Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy

Ricardo Gomes, Marta Sousa Silva, Alexandre Quintas, Carlos Cordeiro, António Freire, Paulino Pereira, Américo Martins, Estela Monteiro, Eduardo Barroso, Ana Ponces Freire

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78 Citations (Scopus)

Abstract

FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming β-fibrils in amyloid deposits. This theory does not explain the formation of β-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to β-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N δ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4′-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40 ± 9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.

Original languageEnglish
Pages (from-to)339-345
Number of pages7
JournalBiochemical Journal
Volume385
Issue number2
DOIs
Publication statusPublished - 15 Jan 2005

Fingerprint

Pyruvaldehyde
Advanced Glycosylation End Products
Polyneuropathies
Amyloid
Prealbumin
Deposits
Amyloid Plaques
p-Dimethylaminoazobenzene
Mutation
Proteins
Ornithine
Poisons
Amyloidosis
Age of Onset
Point Mutation
Serum Albumin
Chlorides
argpyrimidine
Amino Acids
Toxicity

Keywords

  • Advanced glycation end-product (AGE)
  • Amyloid
  • Argpyrimidine
  • Familial amyloidotic polyneuropathy (FAP)
  • Glycation
  • Methylglyoxal

Cite this

Gomes, R., Sousa Silva, M., Quintas, A., Cordeiro, C., Freire, A., Pereira, P., ... Ponces Freire, A. (2005). Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy. Biochemical Journal, 385(2), 339-345. https://doi.org/10.1042/BJ20040833
Gomes, Ricardo ; Sousa Silva, Marta ; Quintas, Alexandre ; Cordeiro, Carlos ; Freire, António ; Pereira, Paulino ; Martins, Américo ; Monteiro, Estela ; Barroso, Eduardo ; Ponces Freire, Ana. / Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy. In: Biochemical Journal. 2005 ; Vol. 385, No. 2. pp. 339-345.
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abstract = "FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming β-fibrils in amyloid deposits. This theory does not explain the formation of β-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to β-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N δ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4′-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40 ± 9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.",
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Gomes, R, Sousa Silva, M, Quintas, A, Cordeiro, C, Freire, A, Pereira, P, Martins, A, Monteiro, E, Barroso, E & Ponces Freire, A 2005, 'Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy', Biochemical Journal, vol. 385, no. 2, pp. 339-345. https://doi.org/10.1042/BJ20040833

Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy. / Gomes, Ricardo; Sousa Silva, Marta; Quintas, Alexandre; Cordeiro, Carlos; Freire, António; Pereira, Paulino; Martins, Américo; Monteiro, Estela; Barroso, Eduardo; Ponces Freire, Ana.

In: Biochemical Journal, Vol. 385, No. 2, 15.01.2005, p. 339-345.

Research output: Contribution to journalArticle

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AU - Gomes, Ricardo

AU - Sousa Silva, Marta

AU - Quintas, Alexandre

AU - Cordeiro, Carlos

AU - Freire, António

AU - Pereira, Paulino

AU - Martins, Américo

AU - Monteiro, Estela

AU - Barroso, Eduardo

AU - Ponces Freire, Ana

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N2 - FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming β-fibrils in amyloid deposits. This theory does not explain the formation of β-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to β-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N δ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4′-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40 ± 9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.

AB - FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming β-fibrils in amyloid deposits. This theory does not explain the formation of β-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to β-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N δ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4′-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40 ± 9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.

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KW - Glycation

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