Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22:6n-3) biosynthesis.
Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22:6n-3) biosynthesis.
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齐薇格综合征敲除小鼠模型挑战了二十二碳六烯酸 (22:6n-3) 生物合成中假定的过氧化物酶体 β-氧化作用。
DOI：
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发表时间：
2001
影响因子：
3.8
通讯作者：
V. Huszagh
中科院分区：
文献类型：
--
作者：
Juan P. Infante;V. Huszagh
假定参与过氧化物酶体β-氧化的二十二碳六烯酸（22：6 n-3，DHA）的合成的生物合成途径进行了严格审查，根据实验与最近开发的基因敲除小鼠模型Zellweger综合征，过氧化物酶体疾病影响大脑发育。这些小鼠通过靶向破坏编码靶向信号受体过氧化物的PEX 2和PEX 5过氧化物酶体组装基因来产生，所述过氧化物酶体组装基因用于识别一组过氧化物酶体酶并将其转运至过氧化物酶体基质，所述过氧化物酶体酶包括过氧化物酶体β-氧化的那些。PEX 2-/-和PEX 5-/-小鼠中酯化22：6 n-3浓度的分析不支持22：6 n-3合成中过氧化物酶体β-氧化的假设要求，因为仅脑22：6 n-3水平降低，而非肝脏或血浆。用22：6 n-3补充PEX 5 +/-母鼠，尽管将脑22：6 n-3在总脂质中的水平恢复到对照组的水平，但表型没有正常化。这些降低的脑22：6 n-3浓度似乎是继发于缩醛磷脂（sn-1-烷基-，烯基-2-酰基甘油磷脂）合成受损，可能是在磷酸二羟丙酮酰基转移酶（DHAP-AT）水平，这是一种过氧化物酶体酶，催化富含22：6 n-3的缩醛磷脂合成的第一步。为了减少这些Zellweger综合征小鼠模型大脑中缩醛磷脂合成受损的混杂效应，建议在肝脏或分离的肝细胞中使用标记前体（如18：3 n-3或20：5 n-3）进行动力学实验，以确定22：6 n-3生物合成速率和代谢产物-产物关系。使用酰基辅酶A氧化酶敲除小鼠模型的脑进行的类似实验被提出来证实22：6 n-3合成中缺乏过氧化物酶体β-氧化参与，因为该突变不会损害缩醛磷脂的合成。
The putative involvement of peroxisomal beta-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal beta-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2-/- and PEX5-/- mice do not support the hypothesized requirement of peroxisomal beta-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/- dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor-product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal beta-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.
DOI：
10.1016/s0021-9258(18)54882-1
发表时间：
1991-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
A. Voss;M. Reinhart;S. Sankarappa;H. Sprecher
通讯作者：
A. Voss;M. Reinhart;S. Sankarappa;H. Sprecher
缩醛磷脂状态影响巨噬细胞系中的二十二碳六烯酸水平。
影响因子：
6.5
作者：
Gaposchkin,DP;Zoeller,RA
通讯作者：
Zoeller,RA