Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents

Vistoli, Giulio; Maddis, Danilo De; Straniero, Valentina; Pedretti, Alessandro; Pallavicini, Marco; Valoti, Ermanno; Carini, Marina; Testa, Bernard

doi:10.1016/j.ejmech.2013.05.009

Cited by 16 publications

(15 citation statements)

References 47 publications

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“…These findings are in line with recent studies demonstrating poor quenching activity of carnosine derivatives towards MG [14, 42]. Quenching capacity of carnosine is higher against other reactive metabolites such as acrolein and HNE [14, 40, 41, 43]. Although both, HNE and MG, belong to the group of reactive carbonyl species reacting with the nucleophilic groups in proteins, the two compounds are chemically distinct with both very different reaction kinetics leading to different stable end products.…”

Section: Discussionsupporting

confidence: 81%

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Weigand

Singler

Fleming

et al. 2018

Cell Physiol Biochem

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Background/Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. Methods: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. Results: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. Conclusion: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.

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Section: Discussionsupporting

confidence: 81%

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Weigand

Singler

Fleming

et al. 2018

Cell Physiol Biochem

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“…An in vitro study showed that carnosine and N-acetylcarnosine prevented salsolinol-mediated oxidative modification of the ferritin, reflected as a decrease in ferritin aggregation and inhibition of the carbonyl and dityrosine formation [94]. This latter finding may be substantiated by the antioxidant [20] and carbonyl-scavenger [24] activities assigned to ID, as previously discussed.…”

Section: Parkinson's Disease (Pd)supporting

confidence: 59%

“…Carnosine is the most studied compound in the group of imidazolic dipeptides and presents putative antioxidant [20], bivalent metal ion chelating [21], radioprotective [22], muscular proton buffering [23], and reactive carbonyl scavenger activities [24]. The latter property was also suggested to the D-enantiomer of carnosine [25].…”

Section: Carnosinementioning

confidence: 99%

“…Recent HPLC and computational studies performed by Vistoli and co-workers [24] with 40 ID that are more stable to enzyme hydrolysis revealed that the peptides LLysyl-L-Histidine-OMe and L-Tyrosyl-D-Histidine-OMe showed a carbonyl quenching activity slightly weaker, but significantly more selective than that of carnosine. These peptides may represent promising candidates for the design of improved carnosine derivatives.…”

Section: Other Disturbances Potentially Age-relatedmentioning

confidence: 99%

“…Evidence on quenching mechanism of ID towards α,β-unsatured aldehydes generated by lipid peroxidation (e.g., 4-hydroxy-trans-2-nonenal and acrolein) suggests that it occurs through a multi-step mechanisms, including: i) the formation of a reversible imine intermediate; ii) a key intramolecular Michael addiction between the histidinic imidazole ring and the acceptor β-carbon atom; and (iii) the hydrolysis of the imine group to give a final hemiacetal adduct (for more details, see reference 24). This was demonstrated in vitro through the reaction of carnosine and homocarnosine with acrolein, with further characterization of the formed adducts [54].…”

Section: Id and Aging: General Mechanismsmentioning

confidence: 99%

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Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders

Cararo¹,

Streck²,

Schuck³

et al. 2015

Aging and disease

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Imidazole dipeptides (ID), such as carnosine (β-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders.

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Small Molecules as Exemplars of Emergent Properties and Diversification into the ‘Adjacent Possible’

Testa¹,

Vistoli²,

Pedretti³

2014

Chemistry & Biodiversity

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Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents

Cited by 16 publications

References 47 publications

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders

Small Molecules as Exemplars of Emergent Properties and Diversification into the ‘Adjacent Possible’

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