CHEMICAL PROPERTIES OF SH GROUPS 637 



their modification often abolishes activity and, since metabolism depends 

 on sulfhydryl enzymes, it is evident that most important metabolic path- 

 ways would be sensitive to SH reagents. In addition, coenzyme A, lipoate, 

 and glutathione function in key metabolic positions. Thus glycolysis, the 

 tricarboxylate cycle, fatty acid oxidation, photosynthesis, phosphate trans- 

 fer, and various synthetic pathways are inhibitable by SH reagents. Many 

 effects of thiols on metabolism have been observed but no detailed mechan- 

 isms emerge. Brain respiration and glycolysis in vivo proceed at only a frac- 

 tion of their maximal rates; it has long been known that glutathione stim- 

 ulates aerobic glycolysis in the brain, and thus it has been implicated in 

 the regulation of cerebral metabolism. Mcllwain (1959) reported that the 

 aerobic glycolysis of brain slices is stimulated by glutathione, cysteine, 

 homocysteine, 2-mercaptoethanol, and other thiols, although the effects on 

 respiration are rather slight. However, the respiratory stimulation by 50 m.M 

 KCl is depressed by these thiols, as is the excess respiration in the presence 

 of dinitrophei|ol. The glycolytic stimulation is accompanied by a decrease 

 in creatine-P and a rise in inorganic phosphate, these changes being corre- 

 lated with the metabolic changes. If the respiratory augmentation produced 

 by increased functional activity were mediated through glutathione or 

 similar thiols, there would have to be a fairly large change in their concen- 

 trations, or in the ratios of the oxidized and reduced forms, which is not 

 observed. The metabolic relations are clear but it is not known by what 

 mechanism the thiols reduce brain creatine-P. 



Studies of the effects of SH reagents on cell function are complicated by 

 the fact that undoubtedly some of the proteins of the functional systems 

 contain SH groups, and may even be dependent upon them. This has been 

 investigated principally in the proteins involved in motility; for example, 

 the polymerization of G- to F-actin, the interaction of actin and myosin, 

 the ATP-induced contractions of glycerinated flagella, the round-up of cul- 

 tured fibroblasts, the formation of the mitotic apparatus, and many other 

 phenomena appear to be dependent on free SH groups. Cell excitability 

 and impulse conduction, based on ionic fluxes and a specific membrane 

 ^ructure, must also involve SH groups in the membrane. Thus effects of 

 SH reagents on cell function cannot be immediately interpreted in terms 

 of an enzymic or metabolic site of action. 



CHEMICAL PROPERTIES OF SH GROUPS 



Only a few characteristics of the SH group that are particularly important 

 in enzyme inhibition will be discussed. A brief and excellent summary of 

 sulfur chemistry is that of Calvin (1954) and much of interest may be found 

 in "Organic Sulfur Compounds" edited by Kharasch (1961), as well as in 

 the general references given earlier in this chapter. 



