Some Transport Lessons Taught by the Organic Solute

SOME TRANSPORT LESSONS TAUGHT BY THE ORGANIC SOLUTE HALVOR N. CHRISTENSEN* I should like to adopt an experimental mood and to consider with you how our understanding of biological transport may perhaps have been advanced through a certain interaction between two contrasting viewpoints . For the first ofthese, we may look back on many decades oftransport interest, which has focused especially on ion transport. The notion of a diffusible complex between the ion and a carrier, which presumably moves within the membrane phase, came into dominance. The stable nature of the inorganic ion often protected the investigator from possible temptations to confuse transport with any lasting metabolic modification or stoichiometric binding ofthe solute; it encouraged, instead, the development ofphysical theory to account for the observed behavior, especially as to its rate, its energy requirements and their sources. From an entirely different point ofview, the investigator ofmetabolism a decade or so ago gradually became aware ofhow frequently an exogenous metabolite failed to mix with its presumed endogenous equivalent. Rather suddenly, at about that time, this formerly irritating circumstance became instead a favored target of study, and the earlier distaste for the so-called permeability problem was replaced by enthusiasm for invoking the concept oftransport, both where it was appropriate and where it was not. These investigators tended to bring with them a desire to find that translocation is produced by enzymes in special membrane-bound positions and an indifference as to whether or not the event corresponded to * Department of Biological Chemistry, The University oí Michigan, Ann Arbor. This paper was presented at the Symposium ofthe Canadian Federation ofBiological Societies, University of British Columbia, Vancouver,June 10, 1966. The experimental results derived from this laboratory were supported in part by a grant (HD-01233) from the Institute ofChild Health and Human Development , National Institutes ofHealth, United States Public Health Service. 47I the pre-existing physical definition oftransport. It has taken most of the subsequent decade for the metabolic investigator to identify his problem with the long-term goal of the first group, who were more often cell physiologists than biochemists. That decade has, however, produced what I believe is proving a highly fruitful interaction between these two approaches . Perhaps that thesis, as I try to develop it, will prove instead no more than a convenient framework for presenting to you the results I want to tell you about. The apparent similarity of the access step to other metabolic steps tempted the student oforganic metabolism to suppose that the two have much the same character. Furthermore, because the transport step can be genetically determined, its enzymatic nature was felt to be confirmed, so it seemed safe to give the presumed affector enzyme the name "permease" [i], pending its anticipated discovery. Tojust what entity a term ofthat nature should apply has been a matter for a sequence ofredecisions perhaps still to be completed. The bet seems a safe one, however, because somewhere around a transport, at least an uphill transport, there must be one or more enzymatic reactions. For example, the whole process must in effect be an ATPase, ifcleavage ofATP provides the energy. Mydiscussion has to do with a narrower question: the nature and function ofthe molecule by which the solute is grasped for transport. One of the reasons for a high degree of similarity between an access step and other metabolic steps may be theneed for the exogenous metabolite to be subtly modified before it becomes identical with its endogenous equivalent. But such an access step is not transport. To prove that an enzyme produces a decisive step in transport, we ought to be sure that we are dealing with a transport, not a purely chemical access step or the sum ofa transport and a chemical modification ofthe substrate. For relevance to our subject, one must follow molecular transport rather than translocation ofa chemical group or radical from a donor to an acceptor. At first, the student oforganic metabolism was reluctant to accept the value ofthat distinction, a lesson he needed to learn from those who had participated longer in the study ofinorganic-ion transport. Also, during the past decade, transported solutes have been shown not to exchange certain of their atoms...