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OBJECTIVES

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OBJECTIVES

After studying this chapter, you should be able to:

  • Explain the concept of whole-body homeostasis.

  • Discuss why the cellular concentrations of substrates for most enzymes tend to be close to Km.

  • List multiple mechanisms by which active control of metabolite flux is achieved.

  • State the advantages of synthesizing certain enzymes as proenzymes.

  • Describe typical structural changes that accompany conversion of a proenzyme to its active form.

  • Indicate two general ways in which an allosteric effector can influence catalytic activity.

  • Outline the roles of protein kinases, protein phosphatases, and of regulatory and hormonal and second messengers in regulating metabolic processes.

  • Explain how the substrate requirements of lysine acetyltransferases and sirtuins can trigger shifts in the degree of lysine acetylation of metabolic enzymes.

  • Describe two ways by which regulatory networks can be constructed in cells.

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BIOMEDICAL IMPORTANCE

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The 19th-century physiologist Claude Bernard enunciated the conceptual basis for metabolic regulation. He observed that living organisms respond in ways that are both quantitatively and temporally appropriate to permit them to survive the multiple challenges posed by changes in their external and internal environments. Walter Cannon subsequently coined the term “homeostasis” to describe the ability of animals to maintain a constant internal environment despite changes in their external surroundings. At the cellular level, homeostasis is maintained by adjusting the rates of key metabolic reactions in response to internal changes. Examples include the levels of key metabolic intermediates such as 5′-AMP and NAD+, or external factors such as hormones acting through receptor-controlled signal transduction cascades.

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Perturbations of the sensor-response machinery responsible for maintaining homeostatic balance can be deleterious to human health. Cancer, diabetes, cystic fibrosis, and Alzheimer disease, for example, are all characterized by regulatory dysfunctions triggered by the interplay between pathogenic agents, genetic mutations, nutritional inputs, and lifestyle practices. For example, many oncogenic viruses contribute to the initiation of cancer by elaborating protein-tyrosine kinases that modify proteins responsible for controlling patterns of gene expression. The cholera toxin produced by Vibrio cholerae disables sensor-response pathways in intestinal epithelial cells by catalyzing the addition of ADP-ribose to the GTP-binding proteins (G-proteins) that link cell-surface receptors to adenylyl cyclase. The ADP-ribose induced activation of the cyclase leads to the unrestricted flow of water into the intestines, resulting in massive diarrhea and dehydration. Yersinia pestis, the causative agent of plague, elaborates a protein-tyrosine phosphatase that hydrolyzes phosphoryl groups on key cytoskeletal proteins, thereby disabling the phagocytic machinery of protective macrophages. Dysfunctions in the proteolytic systems responsible for the degradation of defective or abnormal proteins are believed to play a role in neurodegenerative diseases such as Alzheimer and Parkinson.

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In addition to their immediate function as regulators of enzyme activity, protein degradation, etc, covalent modifications such as phosphorylation, acetylation, and ubiquitination provide a protein-based code for the storage and transmission of information (see Chapter 35). Such DNA-independent hereditary information is referred to ...

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