Quantitative Studies of Urinary β-Aspartyl Oligopeptides<sup>*</sup>

Dorer, Frederic E.; Haley, Edward E.; Buchanan, Donald L.

doi:10.1021/bi00874a025

Cited by 28 publications

(13 citation statements)

References 6 publications

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“…Few peptidases cleave isoaspartyl bonds, but proteolysis of the surrounding residues creates isoaspartyl-containing dipeptides and tripeptides that can be excreted in the urine (33)(34)(35)(36). Thus, if mice lacking endogenous PCMT1 do not have another repair pathway, they might excrete the damaged residues that are normally repaired in the cells of wild-type mice.…”

Section: Accumulation Of Damaged Aspartyl Residues In Brainmentioning

confidence: 99%

“…For example, isoaspartylglycine ("␤-aspartylglycine"), the most abundant of these dipeptides in human urine (35), was present at 28.2 pmol/g creatinine in urine from a 91-day-old Pcmt1Ϫ/Ϫ mouse and at 27.5 pmol/g creatinine in urine from a 40-day-old wild-type mouse. These results suggest that much of this dipeptide might originate in dietary, extracellular, or unrepairable intracellular proteins rather than from the lack of repair in Pcmt1Ϫ/Ϫ cells.…”

Section: Accumulation Of Damaged Aspartyl Residues In Brainmentioning

confidence: 99%

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Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Lowenson¹,

Kim

Young

et al. 2001

Journal of Biological Chemistry

137

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L-Isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1)can initiate the conversion of damaged aspartyl and asparaginyl residues to normal L-aspartyl residues. Mice lacking this enzyme (Pcmt1؊/؊ mice) have elevated levels of damaged residues and die at a mean age of 42 days from massive tonic-clonic seizures. To extend the lives of the knockout mice so that the long term effects of damaged residue accumulation could be investigated, we produced transgenic mice with a mouse Pcmt1 cDNA under the control of a neuron-specific promoter. Pcmt1 transgenic mice that were homozygous for the endogenous Pcmt1 knockout mutation ("transgenic Pcmt1؊/؊ mice") had brain PCMT1 activity levels that were 6.5-13% those of wild-type mice but had little or no activity in other tissues. The transgenic Pcmt1؊/؊ mice lived, on average, 5-fold longer than nontransgenic Pcmt1؊/؊ mice and accumulated only half as many damaged aspartyl residues in their brain proteins. The concentration of damaged residues in heart, testis, and brain proteins in transgenic Pcmt1؊/؊ mice initially increased with age but unexpectedly reached a plateau by 100 days of age. Urine from Pcmt1؊/؊ mice contained increased amounts of peptides with damaged aspartyl residues, apparently enough to account for proteins that were not repaired intracellularly. In the absence of PCMT1, proteolysis may limit the intracellular accumulation of damaged proteins but less efficiently than in wild-type mice having PCMT1-mediated repair.The spontaneous chemical modification of proteins by reaction with oxygen, water, sugars, and other abundant metabolites is unavoidable. The accumulation of such nonenzymatically altered proteins is associated with normal aging as well as atherosclerosis, Alzheimer's disease, and diabetes (1-3). Organisms have several strategies for dealing with damaged proteins, including intracellular proteolysis mediated by proteasome and lysosome action (4 -6). Some types of covalent damage, however, are simple enough to recognize and repair directly (7). Enzymes such as prolyl cis-trans isomerase (8), methionine sulfoxide reductase (9), and disulfide isomerase (8) can restore activity to proteins that have been chemically altered.We are interested in a common type of spontaneous protein damage in which L-aspartyl and L-asparaginyl residues undergo an intramolecular reaction that converts them to L-succinimidyl residues (10, 11). Nonenzymatic hydrolysis of the succinimide ring readily occurs at either carbonyl to generate both normal aspartyl residues and isoaspartyl residues, in which the peptide backbone proceeds through the ␤-carbonyl rather than the ␣-carbonyl moiety (12). The succinimide also racemizes more rapidly than do the open chain forms, and hydrolysis of the D-succinimide produces D-aspartyl and D-isoaspartyl residues (12). Local protein structure causes some L-aspartyl and L-asparaginyl residues to be especially prone to succinimide formation, and the presence of damaged aspartyl residues at these sites can significantly alter the structure, function...

