Should the Human Proteome Project be gene- or protein-centric?
Should the Human Proteome Project be gene- or protein-centric?
复制标题
人类蛋白质组计划应该以基因为中心还是以蛋白质为中心？
DOI：
10.1021/pr800884r
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发表时间：
2008
影响因子：
4.4
通讯作者：
D. Hochstrasser
中科院分区：
文献类型：
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作者：
D. Hochstrasser
疾病是由基因缺陷（突变、缺失等）和/或环境造成的，环境可分为两部分：毒物和微生物。所有人类疾病的病因都属于这三大类：基因、毒物和微生物，每一类都有不同的参与。例如，亨廷顿氏病基本上是由单个基因缺陷引起的，而高血压和糖尿病是多个基因缺陷的结果，通常是食物“毒性”或过量。肺炎通常是由微生物引起的，但遗传易感性和摄入有毒物质（如酗酒）也可能是因素。因此，除了对许多疾病的遗传易感性外，还必须测量微生物和环境的主要影响。后者在遗传或转录水平以及宿主抗体产生（血清学测试）或免疫细胞反应中最有效地检测。前者可以在许多层面上被解开，这取决于有害的化学物质，其中一些会修饰DNA、RNA、蛋白质或代谢物。分析取决于化学物质的反应性和所涉及的生物系统。因此，以基因为中心的人类蛋白质组计划（HPP）只能捕捉到人类疾病中可能发生的一小部分变化。显然，我们需要扩大HPP，纳入对环境因素的研究。生物学和医学。遗传物质，在DNA水平上，似乎在生物物种之间是流动的，但在个体内部相对静止，除了癌症增殖和某些细胞类型。然而，蛋白质是动态的。蛋白质的重塑、生物降解和合成过程受到多种方式的调节，对某些蛋白质来说，这些过程是不断发生的。正如诺贝尔奖得主亚伦·切哈诺沃的一篇开创性论文（《生物化学》）所证明的那样。Biophys。Res. common . 1978, 81, 1100r1105)，胞内蛋白降解受到严格控制，需要能量。蛋白质的半衰期、浓度水平和修饰与细胞代谢密切相关，可能与基因表达水平的直接联系较少。例如，由于某些蛋白质的异常积累或其他蛋白质的过快降解，细胞内多肽降解的失调可能导致阿尔茨海默病或癌症。蛋白质降解系统甚至是药物研究中小分子靶标搜索的一个领域。在生物学和医学中，对细胞的正常和生理病理反应的理解必须涉及到应用系统科学方法来研究蛋白质及其修饰，以及环境影响。生物信息学。外显子预测以及蛋白质结构和功能的最终验证只能在蛋白质水平上完成。虽然Swiss-Prot/UniProtKB现在列出了大多数，
Diseases are due to gene defects (mutations, deletions, etc.) and/or the environment, which can then be divided into two components: toxicants and microbes. The etiology of all human diseases belongs to these three categoriessgenes, toxicants, and microbesswith a variable involvement for each one. For example, Huntington’s disease is essentially caused by a single gene defect, whereas hypertension and diabetes are the result of multiple gene defects and, often, food “toxicity” or overabundance. Pneumonia is frequently caused by microbes, but genetic predisposition and the uptake of toxic products, such as in alcoholism, can be factors, too. Therefore, it is essential to measure the predominant effects of microbes and of the environment in addition to genetic predisposition for many diseases. The latter is most efficiently detected at the genetic or transcriptomic level, as well as with host antibody production (serology testing) or immune-cell responses. The former can be unraveled at many levels, depending on the offending chemicals, some of which modify DNA, RNA, proteins, or metabolites. The analysis depends on the reactivity of the chemicals and the biological system that is implicated. Thus, a gene-centric Human Proteome Project (HPP) would capture only a fraction of the changes that can occur in human disease. Clearly, we need to expand an HPP to include the study of environmental factors.Biology and medicine. Genetic material, at the DNA level, seems to be mobile among living species but relatively static within individuals, except in cancer proliferation and certain cell types. However, proteins are dynamic. The processes of protein remodeling, biodegradation, and synthesis are regulated in diverse ways, and for some proteins, these processes occur constantly. As demonstrated in one of Nobel Prize winner Aaron Ciechanover’s pioneering papers (Biochem. Biophys. Res. Commun. 1978, 81, 1100r1105), intracellular protein degradation is tightly controlled and requires energy. Protein half-lives, concentration levels, and modifications are intimately linked to cell metabolism and are probably less directly linked to gene expression level. For example, deregulation of intracellular polypeptide degradation can lead to Alzheimer’s disease or cancer because of the abnormal accumulation of certain proteins or because of the too-rapid degradation of others. The protein degradation system is even a domain of small-molecule target searching in pharmaceutical research. The understanding of normal and physiopathological responses of cells in biology and medicine has to involve the application of a systems science approach to the study of proteins and their modifications, as well as environmental effects. Bioinformatics. The final verification of exon prediction and of protein structure and function can be done only at the protein level. Although Swiss-Prot/UniProtKB now lists most,