Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr. MC0719, La Jolla, CA, 92093-0719, USA.
Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
J Am Soc Mass Spectrom. 2018 May;29(5):807-816. doi: 10.1007/s13361-018-1914-1. Epub 2018 Apr 17.
Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2-4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell-cell signaling. Graphical Abstract ᅟ.
神经肽是 3-40 个残基组成的短肽，在神经内分泌系统中分泌用于细胞间通讯。在神经系统中，神经肽是最大的神经递质群。在内分泌系统中，神经肽作为肽类激素发挥作用，协调靶生理系统之间的细胞间信号转导。神经肽功能的多样性由其独特的一级序列、肽长度、前神经肽原的蛋白水解加工和共价修饰决定。非靶向性的全局神经肽组学质谱分析有利于定义生物系统中存在的数千到数万种神经肽的结构特征。定义神经肽结构是定义将前神经肽转化为活性肽的蛋白水解加工途径的基础。神经肽组学揭示了前神经肽的加工发生在碱性氨基酸对位点和非碱性氨基酸对位点。加工产生具有已知功能的神经肽，并生成新的肽，这些肽代表由二碱基加工位点侧翼的间隔肽域，通过神经肽组学鉴定。虽然从前神经肽中二碱基加工位点预测到具有 2-4 个残基的非常短的肽产物，但这些肽尚未被轻易识别；因此，在未来的研究中，利用代谢组学结合神经肽组学来识别非常短的肽是合乎逻辑的。蛋白水解加工伴随着神经肽的共价翻译后修饰 (PTM)，包括 C 端酰胺化、N 端焦谷氨酸化、二硫键、磷酸化、硫酸化、乙酰化、糖基化等。神经肽组学可以定义神经肽的 PTM 特征。总之，非靶向性、全局神经肽分析的神经肽组学对于阐明产生用于细胞间信号传递的多样化神经肽的蛋白酶至关重要。
