Phosphorylation metabolic regulation

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Covalent interconversion of enzymes is well established as a fundamental theme in metabolic regulation. The prototypic reversible interconverting systems include the sequence of phosphorylation/dephosphorylation steps in the activation of mammalian glycogen phosphorylase and pyruvate dehydrogenase as well as the nucleotidyla-tion/denucleotidylation using UTP and ATP in the bacterial glutamine synthetase cascade (see Fig. 1.). 

Important reactions of intermediary metabolism regulated by enzyme phosphorylation. Key Blue text = intermediates of carbohydrate metabolism ... 

Figure 2.13. Upper panel is a summary diagram of the standard model of metabolic regulation in this conceptualization, accelerating tissue ATP utilization leads to increasing concentrations of ADP and Pi, which serve as substrates for oxidative phosphorylation, to activate ATP production. Lower panel summarizes an alternate model of metabolic regulation in which ATP demand and ATP supply pathways are simultaneously activated during large-scale change in tissue work rates. See text for further details.

Two key regulatory enzymes involved in the control of glycogen metabolism were first recognized as targets of cAMP and cAMP-dependent protein kinase in liver and skeletal muscle. These are phosphorylase b kinase and glycogen synthase. The molecular details of the phosphorylation and regulation of these enzymes are better understood in muscle than in liver since the liver enzymes have only recently been purified to homogeneity in the native form. However, it appears that they share many key features in common. 

Nutt LK, MargoUs SS, Jensen M, Herman CE, Dunphy WG, Rathmell JC, Kombluth S (2005) Metabolic regulation of oocyte cell death through the CaMKll-mediated phosphorylation of caspase-2. Cell 123 89-103... 

Phosphorylation. In recent years, protein phosphorylation/dephosphoryla-tion catalyzed by protein kinases and phosphatases has been revealed to be widespread among prokaryotes. Many of the purposes of these reactions remain unclear. However, roles for transient phosphorylation have been identified in chemotaxis and nitrogen metabolism regulation. 

Insulin and the counterregulatory hormones exert two types of metabolic regulation (see Chapter 26). The first type of control occurs within minutes to hours of the hormone-receptor interaction and usually results from changes in the catalytic activity or kinetics of key preexisting enzymes, caused by phosphorylation or dephosphorylation of these enzymes. The second type of control involves regulation of the synthesis of key enzymes by mechanisms that stimulate or inhibit transcription and translation of mRNA. These processes are slow and require hours to days. 

Feng, J., Atkinson, M.R., McGleary, W, Stock, J.B., Wanner, B.L. and Nrnfa, A.J. (1992). Role of phosphorylated metabolic intermediates in the regulation of glutamine synthetase synthesis in Escherichia coli. J. Bacteriol. 174, 6061-6070. 

Metabolic regulation of oocyte cell death through the CaMKH-mediated phosphorylation of caspase-2. Cell 123(1) 89-103. 

In liver the situation is different studies of the effect of insulin on glucose phosphorylation have revealed the existence of two hexokinases—the classical hexokinase and glucokinase. Of these two, only the glucoki-nase is decreased in alloxan diabetes and responds to insulin injection (see section on metabolic regulation in Chapter 16). 

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