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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Explain the concept of whole-body homeostasis and its response to fluctuations in the external environment.

  • 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.

  • Describe the advantages of certain enzymes being elaborated as proenzymes.

  • Illustrate the physiologic events that trigger the conversion of a proenzyme to the corresponding active enzyme.

  • Describe typical structural changes that accompany conversion of a proenzyme to the active enzyme.

  • Describe the basic features of a typical binding site for metabolites and second messengers that regulate catalytic activity of certain enzymes.

  • 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 a metabolic process.

  • 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 intracellular environment despite changes in their external surroundings. We now know that organisms respond to changes in their external and internal environment by balanced, coordinated adjustments in the rates of specific metabolic reactions. Metabolic intermediates such as 5′-AMP and NAD+, as well as byproducts such as reactive oxygen species, serve as internal indicators of cellular status. Signal transduction cascades connect the receptors that sense external factors with appropriate intracellular proteins to initiate adaptive responses.

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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’s disease, for example, are all characterized by regulatory dysfunctions triggered by the interplay between pathogenic agents, genetic mutations, nutritional inputs, and lifestyle practices. Many oncogenic viruses elaborate protein-tyrosine kinases that modify the regulatory events that control patterns of gene expression, contributing to the initiation and progression of cancer. The toxin from Vibrio cholerae, the causative agent of cholera, disables sensor-response pathways in intestinal epithelial cells by ADP-ribosylating the GTP-binding proteins (G-proteins) that link cell surface receptors to adenylyl cyclase. The consequent 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. Dysfunctions in the proteolytic systems responsible for the degradation of defective or abnormal proteins are believed to ...

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