Substrate cycling and protein turnover
Substrate or "futile" cycles refer to the dynamic process that must accompany the thermodynamic steady state [13]. In particular, increased cycling of metabolic intermediates utilizes ATP and generates heat. The simplest examples are the numerous kinase-phosphatase pairs that regulate metabolism. In addition, although not generally considered in the category of substrate cycling, inefficiency results from the repeated breakdown and re-synthesis of proteins, lipids, and carbohydrates in cycles that use ATP for no apparent net gain. Such mechanisms, however, far from futile, allow for precision in the regulation of metabolism and constitute one of the uses of ATP. Protein turnover, in particular, provides for error correction or removal of "old" or damaged proteins. The effect of metabolic path on the energetics of oxidation is illustrated in Table 1 which summarizes the analysis from our earlier paper [2]. In this example, a mole of glucose directly oxidized to CO2 and water generates 38 moles of ATP with an overall efficiency of about 38.5%. On the other hand, if glucose is first incorporated into glycogen, followed by hydrolysis of the glucose and subsequent oxidation, 2 moles of ATP are lost per mole in this cycle with overall efficiency reduced to 35%. Similarly an amino acid from an "average" protein, when directly oxidized to CO2, produces ATP with an efficiency of about 33%. If the amino acid is first incorporated into a protein and later hydrolyzed and oxidized, four ATP's per molecule are used for synthesis of the peptide bond. This reduces the efficiency to 27%. Smaller degrees of inefficiency are seen for lipid cycles (Table 1) but multiple cycles may have a cumulative effect. It is estimated, for example, that half of depot fatty acids in triacylglycerol have been through at least one cycle [14]. It should be apparent that variation in efficiency is not a thermodynamic issue but an empiric question to be determined by the requirements of metabolism.