汉斯·克雷布斯与谷氨酰胺在临床营养的应用

Hans Krebs and the foundation of the use of glutamine in clinical nutrition： a personal perspective

汉斯·阿道夫·克雷布斯（Hans Adolf Krebs）（1953年诺贝尔奖获得者）为谷氨酰胺在临床营养的应用开创了新的舞台,本文对其在谷氨酰胺代谢方面的研究贡献进行阐述.本文两位作者在谷氨酰胺代谢方面也进行了多年研究,并在克雷布斯教授指导下完成了牛津大学哲学博士学位训练.1923年,克雷布斯成为一名医生,并参加了3年的临床培训.1926年,他进入奥托·沃伯格（Otto Warburg）（1931年诺贝尔奖获得者）实验室开始了他的科研生涯.克雷布斯利用沃伯格测压法等技术对肿瘤相关蛋白降解代谢进行相关研究.1931年克雷布斯开始研究合成反应,并于1932年描述了第一个生化循环路径——尿素循环.1933年克雷布斯移居英格兰,同时将研究集中于氨基酸代谢,从分子水平阐述动物组织谷氨酰胺代谢,为临床营养应用谷氨酰胺奠定了基础.其研究以谷氨酰胺异常代谢为起点,之后,他将注意力转移到谷氨酰胺水解产生谷氨酸与氨的过程.克雷布斯于1935年发表文章阐述谷氨酰胺代谢的重要酶学研究,如谷氨酰胺的合成是一个吸热反应,需要能量供应.同时,他鉴定了谷氨酰胺酶对谷氨酰胺的水解作用,且不同组织含有不同亚型的谷氨酰胺酶.此外,他还阐述了分布最广泛的“脑型”谷氨酰胺酶的基本调节特点,证实其受谷氨酸负反馈调节,而“肝型”谷氨酰胺酶则不受此调节.1935年的文章发表后,克雷布斯仍致力于应用当时最先进的技术方法对氨基酸代谢进行各种研究,并将注意力转移到谷氨酰胺其他代谢过程.20世纪70年代,克雷布斯与其同事合作,发现谷氨酰胺是肝糖异生与尿素合成的底物,肾糖异生与氨的产物,且是小肠上皮细胞的代谢底物.此外,克雷布斯团队还发现骨骼肌可以释放大量谷氨酰胺,同时阐述了肝在谷氨酰胺利用与合成中的作用.直到克雷布斯去世（1981年）前,他仍致力于支链氨基酸与谷氨酰胺代谢关系的研究.在过去的20-30年大量研究中,威尔莫（Wilmor）与弗斯特（Furst）团队最先发表文章描述谷氨酰胺在临床肠外营养中的补充应用.关于在临床营养中补充谷氨酰胺,已发表了大量研究文章与综述,一些研究展示了其非常显著的有效性,更多的研究显示它具有一定效果,也有研究发现它在某些人群中会产生不良反应.总而言之,谷氨酰胺在临床营养的运用在很大程度上应归功于克雷布斯与他的同事和实习生所做的大量工作.描述与克雷布斯工作“个人追忆”的本文作者,非常感谢作为谷氨酰胺之父的汉斯·阿道夫·克雷布斯教授对他们科学研究技术的培养.

This article details the role of Hans Adolf Krebs （Nobel Laureate 1953） in the study of glutamine metabolism that set the stage for the use of glutamine in clinical nutrition. The authors have carried out research on glutamine metabolism for many years and both trained under Krebs for the degree of Doctor of Philosophy at the Uni-versity of Oxford. In 1923, Krebs qualified in medicine and spent three years in clinical training. He began his sci- entific career in the laboratory of Otto Warlmrg in 1926. Using Warburg manometry, Krebs worked on a number of projects related to degradation reactions in tumors. In 1931 he began to study synthetic reactions and described the urea cycle, the first cyclic biochemical pathway. In 1933 Krebs moved to England where he continued to work on amino acid metabolism and in 1935 he established the first molecular insights into glutamine metabolism in animal tissues that set the stage for the use of glutamine in elinical nutrition. He had identified the hydrolysis of glutanfine by glutaminase and shown that there were different tissue isoforms of the enzyme. He described the fundamental reg- ulatory feature of the most widespread ＂brain-type＂ glutaminase, that it is product-inhibited by glutamate; he showed that the ＂liver-type＂ isoform was not subject to this form of regulation. After the 1935 paper Krebs worked on other aspects of intermediary metabolism but continued to study glutamine, often applying the latest methodological ad- vances. By the early 1970s, Krebs, and his colleagues, had established that glutamine was a good suhstrate for he- patic gluconeogenesis and urea synthesis, for renal glueoneogenesis and ammoniagenesis, and was a good respiratory substrate for enteroeytes d the snkall intestine. Furthermore, the Krebs group had showed that skeletal muscle re- leased significant amounts of glutamine and had defined the role of the liver in both glutamine utilization and synthe- sis. At the time of his death （ 1981 ） he was still working on the relationship of branched chain amino acids to gluta- mine metabolism during the past quarter of a century numerous studies, initially from the groups of Wilmore and Ftirst, have heen published describing the use of supplemental glutamine in TPN. A number of meta-analyses have been published with most reporting positive effects of glutamine supplementation, although a few have indicated ad- verse effects in a select group of patients. Thus the use of glutamine in clinical medicine owes a lot to the work of Krebs and his collaborators and trainees. The authors include a section of ＂Personal Reflections＂ describing working with Krehs and both are grateful for the training in the art of scientific investigation receveived from Professor Sir Hans A. Krehs, the father of glutarnine metabolism.