Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

Peters, Verena; Kebbewar, Moustafa; Jansen, Erwin; Jakobs, Cornelis; Riedl, Eva; Koeppel, Hannes; Frey, Dirk; Adelmann, Katja; Klingbeil, Kristina; Mack, Matthias; Hoffmann, Georg F.; Janssen, Bart; Zschocke, Johannes; Yard, Benito A.

doi:10.1007/s00726-009-0367-z

Cited by 41 publications

(55 citation statements)

References 33 publications

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“…In addition to (CTG) n polymorphism in the CNDP1 gene (10,16,24), the female sex (6,10,29) and increasing age (29) are determinants associated with higher carnosinase activity that cannot be manipulated. In vitro experiments, however, revealed that activity of the carnosinase enzyme was markedly decreased in the presence of both homocarnosine (␥-aminobutyryl-L-histidine) (28,29) and anserine (␤-alanyl-N 1 -methylhistidine) (28). However, the correlation between circulating homocarnosine or anserine levels in fasted subjects and plasma carnosinase activity in vivo is less obvious (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments, however, revealed that activity of the carnosinase enzyme was markedly decreased in the presence of both homocarnosine (␥-aminobutyryl-L-histidine) (28,29) and anserine (␤-alanyl-N 1 -methylhistidine) (28). However, the correlation between circulating homocarnosine or anserine levels in fasted subjects and plasma carnosinase activity in vivo is less obvious (28,29). Importantly, a good glycemic control, either by intervention with insulin, exercise, or diet, seems to be crucial for diabetic patients as this not only directly influences oxidative and glycation stress but also indirectly affects carnosinase activity (31).…”

Section: Discussionmentioning

confidence: 99%

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Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans

Everaert

Taes

Heer

et al. 2012

American Journal of Physiology-Renal Physiology

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A polymorphism in the carnosine dipeptidase-1 gene (CNDP1), resulting in decreased plasma carnosinase activity, is associated with a reduced risk for diabetic nephropathy. Because carnosine, a natural scavenger/suppressor of ROS, advanced glycation end products, and reactive aldehydes, is readily degraded in blood by the highly active carnosinase enzyme, it has been postulated that low serum carnosinase activity might be advantageous to reduce diabetic complications. The aim of this study was to examine whether low carnosinase activity promotes circulating carnosine levels after carnosine supplementation in humans. Blood and urine were sampled in 25 healthy subjects after acute supplementation with 60 mg/kg body wt carnosine. Precooled EDTA-containing tubes were used for blood withdrawal, and plasma samples were immediately deproteinized and analyzed for carnosine and beta-alanine by HPLC. CNDP1 genotype, baseline plasma carnosinase activity, and protein content were assessed. Upon carnosine ingestion, 8 of the 25 subjects (responders) displayed a measurable increase in plasma carnosine up to 1 h after supplementation. Subjects with no measurable increment in plasma carnosine (nonresponders) had approx. 2-fold higher plasma carnosinase protein content and approx. 1.5-fold higher activity compared with responders. Urinary carnosine recovery was 2.6-fold higher in responders versus nonresponders and was negatively dependent on both the activity and protein content of the plasma carnosinase enzyme. In conclusion, low plasma carnosinase activity promotes the presence of circulating carnosine upon an oral challenge. These data may further clarify the link among CNDP1 genotype, carnosinase, and diabetic nephropathy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans

Everaert

Taes

Heer

et al. 2012

American Journal of Physiology-Renal Physiology

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“…Separation was performed by liquid chromatography according to the method previously described (Peters et al 2010).…”

Section: Carnosine Concentrationmentioning

confidence: 99%

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

Forsberg¹,

Botusan²,

Wang³

et al. 2015

Journal of Endocrinology

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IGF binding protein 1 (IGFBP1) is a member of the binding proteins for the IGF with an important role in glucose homeostasis. Circulating IGFBP1 is derived essentially from the liver where it is mainly regulated negatively by insulin. Carnosine, a natural antioxidant, has been shown to improve metabolic control in different animal models of diabetes but its mechanisms of action are still not completely unraveled. We therefore investigate the effect of carnosine treatment on the IGFBP1 regulation in db/db mice. Db/db mice and heterozygous non-diabetic mice received for 4 weeks regular water or water supplemented with carnosine. Igfbp1 mRNA expression in the liver was evaluated using qPCR and the protein levels in plasma by western blot. Plasma IGF1 and insulin were analyzed using immunoassays. HepG2 cells were used to study the in vitro effect of carnosine on IGFBP1. The modulation of hypoxia inducible factor-1 alpha (HIF-1a) which is the central mediator of hypoxia-induction of IGFBP1 was analyzed using: WB, reporter gene assay and qPCR. Carnosine decreased the circulating IGFBP1 levels and the liver expression Igfbp1, through a complex mechanism acting both directly by suppressing the HIF-1a-mediated IGFBP1 induction and indirectly through increasing circulating insulin level followed by a decrease in the blood glucose levels and increased the plasma levels or IGF1. Reduction of IGFBP1 in diabetes through insulin-dependent and insulin-independent pathways is a novel mechanism by which carnosine contributes to the improvement of the metabolic control in diabetes.

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“…into their constituent amino acids, with the highest specificity for carnosine (28,29). Both human genetic association studies and animal models suggest a pivotal role for the carnosinecarnosinase system in microvascular complications of diabetes (3,19,33,34,40).…”

mentioning

confidence: 99%

“…In healthy subjects, sex, age, and particular polymorphisms of CNDP1 are known determinants of plasma carnosinase activity (12,22,29). In one study with diabetic patients (type 1 and 2), carnosinase activity was increased compared with genotype-matched healthy controls (32).…”

mentioning

confidence: 99%

Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes

Stegen

Sigal

Kenny

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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A particular allele of the carnosinase gene (CNDP1) is associated with reduced plasma carnosinase activity and reduced risk for nephropathy in diabetic patients. On the one hand, animal and human data suggest that hyperglycemia increases plasma carnosinase activity. On the other hand, we recently reported lower carnosinase activity levels in elite athletes involved in high-intensity exercise compared with untrained controls. Therefore, this study investigates whether exercise training and the consequent reduction in hyperglycemia can suppress carnosinase activity and content in adults with type 2 diabetes. Plasma samples were taken from 243 males and females with type 2 diabetes (mean age = 54.3 yr, SD = 7.1) without major microvascular complications before and after a 6-mo exercise training program [4 groups: sedentary control ( n = 61), aerobic exercise ( n = 59), resistance exercise ( n = 63), and combined exercise training ( n = 60)]. Plasma carnosinase content and activity, hemoglobin (Hb) A1c, lipid profile, and blood pressure were measured. A 6-mo exercise training intervention, irrespective of training modality, did not decrease plasma carnosinase content or activity in type 2 diabetic patients. Plasma carnosinase content and activity showed a high interindividual but very low intraindividual variability over the 6-mo period. Age and sex, but not Hb A1c, were significantly related to the activity or content of this enzyme. It can be concluded that the beneficial effects of exercise training on the incidence of diabetic complications are probably not related to a lowering effect on plasma carnosinase content or activity.

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Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity

Cited by 41 publications

References 33 publications

Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans

Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes

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