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BRIEF PROPOSAL COULD THOSE RAPIDLY EXCHANGEABLE PHOSPHOPROTEINS BE POLYPHOSPHATE-PROTEIN COMPLEXES? NORMAN W. GABEL* Phosphates, both organic and inorganic, and the metal ions of calcium, magnesium , sodium, and potassium are known to play a significant role in neural function. Cyclic phosphate-exchange mechanisms which involve phosphoproteins, phosphocreatine, and ATP have been proposed to occur during neuronal impulse transmission [I]. More recently, attention has been focused upon the regulatory behavior of Na+, K-|-dependent ATPases on transport phenomena in general [2] in addition to their hitherto proposed role in cation transport [3] . The most elusive component of the neural Na+, K+-dependent ATPase system appears to be an acid-labile phosphoprotein which rapidly exchanges orthophosphate with the ?-orthophosphate group of ATP [4] . During the past decade, a considerable amount of effort has been expended by biochemists to elucidate the structural nature of the "high-energy" rapidly exchangeable phosphate groups of phosphoproteins. Upon degradation, the rapidly incorporated phosphorus always appeared as phosphoserine or phosphothreonine. Enigmatically, these phosphateester bonds are rather hydrolytically stable and have a relatively low free energy of hydrolysis. It seems unreasonable that phosphate bonds which have a high free energy of activation with a low free energy of hydrolysis could participate in any rapid cyclic phosphate-exchange mechanisms with phosphocreatine or ATP. Rodnight, Hems, and Lavin [5] have suggested that the isolation of rapidly, radioactively labeled phosphoserine and phosphothreonine may be an artifact produced by the acidic isolation procedure. In any extraction technique applied to biological samples, the isolated materials should be viewed from the perspective of being possible reaction products which arise from the original tissue components and the reagents introduced during the extraction procedure. The procedure of Berenblum and Chain [6] for determining inorganic phosphate in tissue would hydrolyze or esterify polyphosphate. Inorganic phosphorus determined by this method should not be considered to be a homogeneous pool. At the present time, interest in the function of proteins with rapidly exchangeable phosphate groups remains high, but research into the structure of this highenergy phosphate bond has dropped to a low level. Since it is my conviction that function and structure cannot be fully appreciated or understood independently * Research Department, Illinois State Psychiatric Institute, 1601 West Taylor Street, Chicago, Illinois 60612. 640 I Norman W. Gabel ยท Brief Proposal of each other, the objective of this proposal is the examination of a rational alternative to the structure of high-energy phosphoproteins within the context of function. During the course of an examination of observations associated with excitable membranes, it was recognized that many of the properties of a viable neuronal membrane would also be present in a macromolecular polyphosphate coordination complex in which alkaline earth metals (Ca2+;Mg2+) would have a crosslinking function and in which alkali metals (Na+; K+) would serve as counterions [7, 8]. Polyphosphates, because of the acid anhydride-bond structure of the polymeric backbone, would fit very well into the above-mentioned cyclic exchange mechanism. Polyphosphates are noted for their constant reorganization and state of flux [9]. Furthermore, polyphosphates in microorganisms are known to form tightly bound ionic complexes with proteins and nucleic acids [10]. One method of separating microbiological polyphosphate from proteins and nucleic acids is digestion of the sample in strongly basic solutions [H]. This is the same procedure which is followed in the removal of phosphate from mammalian phosphoproteins [4, 12]. Twenty years ago, it was recognized that high molecular weight, rapidly metabolizing, acid-labile, catabolically unstable phosphorus material was present in the neuronal membrane and was thereby especially concentrated in the white matter of whole brain [13]. Logan and his associates [13] demonstrated that this material was not a nucleic acid as had been previously postulated and that it did not fit the classic description of phosphoproteins. Polyphosphates were first reported as constituents of living cells (yeast) by Wiame [14]. Since then, their occurrence in microorganisms has become well documented. Their biological role, however, remains unclear [10]. Reports of the occurrence of polyphospate in mammalian liver [15, 16] and plant tissue [1719 ] have also been published. During the past few years additional evidence for the occurrence of inorganic polyphosphates in neural tissue as well as several other vertebrate tissues has been obtained...


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