cofactor.…”

Section: Anti‐inflammatory Peptides and Structural Requirementsmentioning

confidence: 99%

“…Furthermore, CQV showed better quenching than its analogues QVC and QCV, despite structural similarities which suggested that the relative amino acid position played an essential role in facilitating the interaction with the enzyme as different peptides would be positioned differently on the enzyme. Molecular docking experiments showed that the peptides interacted with the active site through a series of hydrogen bonds, zinc coordination, and hydrophobic interactions and primarily occupied the S1 and S1′ sites of the enzyme (Udechukwu et al, ).…”

Section: Anti‐inflammatory Peptides and Structural Requirementsmentioning

confidence: 99%

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Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review

2018

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Chronic inflammatory conditions such as obesity, type-2 diabetes, and cardiovascular diseases are the leading causes of mortality worldwide. Hence, much research interest in bioactive peptides has been stimulated due to lack of potent pharmacological interventions. Although many such peptides have been identified from food proteins, insufficient information is available on their structurefunction relationship. Presence of hydrophobic and positively charged amino acids is a common occurrence for the peptides with anti-inflammatory properties. However, inconsistent findings have also been reported. Most of the food-derived peptides exhibited their anti-inflammatory activities primarily by inhibiting signaling components of either NF-jB or MAPK pathway, which are the two major pathways involved in chronic inflammation following uncontrolled signal activation. This review highlighted the structural requirements of the peptides to exhibit antiinflammatory activity based on the current knowledge about food-derived anti-inflammatory peptides and their underlying molecular mechanisms of action. Practical applicationsWhile research in the food-derived bioactive peptide is gaining momentum, but the ability to translate these new findings into the commercial product such as nutraceuticals and functional foods, remains delayed. The most prominent reasons for this delay are the lack of detailed research on, (i) the structure-function relationship of the peptide and the underlying molecular mechanisms of these bioactive peptides, and (ii) the interaction of these peptides with different cellular elements in the disease pathophysiology. This review gives an insight into the structure-activity relationship of bioactive peptides involved in anti-inflammatory responses. The information provided here would be highly beneficial to describe the possible anti-inflammatory activity of any newly identified peptides from different food sources. K E Y W O R D Santi-inflammation, bioactive peptides, food proteins, inflammatory responses, structure-function relationships

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Section: Anti‐inflammatory Peptides and Structural Requirementsmentioning

confidence: 99%

Section: Anti‐inflammatory Peptides and Structural Requirementsmentioning

confidence: 99%

Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review

2018

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“…Although this may seem paradoxical comparison with the results obtained by Madrigal and colleagues (2002) in the cortex, it is likely that the hippocampus undergoes a constrained increase in secreted Tnf-α at the protein level via increased TACE-induced cleavage of pro-Tnf protein already present in the cytosol, and changes at the mRNA level may occur earlier than the time-points examined in the present study ( Madrigal et al, 2002 ; Gooz, 2010 ). Cleavage of pro-Tnf may be facilitated by increased zinc availability, as it has been shown previously that TACE is a zinc-dependent metalloprotease and its catalytic activity can be inhibited by zinc chelating agents ( Moss et al, 2001 ; Udechukwu et al, 2017 ). In this study, we demonstrated that exposure to 60 minutes of restraint stress increased expression of the zinc transporter (Zip14) in the dorsal hippocampus of vehicle-treated animals, an effect that was ameliorated by PF-3845 treatment.…”

Section: Discussionmentioning

confidence: 93%

Inhibition of Fatty Acid Amide Hydrolase by PF-3845 Alleviates the Nitrergic and Proinflammatory Response in Rat Hippocampus Following Acute Stress