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Section: Accumulation Of Damaged Aspartyl Residues In Brainmentioning

confidence: 99%

Section: Accumulation Of Damaged Aspartyl Residues In Brainmentioning

confidence: 99%

Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Lowenson¹,

Kim

Young

et al. 2001

Journal of Biological Chemistry

137

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“…Dorer, Haley & Buchanan, 1966Prockop 8z Sjoerdsma, 1961 ;Prockop et al, 1962). Dorer, Haley & Buchanan, 1966Prockop 8z Sjoerdsma, 1961 ;Prockop et al, 1962).…”

Section: (5) Luteinizing Hormone Releasing Hormone Is Pglu-his-trp-seunclassified

“…Luteinizing hormone releasing hormone is pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. The amidated N-terminal tripeptide fragment, pGlu-His-Trp-NH,, also was active on oral administration.hydroxyproline present in dietary protein also are recovered in intact form in the urine of healthy human subjects (e.g Dorer, Haley & Buchanan, 1966. Prockop 8z Sjoerdsma, 1961 ;Prockop et al, 1962).…”

mentioning

confidence: 99%

Intestinal Assimilation of Intact Peptides and Proteins From the Diet‐a Neglected Field?

Gardner

1984

Biological Reviews

117

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“…We found appreciable amounts of the a-and fi-aspartyl-glycines. These may be derived partly from diet and partly from endogenous sources in the same way as the P-aspartyl and y-glutamyl dipeptides described by Buchanan, Haley & Markiw (1962) and Dorer, Haley & Buchanan (1966).…”

Section: Non Collagen Derived Substancesmentioning

confidence: 99%

A Detailed Study of the Urinary Peptides in a Patient with Osteomalacia and Hyperparathyroidism

1970

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1. The urinary peptides and amino acids have been examined in a 28-year-old female with osteomalacia and severe parathyroid bone disease. Forty ninhydrin positive substances were identified.2. These substances included nine hydroxyproline containing peptides of relatively simple composition. Of these eight contained 4-hydroxyprolineY two contained cis-3-hydroxyproline and one had trans-3-hydroxyproline. Two larger peptides which contained a high proportion of 4-hydroxyproline residues were also found. Free 4-hydroxyprolineY free hydroxylysine and a hydroxylysine complex were found.3. Of the remaining twenty-six substances, which may not be derived from collagen, alaninol is reported as an urinary constituent for the first time, six are less common but have been reported previously whilst the remaining nineteen are well-known urinary constituents.4. The significance of these findings in relation to collagen breakdown is discussed.The urinary excretion of total hydroxyproline (THP), i.e. the free hydroxyproline plus that released by acid hydrolysis, is regarded as a reliable indicator of changes in collagen metabolism and particularly the metabolism of bone collagen (Sjoerdsma et al.

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Quantitative Studies of Urinary β-Aspartyl Oligopeptides^*

Cited by 28 publications

References 6 publications

Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Intestinal Assimilation of Intact Peptides and Proteins From the Diet‐a Neglected Field?

A Detailed Study of the Urinary Peptides in a Patient with Osteomalacia and Hyperparathyroidism

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Quantitative Studies of Urinary β-Aspartyl Oligopeptides*

Cited by 28 publications

References 6 publications

Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Limited Accumulation of Damaged Proteins inl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Intestinal Assimilation of Intact Peptides and Proteins From the Diet‐a Neglected Field?

A Detailed Study of the Urinary Peptides in a Patient with Osteomalacia and Hyperparathyroidism

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Quantitative Studies of Urinary β-Aspartyl Oligopeptides^*