Carnosinase

Hydrolysis of carnosine to p-alanine and L-histidine is catalyzed by carnosinase. The heritable disorder carnosinase deficiency is characterized by carnosinuria. 

Homocarnosine (Figure 31-2), present in human brain at higher levels than carnosine, is synthesized in brain tissue by carnosine synthetase. Serum carnosinase does not hydrolyze homocarnosine. Homocarnosinosis, a rare genetic disorder, is associated with progressive spastic paraplegia and mental retardation. 

The concept of property space is progressively being used to gain a deeper understanding of the dynamic behavior of a single compound in different media (as we illustrate below with acetylcholine, see Section 1.4.2) or bound to biological targets (the carnosine-carnosinase complex, see Section 1.4.3), but it can be used also with a set of compounds to derive fertile descriptors for dynamic QSAR analyses (4D QSAR, see Section 1.4.4). 

The dynamic profile of carnosine was investigated by comparing MD simulations in isotropic solvents (i.e. water and chloroform) with simulation of the compound bound to serum carnosinase (CNl) [22]. This enzyme is characterized by its distribution in plasma and brain, and its ability to hydrolyze also anserine and homocarnosine [23]. The conformational profile of carnosine can be defined by... 

Fig. 1.8 The conformational behavior of the two amino acyl residues of carnosine (1 2 versus plot) as simulated for 5 ns in water (in blue) or when bound to carnosinase (in...

Fig. 1.9 Bidimensional representation of the interaction pattern between carnosinase and its substrate carnosine. The model shows how the enzyme recognizes (binds) the ammonium group, the carboxylate group and...

Vistoli, G., Pedretti, A., Cattaneo, M., Aldini, G., Testa B. Homology modeling of human serum carnosinase, a potential medicinal target, and MD simulations of its allosteric activation by citrate. J. Med. Chem. 2006, 49, 3259-3277. 

CARNITINE O-ACETYLTRANSFERASE CARNITINE O-OCTANOYLTRANSFERASE CARNITINE O-PALMITOYLTRANSFERASE CARNOSINASE CARNOSINE SYNTHETASE CARNOT CYCLE... 

The kidney brush border also possesses a carnosine transport system and there is evidence that kidney also contains an active carnosinase (Sauerhoefer et al., 2005). There is also evidence that carnosine can influence sympathetic nervous activity in kidney (Tanida et al., 2005) as well as brown (Tanida et al., 2007) and white adipose tissue (Shen et al., 2008). Other studies have shown that carnosine has antidepressant activity in rats (Tomonaga et al., 2008). In chicks, carnosine induces hyperactivity (Tsuneyoshi et al., 2007) whereas its reverse structure (L-histidinyl-13-alanine) has sedative and hypnotic effects (Tsuneyoshi et al., 2008). The mechanisms involved in remain obscure however. 

There is one explorative study investigating whether there is any correlation between serum carnosinase levels and dementia. The findings, using a small sample size, indicate that while there was no significant... 

Janssen, B., Hohenadel, D., Brinkkoeter, P., Peters, V., Rind, N., Fischer, C., Rychlik, I., Cerna, M., Rondeau, E., Mathieson, P., Saleem, M. A., Meyer, J., et al. (2005). Carnosine as a protective factor in diabetic nephropathy Association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 54, 2320-2327. 

Serum carnosinase activities in central nervous system disorders. Clin. Chim. Acta 225, 57-64. 

Serum carnosinase activity is readily measured as a marker for carnosinosis, homocarnosinosis and in instances of jS-alanine elevation in physiological fluids [7]. For quantification, carnosine is incubated with sera samples, and the histidine liberated in the reaction is quantified as the fluorescent o-phthalaldehyde derivative [19]. To estimate the activity of methylmalonate semialdehyde dehydrogenase (direct enzyme determination methods have not been reported), fibroblast extracts are incubated with l-14C-/ -alanine and trapping of 14C02. 

Schoen P, Everts H, de Boer T, van Oeveren W (2003) Serum carnosinase activity in plasma and serum validation of a method and values in cardiopulmonary bypass surgery. Clin Chem 49 1930-1932... 

Serum carnosinase deficiency. This relatively rare disease described in children becomes apparent as camosinemia and camosinurea (increased camosine level in blood and urea). This is caused by very low activity of semm carnosinase which in half of the cases analyzed was characterized by sufficiently elevated Km for substrates [108]. From 23 sick children (belonging to different families) 14 were found to have neurological lesions, myoclonal convulsions, mental retardation at the same time, the correlation between intensity of neurological disorders and residual activity of carnosinase was not found [108]. 

Homocamosinosis. This disease is accompanied with pronounced increase of homocamosine level in brain and cerebrospinal liquid as well as camosine in urea with simultaneous disability to metabolize anserine into N -methyl-histidine (see [107]). Normal level of camosine and homocamosine is exceeded 20 and more times and this is accompanied with apparent neurological deficit. At the same time, relatives of the patients can get similar shifts in dipeptides metabolism with no neurological symptomatic. The cause of such disorder of metabolism in patients with homocamosinosis is that camosine splitting enzyme, carnosinase is mainly present in the inactive form [109,110],... 

Carnosinemia 212200 Carnosinase <1 100,000 Mental retardation, myoclonic seizures, possible ascertaimnent bias 7... 

Margolis FL, Grillo M, Grannot-Reisfeld N, Farbman AL 1983 Purification, characterization and immunocytochemical localization of mouse kidney carnosinase. Bio chimica et Biophysica Acta 744 237-248. 

One of the smallest naturally occurring peptides is camosine (jS-Ala-L-His) found in relatively large amounts in various animal tissues. Its exact function is not known. In the kidney an enzyme, carnosinase, hydrolyzes the peptide to its constituent amino acids. Also present in kidney is the highest in vivo concentration of cobalt, and Co complexes with carnosine are known to reversibly bind Oj. The inference is that carnosine (via its Co" complex) in kidney may control the O2 level. Further evidence is still needed for this conclusion. The extra methylene group in the -Ala moiety considerably alters the chelating properties of carnosine relative to other His-containing dipeptides (Chapter 20.2). This is particularly so with Cu" in aqueous solution where the major species is a dimer formed from the His moiety bridging the two metal centres. ... 

Dipeptidases Cleave dipeptides Various dipeptidases (carnosinase, anserinase)... 

A rare inborn error of metabolism in which there is a deficiency of the enzyme carnosinase which converts carnosine to -alanine and histidine. Mental retardation is a clinical feature. 

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