Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides,Journal of Natural Products

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Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-10-29 , DOI: 10.1021/acs.jnatprod.0c00648
Bernhard Retzl ₁ , Roland Hellinger ₁ , Edin Muratspahić ₁ , Meri E F Pinto _{1,

2} , Vanderlan S Bolzani ₂ , Christian W Gruber ₁

Affiliation

Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from beetroot (Beta vulgaris) termed bevuTI-I was isolated, and its primary structure was determined via mass spectrometry-based amino acid sequencing. By sequence homology analysis a few peptides with high similarity to bevuTI-I, also known as the Mirabilis jalapa trypsin inhibitor subfamily of knottin-type protease inhibitors, were discovered. Hence, we assessed bevuTI-I for inhibitory activity toward trypsin (IC₅₀ = 471 nM) and human prolyl oligopeptidase (IC₅₀ = 11 μM), which is an emerging drug target for neurodegenerative and inflammatory disorders. Interestingly, using a customized bioinformatics approach, bevuTI-I was found to be the missing link to annotate 243 novel sequences of M. jalapa trypsin inhibitor-like peptides. According to their phylogenetic distribution they appear to be common in several plant families. Therefore, the presented approach and our results may help to discover and classify other plant-derived cystine knot peptides, a class of plant molecules that play important functions in plant physiology and are currently being explored as lead molecules and scaffolds in drug development.

中文翻译：

发现一种甜菜根蛋白酶抑制剂来鉴定和分类植物来源的胱氨酸结肽

植物肽蛋白酶抑制剂是种子储存代谢和防治害虫的重要分子。它们通常含有多个二硫键，是非常稳定的分子。在这项研究中，从甜菜根（ Beta vulgaris ）中分离出一种名为bevuTI-I的新型肽蛋白酶抑制剂，并通过基于质谱的氨基酸测序确定了其一级结构。通过序列同源性分析，发现了一些与bevuTI-I（也称为knottin型蛋白酶抑制剂的Mirabilis jalapa胰蛋白酶抑制剂亚家族）高度相似的肽。因此，我们评估了 bevuTI-I 对胰蛋白酶 (IC ₅₀ = 471 nM) 和人脯氨酰寡肽酶 (IC ₅₀ = 11 μM) 的抑制活性，胰蛋白酶是神经退行性和炎症性疾病的新兴药物靶点。有趣的是，使用定制的生物信息学方法，发现 bevuTI-I 是注释M. jalapa胰蛋白酶抑制剂样肽的 243 个新序列的缺失链接。根据它们的系统发育分布，它们似乎在几个植物科中很常见。因此，所提出的方法和我们的结果可能有助于发现和分类其他植物来源的胱氨酸结肽，这是一类在植物生理学中发挥重要功能的植物分子，目前正在探索作为药物开发中的先导分子和支架。

更新日期：2020-11-25

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