ANALOG INHIBITION OF MEMBRANE TRANSPORT 261 



(sucli as the cholinesterase and monoamine oxidase inhibitors), or antime- 

 tabolites used in microbial growth suppression or tumoristasis. 



A few general references treating aspects of the subject not included 

 in the present work are suggested for additional information: Welch (1945), 

 Work and Work (1948), Woolley (1950 b, 1952), Martin (1951), Rhoads 

 (1955), Matthews (1958), Albert (1960), Schueler (1960), Schatz (1960), 

 Kaiser (1960), and the Symposium on Antimetabolites sponsored by the 

 National Vitamin Foundation (1955). A great deal of information on the 

 biological actions of many types of analog will be found in Volume I of 

 "Metabolic Inhibitors" edited by Hochster and Quastel (1963), and this 

 aspect of the subject will be mainly omitted in the present work so that 

 the enzymic effects may be discussed in sufficient detail. 



ANALOG INHIBITION OF MEMBRANE TRANSPORT 



Before discussing specific enzyme inhibitions by analogs, we must turn 

 our attention to the possibility that the depression of the utilization of 

 some substrate or metabolite by an analog is not due to an action on any 

 enzyme involved in the metabolism, but is the result of a specific inter- 

 ference with the transport of the substrate or metabolite into the cell. 

 It is quite probable that some of the actions of analogs on metabolism, at- 

 tributed to competition at the enzyme level, are actually exerted at the 

 cell membrane; indeed, certain instances will be discussed. It is becoming 

 more and more evident that many substrates and metabolic precursors 

 are taken up by cells by processes other than simple diffusion, and this 

 applies particularly to certain carbohydrates, amino acids, coenzymes, 

 or coenzyme precursors. It is not necessary that the transport be active 

 to be influenced by analogs; any movement of a substance through a mem- 

 brane which involves a carrier, a special size or configuration of pores, or a 

 specific type of mechanism, active or passive, can be slowed in the presence 

 of an analog of this substance. It is possible, o^ course, that the membrane 

 trasport is mediated through an enzyme reaction, such as a phosphoryla- 

 tion, and the competition by the analog is then truly an enzymatic one. 



It is sometimes difficult to determine if there is inhibition of a transport 

 process. The demonstration of a reduced uptake of a substrate from the 

 medium is generally not sufficient evidence, inasmuch as a decreased in- 

 tracellular utilization might also be responsible. The best procedure is to 

 determine directly the concentration of the substrate within the cells in 

 the absence and presence of the analog, but sometimes the concentration 

 is too low to measure accurately, especially when the substrate is rapidly 

 metabolized. The demonstration of typical competitive inhibition with 

 respect to the action of an analog on some metabolic process is also not 

 sufficient evidence for an enzymic site of action, because the inhibition of 



