Pyridoxamine Protects Proteins from Functional Damage by 3-Deoxyglucosone: Mechanism of Action of Pyridoxamine
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- 作者：Sergei V. Chetyrkin ; Wenhui Zhang ; Billy G. Hudson ; Anthony S. Serianni ; Paul A. Voziyan
- 刊名：Biochemistry
- 出版年：2008
- 出版时间：January 22, 2008
- 年：2008
- 卷：47
- 期：3
- 页码：997 - 1006
- 全文大小：178K
- 年卷期：v.47,no.3(January 22, 2008)
- ISSN：1520-4995
文摘
Pyridoxamine (PM) is a promising drug candidate for treatment of diabetic nephropathy. Thetherapeutic effect of PM has been demonstrated in multiple animal models of diabetes and in phase IIclinical trials. However, the mechanism of PM therapeutic action is poorly understood. One potentialmechanism is scavenging of pathogenic reactive carbonyl species (RCS) found to be elevated in diabetes.We have suggested previously that the pathogenicity of RCS methylglyoxal (MGO) may be due tomodification of critical arginine residues in matrix proteins and interference with renal cell-matrixinteractions. We have also shown that this MGO effect can be inhibited by PM (Pedchenko et al. (2005)Diabetes 54, 2952-2960). These findings raised the questions of whether the effect is specific to MGO,whether other structurally different physiological RCS can act via the same mechanism, and whethertheir action is amenable to PM protection. In the present study, we have shown that the importantphysiological RCS 3-deoxyglucosone (3-DG) can damage protein functionality, including the ability ofcollagen IV to interact with glomerular mesangial cells. We have also demonstrated that PM can protectagainst 3-DG-induced protein damage via a novel mechanism that includes transient adduction of 3-DGby PM followed by irreversible PM-mediated oxidative cleavage of 3-DG. Our results suggest that, indiabetic nephropathy, the therapeutic effect of PM is achieved, in part, via protection of renal cell-matrix interactions from damage by a variety of RCS. Our data emphasize the potential importance of thecontribution by 3-DG, along with other more reactive RCS, to this pathogenic mechanism.