Cells carry out a complex array of metabolic processes that must be regulated in response to a broad spectrum of environmental factors. Hence, interconvertible enzymes and the enzymes responsible for their interconvesion do not act as isolated "on" and "off" switches. In order to meet the demands of maintaining homeostasis, these building blocks are linked to form integrated regulatory networks.
One well-studied example of such a network is the eukaryotic cell cycle that controls cell division. Upon emergence from the quiescent, or G0, state, the extremely complex process of cell division proceeds
through a series of specific phases designated G1, S, G2, and M (Figure 9–8). Elaborate monitoring systems, called checkpoints, assess key indicators of progress to ensure that no phase of the cycle is initiated until the prior phase is complete. Figure 9–8 outlines, in simplified form, part of the checkpoint that controls the initiation of DNA replication, called the S phase. A protein kinase called ATM is associated with the genome.
If the DNA contains a double-stranded break, the resulting change in the conformation of the chromatin activates ATM. Upon activation, one subunit of the activated ATM dimer dissociates and initiates a series, or cascade, of protein phosphorylation-dephosphorylation events mediated by the CHK1 and CHK2 protein kinases, the Cdc25 protein phosphatase, and finally a complex between a cyclin and a cyclin-dependent protein kinase, or Cdk. Activation of the Cdk-cyclin complex blocks the G1 to S transition, thus preventing the replication of damaged DNA. Failure at this checkpoint can lead to mutations in DNA that may lead to cancer or other diseases. Each step in the cascade provides a conduit for monitoring additional indicators of cell status prior to entering S phase.
Figure 9–8.
A simplified representation of the G1 to S checkpoint of the eukaryotic cell cycle. The circle shows the various stages in the eukaryotic cell cycle. The genome is replicated during S phase, while the two copies of the genome are segregated and cell division occurs during M phase. Each of these phases is separated by a G, or growth, phase characterized by an increase in cell size and the accumulation of the precursors required for the assembly of the large macromolecular complexes formed during S and M phases.
SUMMARY
Homeostasis involves maintaining a relatively constant intracellular and intra-organ environment despite wide fluctuations in the external environment. This is achieved via appropriate changes in the rates of biochemical reactions in response to physiologic need.
The substrates for most enzymes are usually present at a concentration close to their Km. This facilitates passive control of the rates of product formation in response to changes in levels of metabolic intermediates.
Active control of metabolite flux involves changes in the concentration, catalytic activity, or both of an enzyme that catalyzes a committed, rate-limiting reaction.
Selective proteolysis of catalytically inactive proenzymes initiates conformational changes that form the active site. Secretion as an inactive proenzyme facilitates rapid mobilization of activity in response to injury or physiologic need and may protect the tissue of origin (eg, autodigestion by proteases).
Binding of metabolites and second messengers to sites distinct from the catalytic site of enzymes triggers conformational changes that alter Vmax or Km.
Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades that respond to
hormonal or second messenger signals constitute regulatory networks that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response.
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Harper's Illustrated Biochemistry, 28e > Chapter 10. Bioinformatics & Computational Biology >
BIOMEDICAL IMPORTANCE
The first scientific models of pathogenesis, such as Louis Pasteur's seminal germ theory of disease, were binary in nature: each disease possessed a single, definable causal agent. Malaria was caused by the amoeba Plasmodium falciparum, tuberculosis by the bacterium Mycobacterium tuberculosis, sickle cell disease by a mutation in a gene encoding one of the subunits of hemoglobin, poliomyelitis by poliovirus, and scurvy by a deficiency in ascorbic acid. The strategy for treating or preventing disease thus could be reduced to a straightforward process of tracing the causal agent and then devising some means of eliminating it, neutralizing its effects, or blocking its route of transmission. This approach has been
successfully employed to understand and treat a wide range of infectious and genetic diseases. However, it has become clear that the determinants of many pathologies—including cancer, coronary heart disease, type II diabetes, and Alzheimer's disease—are multifactorial in nature. Rather than having a specific causal agent or agents whose presence is both necessary and sufficient, the appearance and progression of the aforementioned diseases reflect the complex interplay between each individual's genetic makeup, diet, and lifestyle, as well as a range of environmental factors such as the presence of toxins, viruses, or
bacteria.
The challenge posed by multifactorial diseases demands a quantum increase in the breadth and depth of our knowledge of living organisms capable of matching their sophistication and complexity. We must identify the many as yet unknown proteins encoded within the genomes of humans and of the organisms with which they interact, the functional relationships between these proteins, and the impact of dietary, genetic, and environmental factors thereupon. The sheer mass of information that must be processed to understand, as completely and comprehensively as possible, the molecular mechanisms that underlie the behavior of living organisms, as well as the manner in which perturbations can lead to disease or dysfunction, lies well beyond the ability of the human mind to review and analyze. Biomedical scientists therefore have turned to
sophisticated computational tools to collect and evaluate biologic information on a mass scale.