Brain type carnosinase in dementia: a pilot study

Balion, Cynthia; Benson, Carolyn; Raina, Parminder; Παπαϊωάννου, Αλεξάνδρα; Patterson, Christopher; Ismaila, Afisi S

doi:10.1186/1471-2377-7-38

Cited by 24 publications

(15 citation statements)

References 46 publications

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“…In contrast, normal serum carnosinase activity was reported in patients with idiopathic epilepsy and motor neuron disease (Wassif et al 1994). Recently, Balion et al (2007) showed that patients with dementia had significant lower carnosinase activities in serum compared to controls. It remains unclear whether the reduced activities in some patients are disease-related or have an independent cause, for example reduced liver function.…”

Section: Introductionmentioning

confidence: 95%

Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

et al. 2009

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Activity of carnosinase (CN1), the only dipeptidase with substrate specificity for carnosine or homocarnosine, varies greatly between individuals but increases clearly and significantly with age. Surprisingly, the lower CN1 activity in children is not reflected by differences in CN1 protein concentrations. CN1 is present in different allosteric conformations in children and adults since all sera obtained from children but not from adults were positive in ELISA and addition of DTT to the latter sera increased OD450 values. There was no quantitative difference in the amount of monomeric CN1 between children and adults. Further, CN1 activity was dose dependently inhibited by homocarnosine. Addition of 80 lM homocarnosine lowered V max for carnosine from 440 to 356 pmol/min/lg and increased K m from 175 to 210 lM. The estimated K i for homocarnosine was higher (240 lM). Homocarnosine inhibits carnosine degradation and high homocarnosine concentrations in cerebrospinal fluid (CSF) may explain the lower carnosine degradation in CSF compared to serum. Because CN1 is implicated in the susceptibility for diabetic nephropathy (DN), our findings may have clinical implications for the treatment of diabetic patients with a high risk to develop DN. Homocarnosine treatment can be expected to reduce CN1 activity toward carnosine, resulting in higher carnosine levels.

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Section: Introductionmentioning

confidence: 95%

Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

et al. 2009

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“…In the context of AD, the genes involved in carnosine metabolism have also been investigated. In particular, the activity of the brain-specific carnosinase has been shown to be altered in fluids from patients with AD dementia [38] and, more recently, this enzyme has been validated as a novel biomarker in the cerebro-spinal fluid for staging early AD [39]. Furthermore, the mRNA of PEPT2 [40], a carrier protein involved in transmembrane transport of carnosine, has been studied as a marker for differential staging of AD progression in mammalian models [41].…”

Section: Introductionmentioning

confidence: 99%

Anti-Aggregating Effect of the Naturally Occurring Dipeptide Carnosine on Aβ1-42 Fibril Formation

et al. 2013

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Carnosine is an endogenous dipeptide abundant in the central nervous system, where by acting as intracellular pH buffering molecule, Zn/Cu ion chelator, antioxidant and anti-crosslinking agent, it exerts a well-recognized multi-protective homeostatic function for neuronal and non-neuronal cells. Carnosine seems to counteract proteotoxicity and protein accumulation in neurodegenerative conditions, such as Alzheimer’s Disease (AD). However, its direct impact on the dynamics of AD-related fibril formation remains uninvestigated. We considered the effects of carnosine on the formation of fibrils/aggregates of the amyloidogenic peptide fragment Aβ1-42, a major hallmark of AD injury. Atomic force microscopy and thioflavin T assays showed inhibition of Aβ1-42 fibrillogenesis in vitro and differences in the aggregation state of Aβ1-42 small pre-fibrillar structures (monomers and small oligomers) in the presence of carnosine. in silico molecular docking supported the experimental data, calculating possible conformational carnosine/Aβ1-42 interactions. Overall, our results suggest an effective role of carnosine against Aβ1-42 aggregation.

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“…A number of studies have suggested that CN-1 activity, either in serum or cerebrospinal fluid, might be important in the pathology of chronic kidney disease [ 20 ], diabetic complications [ 4 , 8 , 21 ], Alzheimer’s disease [ 22 , 23 ] or dementia [ 24 ]. CN-1 activity is not only depending on CN-1 concentrations but also on the presence of competing substrates [ 1 ] and the relative proportion of CN-1 that is recognized by RYSK173 [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Monoclonal Antibody RYSK173 Recognizes the Dinuclear Zn Center of Serum Carnosinase 1 (CN-1): Possible Consequences of Zn Binding for CN-1 Recognition by RYSK173

et al. 2016

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Background and AimsThe proportion of serum carnosinase (CN-1) recognized by RYSK173 monoclonal antibody negatively correlates with CN-1 activity. We thus hypothesized that the epitope recognized by RYSK173 is accessible only in a catalytically incompetent conformation of the zinc dependent enzyme and we mapped its position in the CN-1 structure. Since patients with kidney failure are often deficient in zinc and other trace elements we also assessed the RYSK173 CN-1 proportion in serum of these patients and studied the influence of hemodialysis hereon in relation to Zn2+ and Cu2+ concentration during hemodialysis.Methods and ResultsEpitope mapping using myc-tagged CN-1 fragments and overlapping peptides revealed that the RYSK173 epitope directly contributes to the formation of the dinuclear Zn center in the catalytic domain of homodimeric CN-1. Binding of RYSK173 to CN-1 was however not influenced by addition of Zn2+ or Cu2+ to serum. In serum of healthy controls the proportion of CN-1 recognized by RYSK173 was significantly lower compared to end-stage renal disease (ESRD) patients (1.12 ± 0.17 vs. 1.56 ± 0.40% of total CN-1; p<0.001). During hemodialysis the relative proportion of RYSK173 CN-1 decreased in parallel with increased serum Zn2+ and Cu2+ concentrations after dialysis.ConclusionsOur study clearly indicates that RYSK173 recognizes a sequence within the transition metal binding site of CN-1, thus supporting our hypothesis that metal binding to CN-1 masks the epitope. The CN-1 RYSK173 proportion appears overall increased in ESRD patients, yet it decreases during hemodialysis possibly as a consequence of a relative increase in transition metal bound enzyme.

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Brain type carnosinase in dementia: a pilot study

Cited by 24 publications

References 46 publications

Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

Anti-Aggregating Effect of the Naturally Occurring Dipeptide Carnosine on Aβ1-42 Fibril Formation

Monoclonal Antibody RYSK173 Recognizes the Dinuclear Zn Center of Serum Carnosinase 1 (CN-1): Possible Consequences of Zn Binding for CN-1 Recognition by RYSK173

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