Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes
Abstract NG-Methylation of l-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields NG-monomethyl-l-arginine (MMA), NG,NG-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA) and NG,N′G-dimethyl-l-arginine (symmetric dimethylarginine,...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12933-017-0656-x |
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| author | Dimitrios Tsikas Alexander Bollenbach Erik Hanff Arslan Arinc Kayacelebi |
| author_facet | Dimitrios Tsikas Alexander Bollenbach Erik Hanff Arslan Arinc Kayacelebi |
| author_sort | Dimitrios Tsikas |
| collection | DOAJ |
| description | Abstract NG-Methylation of l-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields NG-monomethyl-l-arginine (MMA), NG,NG-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA) and NG,N′G-dimethyl-l-arginine (symmetric dimethylarginine, SDMA). Biological MMA, ADMA and SDMA occur as free acids in the nM-range and as residues of proteins of largely unknown quantity. Arginine:glycine amidinotransferase (AGAT) catalyzes the synthesis of L-homoarginine (hArg) from free Arg and l-lysine. Biological hArg is considered to occur exclusively as free acid in the lower µM-range. Nitric oxide synthase (NOS) catalyzes the conversion of Arg (high affinity) and hArg (low affinity) to nitric oxide (NO) which is a pleiotropic signaling molecule. MMA, ADMA and SDMA are inhibitors (MMA > ADMA ≫ SDMA) of NOS activity. Slightly elevated ADMA and SDMA concentrations and slightly reduced hArg concentrations in the circulation are associated with many diseases including diabetes mellitus. Yet, this is paradox: (1) free ADMA and SDMA are weak inhibitors of endothelial NOS (eNOS) which is primarily responsible for NO-related effects in the cardiovascular system, with free hArg being a poor substrate for eNOS; (2) free ADMA, SDMA and hArg are not associated with oxidative stress which is considered to induce NO-related endothelial dysfunction. This ADMA/SDMA/hArg paradox may be solved by the assumption that not the free acids but their precursor proteins exert biological effects in the vasculature, with hArg antagonizing the effects of NG-methylated proteins. |
| first_indexed | 2024-12-11T03:06:46Z |
| format | Article |
| id | doaj.art-31e08288d9ec4d39a2496ae8a1fc3ed9 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-11T03:06:46Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-31e08288d9ec4d39a2496ae8a1fc3ed92022-12-22T01:22:56ZengBMCCardiovascular Diabetology1475-28402018-01-011711410.1186/s12933-017-0656-xAsymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxesDimitrios Tsikas0Alexander Bollenbach1Erik Hanff2Arslan Arinc Kayacelebi3Institute of Toxicology, Core Unit Proteomics, Hannover Medical SchoolInstitute of Toxicology, Core Unit Proteomics, Hannover Medical SchoolInstitute of Toxicology, Core Unit Proteomics, Hannover Medical SchoolInstitute of Toxicology, Core Unit Proteomics, Hannover Medical SchoolAbstract NG-Methylation of l-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields NG-monomethyl-l-arginine (MMA), NG,NG-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA) and NG,N′G-dimethyl-l-arginine (symmetric dimethylarginine, SDMA). Biological MMA, ADMA and SDMA occur as free acids in the nM-range and as residues of proteins of largely unknown quantity. Arginine:glycine amidinotransferase (AGAT) catalyzes the synthesis of L-homoarginine (hArg) from free Arg and l-lysine. Biological hArg is considered to occur exclusively as free acid in the lower µM-range. Nitric oxide synthase (NOS) catalyzes the conversion of Arg (high affinity) and hArg (low affinity) to nitric oxide (NO) which is a pleiotropic signaling molecule. MMA, ADMA and SDMA are inhibitors (MMA > ADMA ≫ SDMA) of NOS activity. Slightly elevated ADMA and SDMA concentrations and slightly reduced hArg concentrations in the circulation are associated with many diseases including diabetes mellitus. Yet, this is paradox: (1) free ADMA and SDMA are weak inhibitors of endothelial NOS (eNOS) which is primarily responsible for NO-related effects in the cardiovascular system, with free hArg being a poor substrate for eNOS; (2) free ADMA, SDMA and hArg are not associated with oxidative stress which is considered to induce NO-related endothelial dysfunction. This ADMA/SDMA/hArg paradox may be solved by the assumption that not the free acids but their precursor proteins exert biological effects in the vasculature, with hArg antagonizing the effects of NG-methylated proteins.http://link.springer.com/article/10.1186/s12933-017-0656-xl-ArginineCardiovascular diseaseDiabetesl-HomoarginineInhibitionMethylated l-arginine |
| spellingShingle | Dimitrios Tsikas Alexander Bollenbach Erik Hanff Arslan Arinc Kayacelebi Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes Cardiovascular Diabetology l-Arginine Cardiovascular disease Diabetes l-Homoarginine Inhibition Methylated l-arginine |
| title | Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes |
| title_full | Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes |
| title_fullStr | Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes |
| title_full_unstemmed | Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes |
| title_short | Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes |
| title_sort | asymmetric dimethylarginine adma symmetric dimethylarginine sdma and homoarginine harg the adma sdma and harg paradoxes |
| topic | l-Arginine Cardiovascular disease Diabetes l-Homoarginine Inhibition Methylated l-arginine |
| url | http://link.springer.com/article/10.1186/s12933-017-0656-x |
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