Pyridoxamine: An Extremely Potent Scavenger of 1,4-Dicarbonyls
详细信息 查看全文
- 作者：Venkataraman Amarnath ; Kapil Amarnath ; Kalyani Amarnath ; Sean Davies ; and L. Jackson Roberts II
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：March 2004
- 年：2004
- 卷：17
- 期：3
- 页码：410 - 415
- 全文大小：89K
- 年卷期：v.17,no.3(March 2004)
- ISSN：1520-5010
文摘
1,4-Dicarbonyl compounds, which include 2,5-hexanedione and recently discovered endogenous 4-ketoaldehydes (levuglandins, isoketals, and neuroketals), exhibit severe toxicity. Thekey step in the toxicity of these compounds is their reaction with the lysyl residues of proteinsto form pyrrole adducts. To screen for effective scavengers of these toxic compounds, wedetermined the reaction rates of pyrrole formation for a series of primary amines with a model4-ketoaldehyde, 4-oxopentanal (OPA). We found pyridoxamine (PM) to react extremely rapidly,with a second-order rate constant at physiological pH being ~2300 times faster than that ofN
-acetyllysine. The extreme reactivity of PM was unique to 1,4-dicarbonyls, as its reactionswith methylglyoxal and 4-hydroxy-2(E)-nonenal were much slower and only slightly fasterthan with N-acetyllysine. The phenolic group of PM was found to be essential to its highreactivity, and the rate constant for pyrrole formation with OPA exhibited a maximum at pH7.5, close to the second pKa of PM. We therefore propose a mechanism involving transfer ofthe phenolic proton to the carbonyl of the initially formed hemiacetal, which facilitatessubsequent nucleophilic attack and ring closure. Only 1,4-dicarbonyls are likely to participatein the proposed mechanism, thereby conferring unique sensitivity of this class of compoundsto scavenging by PM.
-acetyllysine. The extreme reactivity of PM was unique to 1,4-dicarbonyls, as its reactionswith methylglyoxal and 4-hydroxy-2(E)-nonenal were much slower and only slightly fasterthan with N-acetyllysine. The phenolic group of PM was found to be essential to its highreactivity, and the rate constant for pyrrole formation with OPA exhibited a maximum at pH7.5, close to the second pKa of PM. We therefore propose a mechanism involving transfer ofthe phenolic proton to the carbonyl of the initially formed hemiacetal, which facilitatessubsequent nucleophilic attack and ring closure. Only 1,4-dicarbonyls are likely to participatein the proposed mechanism, thereby conferring unique sensitivity of this class of compoundsto scavenging by PM.