Regulation of Enzyme Activity by Proteolysis

Proteolysis is a versatile tool in the cell for the targeted change in structure, activity, function and subceUular distribution of proteins. 

Most important, in terms of regulation, is the matiuation of proteins and targeted protein degradation. 

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Figure 20.31 The principle of interconversion cycles in regulation of protein activity or changes in protein concentration as exemplified by translation/proteolysis or protein kinase/protein phosphatase. They result in very marked relative changes in regulator concentration or enzyme activity. The significance of the relative changes (or sensitivity in regulation) is discussed in Chapter 3. The principle of regulation by covalent modihcation is also described in Chapter 3. The modifications in cyclin concentration are achieved via translation and proteolysis, which, in effect, is an interconversion cycle. For the enzyme, they are achieved via phosphorylation and dephosphorylation reactions. In both cases, the relative change in concentration/activity by the covalent modification is enormous. This ensures, for example, that a sufficient increase in cyclin can occur so that an inactive cell cycle kinase can be converted to an active cell cycle kinase, or that a cell cycle kinase can be completely inactivated. Appreciation of the common principles in biochemistry helps in the understanding of what otherwise can appear to be complex phenomena.

Protein digestion begins in the stomach, where a proenz5nme called pepsinogen is secreted, autocatalytically converted to Pepsin A, and used for the first step of proteolysis. However, most proteolysis takes place in the duodenum as a consequence of enzyme activities secreted by the pancreas. All of the serine proteases and the zinc peptidases of pancreatic secretions are produced in the form of their respective proenzymes. These proteases are both endopeptidase and exopeptidase, and their combined action in the intestine leads to the production of amino acids, dipeptides, and tripeptides, all of which are taken up by enterocytes of the mucosal wall. How preoteolytic enzymes are regulated ... 

In vivo participation of E3 enzymes can be assumed generally and it seems likely that proteolysis is controlled primarily by regulating the activity of the E3 s. Although they are thought to be most directly involved in substrate recognition this class of enzymes is least well understood. E3s might be divided into distinct families with regard to sequence class and enzymatic... 

The LDL receptor is a key component in the feedback-regulated maintenance of cholesterol homeostasis [1]. In fact, as an active interface between extracellular and intracellular cholesterol pools, it is itself subject to regulation at the cellular level (Fig. 2). LDL-derived cholesterol (generated by hydrolysis of LDL-bome cholesteryl esters) and its intracellularly generated oxidized derivatives mediate a complex series of feedback control mechanisms that protect the cell from over-accumulation of cholesterol. First, (oxy)sterols suppress the activities of key enzymes that determine the rate of cellular cholesterol biosynthesis. Second, the cholesterol activates the cytoplasmic enzyme acyl-CoA cholesterol acyltransferase, which allows the cells to store excess cholesterol in re-esterified form. Third, the synthesis of new LDL receptors is suppressed, preventing further cellular entry of LDL and thus cholesterol overloading. The coordinated regulation of LDL receptors and cholesterol synthetic enzymes relies on the sterol-modulated proteolysis of a membrane-bound transcription factor, SREBP, as described in Chapter 14. 

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