Chen

Spiers

Sernia

et al. 2018

International Journal of Neuropsychopharmacology

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BackgroundLong-term exposure to stress has been demonstrated to cause neuroinflammation through a sustained overproduction of free radicals, including nitric oxide, via an increased inducible nitric oxide synthase activity. We previously demonstrated that inducible nitric oxide synthase activity and mRNA are significantly upregulated in the rat hippocampus following just 4 hours of restraint stress. Similar to nitric oxide, endocannabinoids are synthesized on demand, with preclinical observations suggesting that cannabinoid receptor agonists and endocannabinoid enhancers inhibit nitrergic activity. Specifically, previous work has shown that enhancement of endocannabinoids via inhibition of fatty acid amide hydrolase with PF-3845 reduced inducible nitric oxide synthase-expressing microglia following traumatic brain injury. However, this describes cannabinoid modulation following physical injury, and therefore the present study aimed to examine the effects of PF-3845 in the modulation of nitrergic and inflammatory-related genes within the hippocampus after acute stress exposure.MethodsFollowing vehicle or PF-3845 injections (5 mg/kg; i.p.), male Wistar rats were exposed to 0 (control), 60, 240, or 360 minutes of restraint stress after which plasma and dorsal hippocampus were isolated for further biochemical and gene expression analysis.ResultsThe results demonstrate that pretreatment with PF-3845 rapidly ameliorates plasma corticosterone release at 60 minutes of stress. An increase in endocannabinoid signalling also induces an overall attenuation in inducible nitric oxide synthase, tumor necrosis factor-alpha convertase, interleukin-6, cyclooxygenase-2, peroxisome proliferator-activated receptor gamma mRNA, and the transactivation potential of nuclear factor kappa-light-chain-enhancer of activated B cells in the hippocampus.ConclusionsThese results suggest that enhanced endocannabinoid levels in the dorsal hippocampus have an overall antinitrosative and antiinflammatory effect following acute stress exposure.

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“…For example, 4-(2-pyridylazo) resorcinol and free Zn 2+ form a red-colored complex whose absorbance can be measured at 500 nm. This approach was used to determine the zinc-chelating capacity of whey protein hydrolysates [ 24 ] and rye secalin-derived tripeptides and their analogues [ 33 ]. Furthermore, the ethylenediaminetetraacetic acid (EDTA) complexing titration assay, involving the addition of xylenol orange and hexamethylenetetramine, was developed to determine zinc content.…”

Section: Methods For the Determination Of The Mineral-chelating Acmentioning

confidence: 99%

Peptide–Mineral Complexes: Understanding Their Chemical Interactions, Bioavailability, and Potential Application in Mitigating Micronutrient Deficiency

Sun

Sarteshnizi

Boachie

et al. 2020

Foods

Self Cite

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Iron, zinc, and calcium are essential micronutrients that play vital biological roles to maintain human health. Thus, their deficiencies are a public health concern worldwide. Mitigation of these deficiencies involves micronutrient fortification of staple foods, a strategy that can alter the physical and sensory properties of foods. Peptide–mineral complexes have been identified as promising alternatives for mineral-fortified functional foods or mineral supplements. This review outlines some of the methods used in the determination of the mineral chelating activities of food protein-derived peptides and the approaches for the preparation, purification and identification of mineral-binding peptides. The structure–activity relationship of mineral-binding peptides and the potential use of peptide–mineral complexes as functional food ingredients to mitigate micronutrient deficiency are discussed in relation to their chemical interactions, solubility, gastrointestinal digestion, absorption, and bioavailability. Finally, insights on the current challenges and future research directions in this area are provided.

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Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

Abstract: Rye secalin-derived cysteine-containing tripeptides and analogues inhibited ADAM17 activity via active site zinc coordination, hydrogen bonds and hydrophobic interactions.

Cited by 23 publications

References 49 publications

Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review

Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review

Inhibition of Fatty Acid Amide Hydrolase by PF-3845 Alleviates the Nitrergic and Proinflammatory Response in Rat Hippocampus Following Acute Stress

Peptide–Mineral Complexes: Understanding Their Chemical Interactions, Bioavailability, and Potential Application in Mitigating Micronutrient Deficiency

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