Abstract
Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine β- synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1935-1942 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 272 |
| Issue number | 3 |
| State | Published - Feb 1 1997 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
- Cell Biology
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Metabolism of homocysteine thiolactone in human cell cultures : Possible mechanism for pathological consequences of elevated homocysteine levels. / Jakubowski, Hieronim.
In: Journal of Biological Chemistry, Vol. 272, No. 3, 01.02.1997, p. 1935-1942.Research output: Contribution to journal › Article
TY - JOUR
T1 - Metabolism of homocysteine thiolactone in human cell cultures
T2 - Possible mechanism for pathological consequences of elevated homocysteine levels
AU - Jakubowski, Hieronim
PY - 1997/2/1
Y1 - 1997/2/1
N2 - Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine β- synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
AB - Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine β- synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
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UR - http://www.scopus.com/inward/citedby.url?scp=0031035742&partnerID=8YFLogxK
M3 - Article
C2 - 8999883
AN - SCOPUS:0031035742
VL - 272
SP - 1935
EP - 1942
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 3
ER -