S-Adenosyl-L-methionine synthetase from human erythrocytes: role in the regulation of cellular S-adenosylmethionine levels

Oden, Kristine L.; Clarke, Steven

doi:10.1021/bi00281a030

Cited by 74 publications

(25 citation statements)

References 29 publications

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“…Protein methyl esterification is quantitatively the most important AdoMet-consuming reaction in human erythrocytes, accounting for the bulk ofthe utilization ofthis thioether (25). In our study, we were able to confirm that methyl esters, measured as base-labile methyl groups, accounted for the large majority oftotal radioactivity incorporated into membranes in all samples.…”

Section: Introductionsupporting

confidence: 67%

“…This enzyme has been found to be crucial in the repair of isoaspartyl-containing damaged proteins through the conversion of the isopeptide bond into a normal peptide bond (21)(22)(23)(24). Type II MTase utilizes S-adenosylmethionine (AdoMet), as the methyl donor (25). The reaction generates S-adenosylhomocysteine (AdoHcy), which represents the natural inhibitor of this methyl transfer reaction (26,27), as well as of most AdoMet-dependent methylations (28,29 PMSF, and centrifuged at 10,000 g for 30 min.…”

Section: Introductionmentioning

confidence: 99%

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Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Perna¹,

Ingrosso²,

Zappia³

et al. 1993

J. Clin. Invest.

105

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The enzyme protein carboxyl methyltransferase type II has been recently shown to play a crucial role in the repair of damaged proteins. S-adenosylmethionine (AdoMet) is the methyl donor of the reaction, and its demethylated product, S-adenosylhomocysteine (AdoHcy), is the natural inhibitor ofthis reaction, as well as of most AdoMet-dependent methylations. We examined erythrocyte membrane protein methyl esterification in chronic renal failure (CRF) patients on conservative treatment or hemodialyzed to detect possible alterations ofthe methylation pattern, in a condition where a state of disrupted red blood cell function is present.We observed a significant reduction in membrane protein methyl esterification in both groups, compared to control. The decrease was particularly evident for cytoskeletal component ankyrin, which is known to be involved in membrane stability and integrity. Moreover, we observed a severalfold rise in AdoHcy levels, while AdoMet concentration was comparable to that detected in the control, resulting in a lower lAdoMeti! [AdoHcyl ratio (P < 0.001).Our findings show an impairment of this posttranslational modification of proteins, associated with high AdoHcy intracellular concentration in CRF. The data are consistent with the notion that, in CRF, structural damages accumulate in erythrocyte membrane proteins, and are not adequately repaired. (J.

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Section: Introductionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Perna¹,

Ingrosso²,

Zappia³

et al. 1993

J. Clin. Invest.

105

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“…study revealed a decrease of both the transcript and protein of AdoMet synthetase that may act as a compensatory strategy induced to maintain AdoMet levels. The exact mechanism behind this regulation needs to be elucidated, but in MDL73811-treated mammalian cells the AdoMet concentration was effectively regulated through substrate feedback inhibition of AdoMet synthetase activity (52,60). In contrast, the trypanosomal enzyme is apparently poorly regulated resulting in the substantial accumulation of AdoMet after AdoMetDC inhibition (60).…”

Section: Discussionmentioning

confidence: 99%

Co-inhibition of Plasmodium falciparum S-Adenosylmethionine Decarboxylase/Ornithine Decarboxylase Reveals Perturbation-specific Compensatory Mechanisms by Transcriptome, Proteome, and Metabolome Analyses

