Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism.
Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism.
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DOI：
10.1038/sj.bjc.6604928
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发表时间：
2009-03-10
影响因子：
8.8
通讯作者：
MacRobert, A. J.
中科院分区：
文献类型：
--
作者：
Bourre, L.;Giuntini, F.;Eggleston, I. M.;Wilson, M.;MacRobert, A. J.
关键词：
在转化的PAM 212小鼠角质形成细胞中研究了血红素前体5-氨基乙酰丙酸（ALA）的一系列二肽衍生物的光敏剂原卟啉IX的细胞内生成，以及它们的细胞内代谢的研究。与等摩尔ALA相比，使用N-乙酰基封端的苯丙氨酰、亮氨酰和甲硫氨酰ALA甲酯衍生物（顺序为：Ac-L-苯丙氨酰-ALA-Me、Ac-L-甲硫氨酰-ALA-Me和Ac-L-亮氨酰-ALA-Me），卟啉产量显著增加。然而，在N末端没有乙酰基/酰基的苯丙氨酰基衍生物诱导的卟啉显著减少，并且乙酰基被苄氧基羰基取代导致没有卟啉产生。卟啉生产减少类特异性蛋白酶抑制剂，即丝氨酸蛋白酶抑制剂的存在下。使用siRNA敲低酰基肽水解酶（ACPH）蛋白的表达，我们表明参与ACPH，脯氨酰寡肽酶家族的丝氨酸肽酶的成员，从肽衍生物的ALA的水解裂解。总之，ALA肽衍生物能够有效地将ALA递送至细胞并增强卟啉合成和光细胞毒性;然而，N-末端状态，无论是游离的还是取代的，在确定ALA肽衍生物的生物学功效中起重要作用。
Intracellular generation of the photosensitiser, protoporphyrin IX, from a series of dipeptide derivatives of the haem precursor, 5-aminolaevulinic acid (ALA), was investigated in transformed PAM212 murine keratinocytes, together with studies of their intracellular metabolism. Porphyrin production was substantially increased compared with equimolar ALA using N-acetyl terminated phenylalanyl, leucinyl and methionyl ALA methyl ester derivatives in the following order: Ac-L-phenylalanyl-ALA-Me, Ac-L-methionyl-ALA-Me and Ac-L-leucinyl-ALA-Me. The enhanced porphyrin production was in good correlation with improved photocytotoxicity, with no intrinsic dark toxicity apparent. However, phenylalanyl derivatives without the acetyl/acyl group at the N terminus induced significantly less porphyrin, and the replacement of the acetyl group by a benzyloxycarbonyl group resulted in no porphyrin production. Porphyrin production was reduced in the presence of class-specific protease inhibitors, namely serine protease inhibitors. Using siRNA knockdown of acylpeptide hydrolase (ACPH) protein expression, we showed the involvement of ACPH, a member of the prolyl oligopeptidase family of serine peptidases, in the hydrolytic cleavage of ALA from the peptide derivatives. In conclusion, ALA peptide derivatives are capable of delivering ALA efficiently to cells and enhancing porphyrin synthesis and photocytotoxicity; however, the N-terminus state, whether free or substituted, plays an important role in determining the biological efficacy of ALA peptide derivatives.
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影响因子：
4.7
作者：
Novotny, A;Xiang, J;Keep, RF
通讯作者：
Keep, RF
影响因子：
8.8
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0306111101
发表时间：
2004-02-17
影响因子：
11.1
作者：
Gupta, S;Schoer, RA;Mittal, V
通讯作者：
Mittal, V