Spontaneous Degradation and Enzymatic Repair of Aspartyl and Asparaginyl Residues in Aging Red Cell Proteins Analyzed by Computer Simulation

Lowenson, Jonathan D.; Clarke, Steven

doi:10.1159/000213255

Cited by 30 publications

(11 citation statements)

References 32 publications

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“…Even oxidized sulphur species in many amino acid residues including cysteine, cystine and methionine appear to have a negligible effect on the observed activity. Neither does possible deamidation bring down the enzymic activity to zero as repeatedly reported for other enzymes (Weser, 1985;Ambler & Daniel, 1991;Lowenson & Clarke, 1991;Hensel & Jakob, 1994;Garza-Ramos et al, 1994;Tomizawa et al, 1995). In conclusion diagenesis of archaeological bone alkaline phosphatase seems to reduce the overall M r but activity is still seen in many of the samples examined.…”

Section: Discussionsupporting

confidence: 59%

Biochemically and Immunologically Active Alkaline Phosphatase in Archaeologically Important Bone Samples

Weser

Kaup

Etspüler

et al. 1996

Journal of Archaeological Science

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Section: Discussionsupporting

confidence: 59%

Biochemically and Immunologically Active Alkaline Phosphatase in Archaeologically Important Bone Samples

Weser

Kaup

Etspüler

et al. 1996

Journal of Archaeological Science

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“…Rather, the enzyme recognizes the products of spontaneous reactions involving the deamidation, isomerization, and racemization of L-asparaginyl and L-aspartyl residues that generate L-isoaspartyl and Daspartyl residues in polypeptides [14,53]. The methyltransferase can specifically recognize these residues and catalyze the first step that leads to their conversion back to normal L-aspartyl residues in vitro [6,11,19,20,31,36], suggesting that repair of these damaged residues in vivo is possible.…”

Section: Introductionmentioning

confidence: 99%

A distinctly regulated protein repair L-isoaspartylmethyltransferase from Arabidopsis thaliana

Mudgett

Clarke

1996

Plant Mol Biol

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Protein-L-isoaspartate (D-aspartate) O-methyltransferases (EC 2.1.1.77) that catalyze the transfer of methyl groups from S-adenosylmethionine to abnormal L-isoaspartyl and D-aspartyl residues in a variety of peptides and proteins are widely distributed in procaryotes and eucaryotes. These enzymes participate in the repair of spontaneous protein damage by facilitating the conversion of L-isoaspartyl and D-aspartyl residues to normal L-aspartyl residues. In this work, we have identified an L-isoaspartyl methyltransferase activity in Arabidopsis thaliana, a dicotyledonous plant of the mustard family. The highest levels of activity were detected in seeds. Using degenerate oligonucleotides corresponding to two highly conserved amino acid regions shared among the Escherichia coli, wheat, and human enzymes, we isolated and sequenced a full-length genomic clone encoding the A. thaliana methyltransferase. Several methyltransferase cDNAs were also characterized, including ones that would encode full-length polypeptides of 230 amino acid residues. Messenger RNAs for the A. thaliana enzyme were found in a variety of tissues that did not contain significant amounts of active enzyme suggesting the possibility of translational or posttranslational controls on methyltransferase levels. We have identified a putative abscisic acid-response element (ABRE) in the 5'-untranslated region of the A. thaliana L-isoaspartyl methyltransferase gene and have shown that the expression of the mRNA is responsive to exogenous abscisic acid (ABA), but not to the environmental stresses of salt or drought. The expression of the A. thaliana enzyme appears to be regulated in a distinct fashion from that seen in wheat or in animal tissues.

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“…These facts point to a general housekeeping role of this enzyme in the repair or degradation of damaged proteins. If this is true, the methyltransferase may be particularly important in cells with limited abilities to otherwise replace their aged proteins (21,22).…”

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confidence: 99%

A protein methyltransferase specific for altered aspartyl residues is important in Escherichia coli stationary-phase survival and heat-shock resistance.

Clarke

1992

Proc. Natl. Acad. Sci. U.S.A.

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Proteins are subject to spontaneous degradation reactions including the deamidation, isomerization, and racemization of asparaginyl and aspartyl residues. A major product of these reactions, the L-isoaspartyl residue, is recognized with high affinity by the protein-L-isoaspartate(Daspartate) O-methyltransferase (EC 2.1.1.77). This enzyme catalyzes the methyl esterification of the L-isoaspartyl residue in a reaction that can initiate its conversion to the normal aspartyl configuration. To directly study the physiological role of this methyltransferase, especially with respect to the potential repair of isomerized aspartyl residues in aging proteins, we examined the ability of the bacterium Escherichia coli to survive in the absence of its activity. We utilized gene disruption techniques to replace the chromosomal copy of the pcm gene that encodes the methyltransferase with a kanamycinresistance cassette to produce mutants that have no detectable L-isoaspartyl methyltransferase activity. Although no changes in exponential-phase growth were observed, pcm-mutants did not survive well upon extended culture into stationary phase or upon heat challenge at 550C. These results provide genetic evidence for a role of the L-isoaspartyl methyltransferase in the metabolism of altered proteins that can accumulate in aging cells and limit their viability.Although genetically encoded information can be transcribed and translated with high fidelity into protein sequences, newly synthesized proteins are immediately subjected to a variety of spontaneous chemical degradation reactions (1, 2). For example, L-aspartyl and L-asparaginyl residues are susceptible to nucleophilic attack on the side chain carbonyl carbon by the neighboring peptide bond nitrogen. This reaction results in the formation of an unstable five-membered succinimide ring structure that can both racemize and hydrolyze to generate a mixture of DL-isoaspartyl and DLaspartyl residues, with the predominant product being the L-isoaspartyl residue (3, 4). Since L-isoaspartyl-containing proteins or peptides may not perform their biological functions as efficiently as the native forms (5-7), the accumulation of these altered species would be expected to have deleterious effects upon cells.Interestingly, an enzyme exists that can catalyze the transfer of the methyl group from S-adenosylmethionine to the a-carboxyl group of L-isoaspartyl residues and the 3-carboxyl

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Spontaneous Degradation and Enzymatic Repair of Aspartyl and Asparaginyl Residues in Aging Red Cell Proteins Analyzed by Computer Simulation

Cited by 30 publications

References 32 publications

Biochemically and Immunologically Active Alkaline Phosphatase in Archaeologically Important Bone Samples

Biochemically and Immunologically Active Alkaline Phosphatase in Archaeologically Important Bone Samples

A distinctly regulated protein repair L-isoaspartylmethyltransferase from Arabidopsis thaliana

A protein methyltransferase specific for altered aspartyl residues is important in Escherichia coli stationary-phase survival and heat-shock resistance.

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