溶酶体酶芳基硫酸酯酶A和-半乳糖脑苷酶的纯化选择及其对髓磷脂完整性的进化影响。

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Lipid Research Pub Date : 2025-04-01 Epub Date: 2025-03-05 DOI:10.1016/j.jlr.2025.100769
Matthew A Luetzen, Richik Chakraborty, Oscar Andrés Moreno-Ramos, Olga Yaneth Echeverri-Peña, Yoko Satta, Adriana M Montaño
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引用次数: 0

摘要

髓磷脂负责为神经细胞的轴突提供稳定性,但最重要的是提高脊椎动物神经冲动的传输速度。超过70%的髓鞘由脂质组成,其余部分由大约2000种蛋白质组成。髓鞘一直在不断进化,已知异常高浓度的GalCer及其硫酸盐化形式在髓鞘的生物物理特性中起主要作用。为了深入了解GalCer的进化作用,我们研究了参与GalCer降解的两种溶酶体酶,芳基硫酸酯酶A (ARSA)和半乳糖脑苷酶(GALC)。ARSA或GALC缺乏引起脱髓鞘疾病。我们对105个ARSA和110个GALC同源物进行了系统发育分析,这些同源物代表了超过600万年的进化。我们检查了1)非同义核苷酸取代率与同义核苷酸取代率(dN/dS)的低值,表明纯化选择,以及2)位于活性位点的氨基酸的负选择,防止致病性突变。基因结构分析显示外显子的增加和减少是重排的证据,而保守区域主要位于活性位点周围。我们还发现,在正选择压力下,有限数量的位点不会导致整体蛋白质结构的改变。我们的研究结果表明,在进化过程中,ARSA和GALC高度保守,以维持GalCer的代谢,这对脊椎动物白质的完整性至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Purifying selection of the lysosomal enzymes arylsulfatase A and beta-galactocerebrosidase and their evolutionary impact on myelin integrity.

The myelin is responsible for providing stability to the axons of the nerve cells, but above all, to improve transmission speed of the nerve impulse in vertebrates. Over 70% of the myelin sheath is composed of lipids and the remaining portion by approximately 2,000 proteins. The myelin sheath has been constantly evolving, and it is known that unusually high concentrations of galactosylceramide (GalCer) and its sulfated form play a major role in the biophysical properties of the myelin. To gain insights of the evolutionary role of GalCer, we have studied two lysosomal enzymes involved in GalCer degradation, arylsulfatase A (ARSA) and galactocerebrosidase (GALC). Deficiency of ARSA or GALC causes demyelinating disorders. We conducted phylogenetic analyses of 105 ARSA and 110 GALC orthologs representing more than 600 million years ago of evolution. We examined i) low values of the ratio of nonsynonymous to synonymous nucleotide-substitution rates (dN/dS) indicating purifying selection and ii) negative selection of amino acids located in the active site preventing pathogenic mutations. Gene structure analyses showed evidence of rearrangement with gain and loss of exons while there were conserved regions mainly located around the active site. We also found a limited number of sites under positive selection pressure that do not cause alterations to the overall protein structure. Our results indicate that ARSA and GALC have been highly conserved during the evolutionary process to maintain the metabolism of GalCer, which is essential for the integrity of the white matter in vertebrate species.

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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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