Homoarginine, the methylene homologue of arginine, as a substrate of human arginine:glycine amidinotransferase and arginases
https://doi.org/10.20538/1682-0363-2018-1-7-14
Abstract
L-homoarginine (hArg) is a non-coding amino acid, the blood level reduction of which is associated with an increased risk of stroke and heart attack. In humans and animals, hArg is mainly formed during the reaction catalyzed by the enzyme of the metabolic pathway of creatine biosynthesis:arginine: glycine amidotransferase (AGAT, EC 2.1.4.1), in the case where L-lysine acts instead of glycine as an acceptor of the arginine amidine group. It has been shown that hArg can serve for nitric oxide biosynthesis which is seemed a single significant enzymatic pathway established for hArg.
The aim of this study was to investigate hArg as a substrate human AGAT and arginases.
Materials and methods. In experiments with recombinant enzymes we established that Km for hArg in the reaction catalyzed by AGAT towards the formation of guanidinoacetic acid is 12.0 ± 1.1 mM. In reactions catalyzed by both types of arginase activity against hArg, unlike arginine, was not detected.
Conclusions. Thus, the present study established that hArg may be considered as a substrate of AGAT additionally to nitric oxide synthases. Metabolic value of hArg, in addition to regulation of vascular tone, can be associated with cell energy metabolism. According to our data a decrease of hArg blood levels in cardiovascular diseases appears to be unrelated to a detectable increase of arginase activity.
About the Authors
E. S. Alekseevskaya
Academician I.P. Pavlov First St. Petersburg State Medical University; V.A. Almazov Federal North-West Medical Research Centre.
Russian Federation
Russian Federation
Alekseevskaya Elizaveta S., Researcher, Biochemistry Department; Junior Researcher, Proteomics Group.
6/8, Lva Tolstogo Str., Saint Petersburg, 197022; 2, Akkuratova Str., Saint Petersburg, 197341.
T. F. Subbotina
Academician I.P. Pavlov First St. Petersburg State Medical University; V.A. Almazov Federal North-West Medical Research Centre.
Russian Federation
Russian Federation
Subbotina Tatiana F., DM, Professor, Head of the Biochemistry Laboratory; Leading Researcher of Proteomics Group.
6/8, Lva Tolstogo Str., Saint Petersburg, 197022; 2, Akkuratova Str., Saint Petersburg, 197341.
A. A. Zhloba
Academician I.P. Pavlov First St. Petersburg State Medical University; V.A. Almazov Federal North-West Medical Research Centre.
Russian Federation
Russian Federation
Zhloba Aleksandr A., DM, Professor, Head of the Biochemistry Department; Leading Researcher and Head of the Proteomics Group.
6/8, Lva Tolstogo Str., Saint Petersburg, 197022; 2, Akkuratova Str., Saint Petersburg, 197341.
References
1. Onar A.N., Erdoğan B.Y., Ayan I., Acar Z. Homoarginine, β-ODAP, and asparagine contents of grass pea landraces cultivated in Turkey. Food Chem. 2014; 143: 277–281. DOI: 10.1016/j.foodchem.2013.07.051.
2. Davids M., Ndika J.D., Salomons G.S., Blom H.J., Teer- link T. Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett. 2012; 586 (20): 3653–3657. DOI: 10.1016/j.febslet.2012.08.020.
3. Choe C.U., Atzler D., Wild P.S., Carter A.M., Böger R.H., Ojeda F., Simova O., Stockebrand M., Lackner K., Nabuurs C., Marescau B., Streichert T., Müller C., Lüneburg N., De Deyn P.P., Benndorf R.A., Baldus S., Gerloff C., Blankenberg S., Heerschap A., Grant P.J., Magnus T., Zeller T., Isbrandt D., Schwedhelm E. Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation. 2013; 128 (13): 1451–1461. DOI: 10.1161/CIRCULATIONAHA.112.000580.
4. Van Pilsum J.F., Stephens G.C., Taylor D. Distribution of creatine, guanidinoacetate and the enzymes for their biosynthesis in the animal kingdom. Implications for phylogeny. Biochem. J. 1972; 126 (2): 325–345. DOI: 10.1042/ bj1260325.
5. März W., Meinitzer A., Drechsler C., Pilz S., Krane V., Kle- ber M.E., Fischer J., Winkelmann B.R., Böhm B.O., Ritz E., Wanner C. Homoarginine, cardiovascular risk, and mortality. Circulation. 2010; 122 (10): 967–975. DOI: 10.1161/CIRCULATIONAHA.109.908988.
6. Drechsler C., Meinitzer A., Pilz S., Krane V., Tomaschitz A., Ritz E., März W., Wanner C. Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients. Eur. J. Heart Fail. 2011; 13 (8): 852–859. DOI: 10.1093/eurjhf/ hfr056.
7. Atzler D., Gore M.O., Ayers C.R., Choe C.U., Böger R.H., de Lemos J.A., McGuire D.K., Schwedhelm E. Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler. Thromb. Vasc. Biol. 2014; 34 (11): 2501–2507. DOI: 10.1161/ATVBAHA.114.304398.
8. Moali C., Boucher J.L., Sari M.A., Stuehr D.J., Mansuy D. Substrate specificity of NO synthases: detailed comparison of L-arginine, homo-L-arginine, their Nomega-hydroxy derivatives, and Nomega-hydroxynor-L-arginine. Biochemistry. 1998; 37 (29): 10453–10460. DOI: 10.1021/bi980742t.