Brummelen

Olszewski

Wilinski

et al. 2009

Journal of Biological Chemistry

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Polyamines are ubiquitous components of all living cells, and their depletion usually causes cytostasis, a strategy employed for treatment of West African trypanosomiasis. To evaluate polyamine depletion as an anti-malarial strategy, cytostasis caused by the co-inhibition of S-adenosylmethionine decarboxylase/ ornithine decarboxylase in Plasmodium falciparum was studied with a comprehensive transcriptome, proteome, and metabolome investigation. Highly synchronized cultures were sampled just before and during cytostasis, and a novel zero time point definition was used to enable interpretation of results in lieu of the developmentally regulated control of gene expression in P. falciparum. Transcriptome analysis revealed the occurrence of a generalized transcriptional arrest just prior to the growth arrest due to polyamine depletion. However, the abundance of 538 transcripts was differentially affected and included three perturbation-specific compensatory transcriptional responses as follows: the increased abundance of the transcripts for lysine decarboxylase and ornithine aminotransferase and the decreased abundance of that for S-adenosylmethionine synthetase. Moreover, the latter two compensatory mechanisms were confirmed on both protein and metabolite levels confirming their biological relevance. In contrast with previous reports, the results provide evidence that P. falciparum responds to alleviate the detrimental effects of polyamine depletion via regulation of its transcriptome and subsequently the proteome and metabolome.Polyamines such as putrescine, spermidine, and spermine are small organic compounds containing two or more amino groups. At physiological pH, these polycations interact electrostatically with numerous anionic macromolecules, thereby stabilizing DNA, RNA, nucleoside triphosphates (e.g. ATP), phospholipids, and proteins (1, 2). These interactions with polyamines can alter DNA conformation, regulate replication and transcription, strengthen membranes, regulate ion channels, and protect DNA and phospholipids from oxidative stress (1-5). Yet polyamines are also implicated in apoptosis (5). Polyamine depletion generally causes cytostasis or growth arrest, which implies that these molecules are involved in cell cycle progression and regulation, and it is speculated that polyamines regulate cyclin degradation (1, 6, 7). Therefore, polyamines are essential for cellular growth, differentiation, and macromolecular synthesis and are ubiquitous components of all living cells, except two orders of Archaea (1). Polyamine metabolism is particularly important in rapidly proliferating cells and has been exploited in the treatment of cancer (1) and parasitic diseases (8). Polyamine metabolism of the malaria parasite Plasmodium falciparum is also a potential target for therapeutic intervention (9, 10).Polyamine and methionine metabolism are closely connected. This is particularly evident in Plasmodium where the two rate-limiting enzymes of polyamine biosynthesis, ornithine decarboxylase (ODC) 2 and S-adenosylme...

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“…MAT I and III are referred to as the hepatic forms because their expression is confined to the liver. By contrast, MAT II is found in all mammalian tissues that have been examined to date, including erythrocytes, lymphocytes, brain, kidney, testis, and liver (10,(12)(13)(14)(15)(16)(17)(18). MAT I is a tetramer and MAT III is a dimer of an identical catalytic subunit, ␣ 1 , encoded by the MATIA gene (7, 19 -22).…”

mentioning

confidence: 99%

Expression and Functional Interaction of the Catalytic and Regulatory Subunits of Human Methionine Adenosyltransferase in Mammalian Cells

Halim¹,

LeGros²,

Geller³

et al. 1999

Journal of Biological Chemistry

121

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. The recombinant MAT II ␣ 2 and r␤ subunit associated spontaneously either in cell-free system or in COS-1 cells coexpressing both subunits. Analysis of nickel-agarosepurified His-tagged r␣ 2 subunit from COS-1 cell extracts showed that the ␤ subunit co-purified with the ␣ 2 subunit. Furthermore, the ␣ 2 and ␤ subunits co-migrated in native polyacrylamide gels. Together, the data provide evidence for ␣ 2 and ␤ MAT subunit association. In addition, the ␤ subunit regulated MAT II activity by reducing its K m for L-Met and by rendering the enzyme more susceptible to feedback inhibition by AdoMet. We believe that the previously described differential expression of MAT II ␤ subunit may be an important mechanism by which MAT activity can be modulated to provide different levels of AdoMet that may be required at different stages of cell growth and differentiation.

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S-Adenosyl-L-methionine synthetase from human erythrocytes: role in the regulation of cellular S-adenosylmethionine levels

Cited by 74 publications

References 29 publications

Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Co-inhibition of Plasmodium falciparum S-Adenosylmethionine Decarboxylase/Ornithine Decarboxylase Reveals Perturbation-specific Compensatory Mechanisms by Transcriptome, Proteome, and Metabolome Analyses

Expression and Functional Interaction of the Catalytic and Regulatory Subunits of Human Methionine Adenosyltransferase in Mammalian Cells

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