The finding that cellular proteins are turning over—synthesized and
degraded constantly—has traversed a torturous road from its discovery in
the 1940s until it has reached its current central position as a major
regulatory pathway. The dynamic state of the proteome was discovered by
Rudolph Schoenheimer who used radiolabeled compounds to demonstrate
that proteins are in a constant state of generation and destruction (1). Yet,
the extent, the mechanisms and the physiological significance of roles of
protein degradation have remained elusive for many years. Simpson
reported that degradation of labeled proteins in liver slices requires
metabolic energy (2). This—thermodynamically paradoxical finding—
where investment of energy is still required for the degradation of energyrich
macromolecules—proteins—to low energy small molecules—amino
acids—has been corroborated in many studies ever since in both eukaryotes
and prokaryotes. Since proteolysis is an exergonic process, the requirement
for energy had remained an enigma. Simpson tried to explain that "The fact
that a supply of energy seems to be necessary for both the incorporation and
the release of amino acids from protein might well mean that the two
processes are interrelated". He concluded however by saying that "...the
fact that protein hydrolysis as catalyzed by the familiar proteases and
peptidases occurs exergonically, together with the consideration that
autolysis in excised organs or tissue minces continues for weeks, long after
phosphorylation or oxidation ceased, renders improbable the hypothesis of
the direct energy dependence of the reactions leading to protein
breakdown" (2). The basic principle that cleavage of a peptide bond is
exergonic, has not and could not have been challenged. Yet, the simple
notion that proteases cannot exist in one compartment with their substrates
without an energy barrier separating them, along with the high specificity of
the process as we currently know it, makes energy investment in an
apparently exergonic process something we all accept now. Yet, the road to
this acceptance has been long.