Waterlow J C
Human Nutrition Unit, London School of Hygiene & Tropical Medicine, 50 Bedford Square, London WC1B 3DP, UK.
Nutr Res Rev. 1999 Jun;12(1):25-54. doi: 10.1079/095442299108728857.
The first part of this review is concerned with the balance between N input and output as urinary urea. I start with some observations on classical biochemical studies of the operation of the urea cycle. According to Krebs, the cycle is instantaneous and automatic, as a result of the irreversibility of the first enzyme, carbamoyl-phosphate synthetase 1 (EC 6.3.5.5; CPS-I), and it should be able to handle many times the normal input to the cycle. It is now generally agreed that acetyl glutamate is a necessary co-factor for CPS-1, but not a regulator. There is abundant evidence that changes in dietary protein supply induce coordinated changes in the amounts of all five urea-cycle enzymes. How this coordination is achieved, and why it should be necessary in view of the properties of the cycle mentioned above, is unknown. At the physiological level it is not clear how a change in protein intake is translated into a change of urea cycle activity. It is very unlikely that the signal is an alteration in the plasma concentration either of total amino-N or of any single amino acid. The immediate substrates of the urea cycle are NH3 and aspartate, but there have been no measurements of their concentration in the liver in relation to urea production. Measurements of urea kinetics have shown that in many cases urea production exceeds N intake, and it is only through transfer of some of the urea produced to the colon, where it is hydrolysed to NH3, that it is possible to achieve N balance. It is beginning to look as if this process is regulated, possibly through the operation of recently discovered urea transporters in the kidney and colon. The second part of the review deals with the synthesis and breakdown of protein. The evidence on whole-body protein turnover under a variety of conditions strongly suggests that the components of turnover, including amino acid oxidation, are influenced and perhaps regulated by amino acid supply or amino acid concentration, with insulin playing an important but secondary role. Molecular biology has provided a great deal of information about the complex processes of protein synthesis and breakdown, but so far has nothing to say about how they are coordinated so that in the steady state they are equal. A simple hypothesis is proposed to fill this gap, based on the self-evident fact that for two processes to be coordinated they must have some factor in common. This common factor is the amino acid pool, which provides the substrates for synthesis and represents the products of breakdown. The review concludes that although the achievement and maintenance of N balance is a fact of life that we tend to take for granted, there are many features of it that are not understood, principally the control of urea production and excretion to match the intake, and the coordination of protein synthesis and breakdown to maintain a relatively constant lean body mass.
本综述的第一部分关注氮输入与作为尿尿素的氮输出之间的平衡。我首先对尿素循环运作的经典生化研究进行一些观察。根据克雷布斯的观点，由于第一种酶即氨甲酰磷酸合成酶1（EC 6.3.5.5；CPS-I）的不可逆性，该循环是瞬间且自动的，并且它应该能够处理比循环正常输入量多许多倍的量。现在人们普遍认为乙酰谷氨酸是CPS-1的必要辅助因子，但不是调节因子。有充分证据表明，饮食蛋白质供应的变化会引起所有五种尿素循环酶量的协同变化。这种协同是如何实现的，以及鉴于上述循环的特性为何有必要这样做，目前尚不清楚。在生理层面，尚不清楚蛋白质摄入量的变化是如何转化为尿素循环活性的变化的。信号极不可能是总氨基氮或任何单一氨基酸的血浆浓度变化。尿素循环的直接底物是氨和天冬氨酸，但尚未有关于它们在肝脏中的浓度与尿素生成关系的测量。尿素动力学测量表明，在许多情况下尿素生成超过氮摄入量，只有通过将部分生成的尿素转运至结肠（在结肠中尿素被水解为氨），才有可能实现氮平衡。看起来这个过程可能受到调节，可能是通过肾脏和结肠中最近发现的尿素转运体的运作来调节。综述的第二部分涉及蛋白质的合成与分解。在各种条件下关于全身蛋白质周转的证据有力地表明，周转的各个组成部分，包括氨基酸氧化，受到氨基酸供应或氨基酸浓度的影响，甚至可能受其调节，胰岛素发挥着重要但次要的作用。分子生物学已经提供了大量关于蛋白质合成和分解复杂过程的信息，但到目前为止对于它们如何协同使得在稳态下二者相等却没有任何说法。基于两个过程要协同就必须有一些共同因素这一不言而喻的事实，提出了一个简单假设来填补这一空白。这个共同因素就是氨基酸池，它为合成提供底物并代表分解的产物。综述得出结论，尽管实现和维持氮平衡是我们往往认为理所当然的生活事实，但其中有许多特征尚未被理解，主要是控制尿素生成和排泄以匹配摄入量，以及协调蛋白质合成和分解以维持相对恒定的瘦体重。