9. Ratner S., Rochovansky O. Biosynthesis of guanidinoacetic acid. I. Purification and properties of transamidinase. Arch. Biochem. Biophys. 1956; 63 (2): 277–295. DOI: 10.1016/0003-9861(56)90044-3.
10. Walker J.B. Arginine-ornithine transamidination in kidney. J. Biol. Chem. 1956; 221 (2): 771–776.
11. Walker J.B. Studies on the mechanism of action of kidney transamidinase. J. Biol. Chem. 1957; 224 (1): 57–66.
12. Conconi F., Grazi E. Transamidinase of hog kidney. I. Purification and properties. J. Biol. Chem. 1965; 240 (6): 2461–2464.
13. Hrabák A., Bajor T., Temesi A. Comparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages. Biochem. Biophys. Res. Commun. 1994; 198 (1): 206–212. DOI: 10.1006/ bbrc.1994.1029.
14. Christiansen B., Wellendorph P., Bräuner-Osborne H. Known regulators of nitric oxide synthase and arginase are agonists at the human G-protein-coupled receptor GPRC6A. Br. J. Pharmacol. 2006; 147 (8): 855–863. DOI: 10.1038/sj.bjp.0706682.
15. Mielczarek-Puta M., Chrzanowska A., Barańczyk-Kuź- ma A. Nowe oblicza arginazy. Część I. Struktura i właściwości. Postepy Hig. Med. Dosw. (Online). 2008; 62: 206–213.
16. Pernow J., Jung C. Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal? Cardiovasc. Res. 2013; 98 (3): 334–343. DOI: 10.1093/cvr/cvt036.
17. Bartolomeo M.P., Maisano F. Validation of a reversed-phase HPLC method for quantitative amino acid analysis. J. Biomol. Tech. 2006; 17 (2): 131–137.
18. Zhloba A.A., Subbotina T.F., Lupan D.S., Bogova V.A., Kusheleva O.A. Arginine and lysine as products of basic carboxypeptidase activity associated with fibrinolysis. Biochemistry (Moscow) Suppl. Ser. B: Biomed. Chem. 2012; 6 (3): 261–265. DOI:10.1134/S1990750812030158.
19. Hou Y., Jia S., Nawaratna G., Hu S., Dahanayaka S., Bazer F.W., Wu G. Analysis of L-homoarginine in biological samples by HPLC involving precolumn derivatization with o-phthalaldehyde and N-acetyl-L-cysteine. Amino Acids. 2015; 47 (9): 2005–2014. DOI: 10.1007/s00726015-1962-9.
20. Scolnick L.R., Kanyo Z.F., Cavalli R.C., Ash D.E., Christianson D.W. Altering the binuclear manganese cluster of arginase diminishes thermostability and catalytic function. Biochemistry. 1997; 36 (34): 10558–10565. DOI: 10.1021/bi970800v.
21. Spector E.B., Rice S.C.H., Moedjono S., Bernard B., Cederbaum, S.D. Biochemical properties of arginase in hu man adult and fetal tissues. Biochemical Medicine. 1982; 28 (2): 165–175. DOI: 10.1016/0006-2944(82)90067-9.
22. Colleluori D.M., Morris S.M. Jr., Ash D.E. Expression, purification, and characterization of human type II arginase. Arch. Biochem. Biophys. 2001; 389 (1): 135–143. DOI: 10.1006/abbi.2001.2324.
23. Gross M.D., Eggen M.A., Simon A.M., Van Pilsum J.F. The purification and characterization of human kidney L-arginine:glycine amidinotransferase. Arch. Biochem. Biophys. 1986; 251 (2): 747–755. DOI: 10.1016/00039861(86)90385-1.
24. Fritsche E., Humm A., Huber R. Substrate binding and catalysis by L-arginine:glycine amidinotransferase. A mutagenesis and crystallographic study. Eur. J. Biochem. 1997; 247 (2): 483–490. DOI: 10.1111/j.14321033.1997.00483.x.
25. Knowles R.G., Merrett M., Salter M., Moncada S. Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem. J. 1990; 270 (3): 833–836. DOI: 10.1042/bj2700833.
26. Kato T., Sano M., Mizutani N., Hayakawa C. Homocitrullinuria and homoargininuria in hyperargininaemia. J. Inherit. Metab. Dis. 1988; 11 (3): 261–265. DOI: 10.1007/bf01800367.
27. Amayreh W., Meyer U., Das A.M. Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev. Med. Child Neurol. 2014; 56 (10): 1021–1024. DOI: 10.1111/dmcn.12488.
28. Atzler D., McAndrew D.J., Cordts K., Schneider J.E., Zervou S., Schwedhelm E., Neubauer S., Lygate C.A. Dietary supplementation with homoarginine preserves cardiac function in a murine model of post-myocardial infarction heart failure. Circulation. 2017; 135 (4): 400–402. DOI: 10.1161/CIRCULATIONAHA.116.025673.
Review
For citations:
Alekseevskaya E.S., Subbotina T.F., Zhloba A.A. Homoarginine, the methylene homologue of arginine, as a substrate of human arginine:glycine amidinotransferase and arginases. Bulletin of Siberian Medicine. 2018;17(1):7-14. (In Russ.) https://doi.org/10.20538/1682-0363-2018-1-7-14
Views:
1651
Email this article 