Aging as war between chemical and biochemical …老化之间的战争化学和生化u2026.pdfVIP

Ageing Research Reviews 2 (2003) 263–285 Aging as war between chemical and biochemical processes: Protein methylation and the recognition of age-damaged proteins for repair Steven Clarke∗ Department of Chemistry and Biochemistry, the Molecular Biology Institute, University of California, Los Angeles, CA 90095-1569, USA Received 24 December 2002; accepted 27 December 2002 Abstract Deamidated, isomerized, and racemized aspartyl and asparaginyl residues represent a significant part of the spontaneous damage to proteins that results from the aging process. The accumulation of these altered residues can lead to the loss of protein function and the consequent loss of cellular function. However, almost all cells in nature contain a methyltransferase that can recognize the major damaged form of the l-isoaspartyl residue, and some of these enzymes can also recognize the racemized d-aspartyl residue. The methyl esterification reaction can initiate the conversion of these altered residues to the normal l-aspartyl form, although there is no evidence yet that the l-asparaginyl form can be regenerated. This enzyme, the protein l-isoaspartate (d-aspartate) O-methyltransferase (EC 2.1.1.77), thus functions as a protein repair enzyme. The importance of this enzyme in attenuating age-related protein damage can be seen by the phenotypes of organisms where the gene encoding has been disrupted, or where its expression has been augmented. © 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Spontaneous protein damage; Isoaspartyl residues; Protein methyltransferases 1. Biological aging—chemistry versus biochemistry? It is clear that almost all measures of physiological function decline in human aging. How