Аннотация и ключевые слова
Аннотация (русский):
Kinetics of the metabolism of the heterocyclic amino acid histidine exposed to the L-histidine ammonia-lyase enzyme has been investigated and the technology of extraction of histidine biotransformation products (urocanic acid and ammonia) from casein hydrolyzates enabling the subsequent use of these hydrolyzates as a milk protein concentrate for the production of specialized dietary products for the nutrition of histidinemia patients has been developed.

Ключевые слова:
histidine, biotransformation, L-histidine-ammonia-lyase, the removal of ammonia, urocanic acid, histidinemia


Over 600 inherited metabolic disorders, including hereditary disorders of amino acid metabolism (histi-dinemia, phenylketonuria, tyrosinemia, alkaptonuria, and others), have been identified to date. Diseases associated with disturbed amino acid metabolism develop if the activity of an enzyme involved in the metabolism of ingested amino acids is selectively reduced. These diseases affect the central nervous system, resulting in mental retardation with motor and speech defects, impaired vision and hearing, emotional and behavioral disorders, and seizures [1, 4].

Hereditary metabolic disorders are caused by mutations introducing changes into the nucleotide sequence of genomic DNA. Mutations result in the synthesis of abnormal proteins (including structural proteins, enzymes, hormones, growth factors, and receptor proteins). For instance, if the mutation affects a gene encoding an enzyme, the latter loses its catalytic activity partially or completely [2, 21]. The vast majority of hereditary metabolic disorders is caused by genetic defects affecting enzymes involved in the metabolism of amino acids, carbohydrates, and lipids. Pathogenesis and clinical manifestations are determined by the lack of normal metabolites (intermediate or final) and the ac-cumulation of toxic metabolites. The clinical presentation largely depends on the degree of the mutant gene expression, as well as on other genetic factors and environmental conditions. Mental retardation and neurological disorders are among the most frequent and severe consequences of the biochemical defect in the majority of patients [3, 5, 17].

Total screening for histidinemia, an innate defect of amino acid metabolism, in newborn babies has been recently introduced in Russia. Histidinemia is a hereditary disease associated with a disturbance of the metabolism of the amino acid histidine. The disease is a congenital defect of histidine-ammonia-lyase, an enzyme that belongs to the lyase class (EC, gene HAL, 12q22-q23) and catalyzes the deamination of L-histidine to form urocanic acid and ammonia. Histidine (L-α-amino-β-imidazolylpropionic acid) is an essential amino acid which must be present in the diet of young children. Besides, a histidine residue is often present in the active centers of enzyme molecules, and the biosynthesis of histamine in the human organism requires histidine as well. The metabolic block leads to accumulation of large amounts of histidine and the products of its abnormal metabolism (imidazolepyruvic, imidazolelactic, and imidazoleacetic acids) in the tissues and body fluids of the patient, this having a toxic effect on the central nervous system [8, 9, 14, 19, 24].

Diet therapy based on limiting the ingestion of histidine to a value that is the most appropriate for the individual metabolic requirements of the patient’s organism is the only efficient treatment for histidinemia currently available [6, 7, 13, 20].

The aim of the present work was to study histidine biotransformation in milk protein hydrolyzates treated by L-histidine-ammonia-lyase, to develop a technique for biotransformation, and to elaborate a procedure for the production of a milk protein concentrate for use in specialized dietary products.

Список литературы

1. Prosekov, A.Yu. and Kurbanova, M.G., Analiz sostava i svoistv belkov moloka s tsel’yu ispol’zovaniya v razlichnykh otraslyakh pishchevoi promyshlennosti (Analysis of the composition and properties of milk proteins for use in various sectors of the food industry), Tekhnika i tekhnologiya pishchevyh proizvodstv (Engineering and technology in food industry), 2009, no. 4, pp. 68a–71.

2. Babich, O.O., Kozlova, O.V., Razumnikova, I.S., and Prosekov, A.Yu., Biologicheski aktivnye peptidy iz belkov moloka (Biologically active peptides from milk proteins), Molochnaya promyshlennost’ (Dairy industry), 2010, no. 9, pp. 68–69.

3. Barashnev, Yu.I., Baharev, V.A., and Novikov, P.V., Diagnosis and Treatment of Congenital Genetic Disorders in Children. A Guide to Clinical Genetics (Diagnosis and treatment of congenital genetic disorders in children. A guide to Clinical Genetics), Moscow: Triada-X, 2004.

