Reversible Covalent Modification Regulates Key Mammalian Enzymes

Mammalian proteins are the targets of a wide range of covalent modification processes. Modifications such as glycosylation, hydroxylation, and fatty acid acylation introduce new structural features into newly synthesized proteins that tend to persist for the lifetime of the protein. Among the covalent modifications that regulate protein function (eg, methylation, adenylylation), the most common by far is phosphorylation-dephos-phorylation. Protein kinases phosphorylate proteins by catalyzing transfer of the terminal phosphoryl group of ATP to the hydroxyl groups of seryl, threonyl, or tyro-syl residues, forming O-phosphoseryl, O-phosphothre-onyl, or O-phosphotyrosyl residues, respectively (Figure 9-7). Some protein kinases target the side chains of his-tidyl, lysyl, arginyl, and aspartyl residues. The unmodified form of the protein can be regenerated by hy-drolytic removal of phosphoryl groups, catalyzed by protein phosphatases.

A typical mammalian cell possesses over 1000 phos-phorylated proteins and several hundred protein kinases and protein phosphatases that catalyze their interconversion. The ease of interconversion of enzymes between their phospho- and dephospho- forms in part

Figure 9-7. Covalent modification of a regulated enzyme by phosphorylation-dephosphorylation of a seryl residue.

Figure 9-7. Covalent modification of a regulated enzyme by phosphorylation-dephosphorylation of a seryl residue.

accounts for the frequency of phosphorylation-dephos-phorylation as a mechanism for regulatory control. Phosphorylation-dephosphorylation permits the functional properties of the affected enzyme to be altered only for as long as it serves a specific need. Once the need has passed, the enzyme can be converted back to its original form, poised to respond to the next stimulatory event. A second factor underlying the widespread use of protein phosphorylation-dephosphorylation lies in the chemical properties of the phosphoryl group itself. In order to alter an enzyme's functional properties, any modification of its chemical structure must influence the protein's three-dimensional configuration. The high charge density of protein-bound phosphoryl groups—generally —2 at physiologic pH—and their propensity to form salt bridges with arginyl residues make them potent agents for modifying protein structure and function. Phosphorylation generally targets amino acids distant from the catalytic site itself. Consequent conformational changes then influence an enzyme's intrinsic catalytic efficiency or other properties. In this sense, the sites of phosphorylation and other co-valent modifications can be considered another form of allosteric site. However, in this case the "allosteric li-gand" binds covalently to the protein.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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