Polymorphic forms of the protein L-isoaspartate (D-aspartate) O-methyltransferase involved in the repair of age-damaged proteins
Polymorphic forms of the protein L-isoaspartate (D-aspartate) O-methyltransferase involved in the repair of age-damaged proteins
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DOI：
10.1007/s100380050161
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Clarke, S
中科院分区：
文献类型：
--
作者：
DeVry, CG;Clarke, S
蛋白质L-异天冬氨酸（D-天冬氨酸）O-甲基转移酶（PCMT 1）可以启动细胞内蛋白质的年龄损伤的天冬酰胺基和天冬酰胺基残基的修复。编码该酶的人基因PCMT 1具有至少四个多态性位点，其中一个导致在氨基酸位置119处具有Ile残基或瓦尔残基的两个主要同种型。编码Ile（119）和瓦尔（119）变体的等位基因的频率在高加索人群中相似，但Ile（119）等位基因在亚洲和非洲人群中占优势。红细胞裂解物中Ile（119）和瓦尔（119）变体的酶活性分析表明，Ile（119）同种型的较高比活性和热稳定性被瓦尔（119）同种型的潜在补偿性较高底物亲和力平衡。在一个初步的尝试，以找到在PCMT 1基因座的基因型频率和健康老龄化之间的关联，我们比较了基因型的分布在一个健康的老年人口的德系犹太人与年轻的种族匹配的对照组。我们发现，65%的健康老年人有杂合子基因型，大于Hardy-Weinberg平衡预期的50%，这表明在成功衰老中具有修复甲基转移酶的两个等位基因的可能选择。在甲基转移酶基因的非编码区的三个额外的多态性被发现是双等位基因，并表现出非随机关联在一个特定的单倍型与密码子119多态性。最后，我们还检测到一个杂合突变的剪接分支网站的内含子2，并没有出现影响活动。这项研究将有助于确定这种修复甲基转移酶的正常生理活性范围，并使我们更好地了解其在衰老和疾病过程中的作用。
The protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) can initiate the repair of age-damaged aspartyl and asparaginyl residues of intracellular proteins. The human gene PCMT1 encoding this enzyme has at least four polymorphic sites, one of which results in two major isoforms with either an Ile residue or a Val residue at amino acid position 119. The frequencies of the alleles encoding the Ile(119) and Val(119) variants are similar in Caucasian populations, but a predominance of the Ile(119) allele exists in Asian and African populations. Analyses of the enzymatic activities of the Ile(119) and Val(119) variants in red blood cell lysates show that the higher specific activity and thermostability of the Ile(119) isoform is balanced by the potentially compensating higher substrate affinity of the Val(119) isoform. In a preliminary attempt to find an association between genotype frequency at the PCMT1 locus and healthy aging, we compared the distribution of genotypes in a healthy older population of Ashkenazi Jewish individuals with that in a younger ethnically matched control group. We found that 65% of the healthy older population had the heterozygous genotype, greater than the 50% expected by Hardy-Weinberg equilibrium, suggesting a possible selection for having both alleles of the repair methyltransferase in successful aging. Three additional polymorphisms in noncoding regions of the methyltransferase gene were found to be biallelic and demonstrated nonrandom association in a specific haplotype with the codon 119 polymorphism. Finally, we also detected a heterozygous mutation in the splicing branch site of intron 2 that did not appear to affect activity. This study will help define the normal physiological range of activity for this repair methyltransferase and give us a better understanding of its role in the processes of aging and disease.