4. Barashnev, Yu.I. Rozanov, A.V., Petrova, L.A., et al., Vrozhdennye poroki razvitiya golovnogo mozga, vyyavlyaemye u plodov i novorozhdennykh (Congenital malformations of the brain detected in fetuses and newborns), Rossiiskii vestnik perinatologii i pediatrii (Russian Journal of Perinatology and Pediatrics), 2005, no. 6, pp. 9–12.

5. Berezov, T.V. and Korovin, B.F., Bioorganicheskaya khimiya (Bioorganic Chemistry), Moscow: Meditsina, 1990.

6. Borovik, T.E., Roslavtseva, E.A., and Gmoshinsky, I.V., Ispol’zovanie spetsializirovannykh produktov na osnove gidrolizatov belka v pitanii detei s pishchevoi allergiei. Allergologiya (The use of specialized products based on protein hydrolysates in the diet of children with food allergies. Allergology), Pediatriya (Pediatrics-Moscow), 2001, no. 2, pp. 38–42.

7. Borovik, T.E., Makarova, S.G., Gamaleeva, A.V., and Kazakova, S.N., Spetsializirovannye smesi v profilaktike i lechenii pishchevoi allergii u detei (Specialized mixtures for the prevention and treatment of food allergies in children). Consilium medicum. Pediatriya (Pediatrics-Moscow), 2008, no. 1, pp. 64–68.

8. Varfolomeev, S.D., Khimicheskaya enzimologiya (Chemical Enzymology), Moscow: Izdatel’skii tsentr “Akademiya”, 2005, p. 480.

9. Rybakova, E.P., Bushueva, T.V., Ladodo, K.S., et al., Dietoterapiya nasledstvennykh narushenii aminokislotnogo obmena (Diet therapy of inherited disorders of amino acid metabolism), Voprosy detskoi dietologii (Problems of pediatric nutritiology), 2005, vol. 3, no. 1, pp. 11–17.

10. Nielsen, P.M. Casein hydrolysate and method for production of such casein hydrolysate, European Patent № 0.610.411.B1, 1994.

11. Ernster, J.H., Milk protein hydrolysate and process of preparation, U.S. patent № 4600588, 1986.

12. Gigienicheskie trebovaniya bezopasnosti i pishchevoi tsennosti pishchevykh produktov. SanPiN (Hygienic safety and nutritional value of foods. Sanitary rules and regulations, Moscow: Ministry of Health of the Russian Federation, 2002.

13. Spetsializirovannye produkty pitaniya dlya detei s razlichnoi patologiei. Katalog. (Specialized food products for children with different pathologies. Catalog), Ladodo, K.S. and Sazhinov, G.Yu., Eds., Moscow: Ministry of Agriculture of the Russian Federation, 2000.

14. Armstrong, M.D., Maternal histidinaemia, Arch. Dis. Child., 1975, pp. 831–832.

15. Givot, I.L., Smith, T.A., and Abeles, R.A., Studies on the mechanism of action and the structure of the electrophilic center of histidine-ammonia-lyase, J Biol. Chem., 1969, pp. 6341–6353.

16. Surhone, L.M., Tennoe, M.T. and Henssonow, S.F., Eds. Histidine-Ammonia-Lyase, Betascript Publishing, 2011, p. 84.

17. Levy, H.L., and Benjamin, R., Maternal histidinemia: Study of families identified by routine cord blood screening. Pediatr Res., 1985, no. 19, p. 250 A.

18. Levy, H.L., Taylor, R.G., and McInnes, R.R., Disorders of histidine metabolism, New York: McGraw Hill, 2001, p. 1807.

19. Matsuda, I., Navada, N., and Endo, F., A family with histidinemic parents, Pediatrics, 1983, no. 103, p. 169.

20. Goldman, A.S., Anderson, D.W., and Sellers, W.A., Milk allergy, I: oral challenge with milk and isolated milk proteins in allergic children, Pediatrics, 1963, vol. 32, pp. 425–443.

21. Nowacki, P.M., Byck, S., Prevost, L., et al., Prototype for relational locus-specific mutation databases, Nucleic Acids Res., 1998, pp. 220–225.

22. Schwede, T.F., Retey, J., and Schulz, G.E., Crystal structure of histidine-ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile, Biochemistry, 1999, p. 5355–5361.

23. Suchi, M., Sano, H., Mizuno, H., and Wada, Y. Molecular cloning and structural characterization of the human histidase gen (HAL), Genomics, 1995, p. 104.

24. Taylor, R.G., Levy, H.L., and. McInnes, R.R., Histidase and histidinemia. Clinical and molecular considerations, Mol. Biol. Med., 1991, pp. 101–116.

Войти или Создать
* Забыли пароль?