Cellular Metabolism 



79 



the initial linkage. A series of "trans" en- 

 zymes have been described (cf. Cohen, in 

 Lardy, '50) in addition to the transphosphor- 

 ylases already mentioned. Transaminase, 

 transiminase, transulfiirase, transmethylase 

 have all been studied with considerable pre- 

 cision. The dehydrogenase enzymes are essen- 

 tially transhydrogenases and, with the DPN 

 coenzyme system, function in a fashion per- 

 fectly analogous to the transphosphorylases 

 working with the adenylic acid coenzyme 

 system. 



While mechanisms of protein and fat syn- 

 thesis are not clearly understood as the car- 

 bohydrate models, essentially similar systems 

 have been postulated on the basis of very 

 suggestive data (cf. Ratner, '49; Lipmann, 

 '49; Borsook et al., '49).* Fruton ('50), in an 

 interesting paper, suggests that cellular pep- 

 tidase may act in building up polypeptides 

 and proteins by transferring peptides to al- 

 ready existing peptide chains, the process 

 being in many respects similar to the reac- 

 tions noted for the formation of polysac- 

 charide by tranferring a monosaccharide 

 from a disaccharide to an existing chain of 

 sugar residues. 



THE CONTROL OF CELLULAR 

 METABOLISMt 



A living cell at work must depend upon 

 the precise integration of a complex mosaic 

 of active units. The examples chosen from 

 the glycolytic and oxidative cycles illustrate 

 both the multiplicity of the parts involved 

 and their interdependence. In addition, it 



* The discussion by Borsook is especially illumi- 

 nating with respect to the general nature of the 

 problems considered and the careful speculations 

 about cellular mechanisms that may be concerned 

 with amino acid incorporation into tissues. 



f In this section, as in the preceding one on gly- 

 colytic and oxidative mechanisms, we shall discuss 

 examples rather than attempt a complete coverage 

 of all experiments designed to elucidate control of 

 metabolism. Much good work has been done in an 

 attempt to analyze the relationship of physiological 

 processes and chemical reactions, mainly by defin- 

 ing enzyme systems in tissue breis and by deter- 

 mining the effects of added inhibitors on functions, 

 or the effects of addition or depletion of substrate. 

 No single formula is yet available that will ensure 

 that such studies are meaningful in terms of the life 

 of the cell. The interpretation of studies which in- 

 volve upsetting the metabolic machinery must al- 

 ways be made cautiously against the background of 

 the material so well set forth by Heilbrunn in his 

 "Outline of General Physiology," as well as the 

 details of our knowledge of enzyme systems. 



must be remembered that there are many 

 special pathways associated with special cel- 

 lular functions. The existence of multi-unit 

 systems that function in an orderly manner 

 implies also the existence of precise con- 

 trolling mechanisms. Probably the most chal- 

 lenging problem confronting the general 

 physiologist today is that of piecing together 

 our knowledge of fragments of the active 

 framework of the living cell in such a fashion 

 that not only will the energy balances hold 

 true, but the orderliness of life will also 

 follow. 



If the components of the glycolytic and 

 oxidative systems are mixed together in a 

 test tube, some orderly controlled reactions 

 will take place by virtue of the sharing of 

 reactants and reaction products of unit proc- 

 esses of the system. For example, in the 

 fermentation of sugar by cell-free extracts of 

 yeast, the rate of carbon dioxide production 

 can be controlled by the concentration of such 

 components as sugar, phosphate, ATP and 

 so forth. If the enzymes hydrolyzing ATP 

 are blocked, phosphate tends to disappear as 

 new ATP is formed; thus further phosphory- 

 lation of sugars is inhibited and hexose mono- 

 phosphate accumulates. Thus a "control" of 

 sugar phosphorylation can be effected by 

 controlling ATP dephosphorylation. This 

 type of control, however, would have dis- 

 tinct limitations and, in particular, it is 

 difficult to visualize regulation of the many 

 rather fast "off-on" shifts in metabolism in 

 this fashion. Fortunately, there is good evi- 

 dence that the components of the reactions 

 are not free to mix as in the test tube, but 

 are highly and precisely localized within 

 the structure of the cell. Evidence for intra- 

 cellular localization of enzymes has been 

 accumulating over a period of years and 

 need not be detailed here (cf. Schneider, in 

 Lardy, '50). Ever since the work of Warburg, 

 it has been recognized that the metal-con- 

 taining oxidases are associated with insoluble 

 cell fragments in a suspension of fragmented 

 tissue. Cytochrome c appears to be reasonably 

 soluble but the other cytochromes and the 

 oxidase are put into solution only with great 

 difficulty. Similarly, the cytochrome-linked 

 dehydrogenases are separated from insoluble 

 cell particles only with difficulty (cf. Mc- 

 Shan, in Lardy, '50). Green (in Lardy, '50) 

 discusses evidence that the enzymes of the 

 citric acid cycle are always associated with 

 the insoluble residue of tissue homogenates; 

 partly on this basis he names the system 

 cyclophorase. The enzymes primarily asso- 



