H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 13
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They share genes thatcontrol similar processes, such as growth of heart and eyes andorganization of the body plan, indicating conservation of functionfrom ancient times. (a) Hox genes are found in clusters on thechromosomes of most or all animals. Hox genes encode relatedproteins that control the activities of other genes. Hox genesdirect the development of different segments along the head-totail axis of many animals as indicated by corresponding colors.Each gene is activated (transcriptually) in a specific region alongthe head-to-toe axis and controls the growth of tissues there. Forexample, in mice the Hox genes are responsible for thedistinctive shapes of vertebrae. Mutations affecting Hox genes inflies cause body parts to form in the wrong locations, such aslegs in lieu of antennae on the head.
These genes provide ahead-to-tail address and serve to direct formation of the rightstructures in the right places. (b) Development of the largecompound eyes in fruit flies requires a gene called eyeless(named for the mutant phenotype). (c) Flies with inactivatedeyeless genes lack eyes. (d) Normal human eyes require thehuman gene, called Pax6, that corresponds to eyeless. (e) Peoplelacking adequate Pax6 function have the genetic disease aniridia,a lack of irises in the eyes. Pax6 and eyeless encode highlyrelated proteins that regulate the activities of other genes, andare descended from the same ancestral gene. [Parts (a) and (b)Andreas Hefti, Interdepartmental Electron Microscopy (IEM) Biocenter,University of Basel. Part (d) © Simon Fraser/Photo Researchers, Inc.]This is not to say that all genes or proteins are evolutionarily conserved.
Many striking examples exist of proteinsthat, as far as we can tell, are utterly absent from certain lineages of animals. Plants, not surprisingly, exhibit many suchdifferences from animals after a billion-year separation intheir evolution. Yet certain DNA-binding proteins differ between peas and cows at only two amino acids out of 102!Despite all the evidence for evolutionary unity at the cellular and physiological levels, everyone expected that genesregulating animal development would differ greatly fromone phylum to the next.
After all, insects and sea urchinsand mammals look so different. We must have many uniqueproteins to create a brain like ours . . . or must we? Thefruits of research in developmental genetics during the pasttwo decades reveal that insects and mammals, which havea common ancestor about half a billion years ago, possessmany similar development-regulating genes (Figure 1-26).Indeed, a large number of these genes appear to be conserved in many and perhaps all animals.
Remarkably, thedevelopmental functions of the proteins encoded by thesegenes are also often preserved. For instance, certain proteinsinvolved in eye development in insects are related to protein regulators of eye development in mammals. Same fordevelopment of the heart, gut, lungs, and capillaries and forplacement of body parts along the head-to-tail and backto-front body axes (Chapter 15).Darwin’s Ideas About the Evolution of WholeAnimals Are Relevant to GenesDarwin did not know that genes exist or how they change,but we do: the DNA replication machine makes an error, ora mutagen causes replacement of one nucleotide with another or breakage of a chromosome.
Some changes in thegenome are innocuous, some mildly harmful, some deadly;a very few are beneficial. Mutations can change the sequenceof a gene in a way that modifies the activity of the encodedprotein or alters when, where, and in what amounts the protein is produced in the body.Gene-sequence changes that are harmful will be lost froma population of organisms because the affected individualscannot survive as well as their relatives. This selectionprocess is exactly what Darwin described without knowingthe underlying mechanisms that cause organisms to vary.Thus the selection of whole organisms for survival is reallya selection of genes, or more accurately sets of genes.
A population of organisms often contains many variants that are28CHAPTER 1 • Life Begins with Cellsall roughly equally well-suited to the prevailing conditions.When conditions change—a fire, a flood, loss of preferredfood supply, climate shift—variants that are better able toadapt will survive, and those less suited to the new conditions will begin to die out.
In this way, the genetic composition of a population of organisms can change over time.Human Medicine Is Informed by Researchon Other OrganismsMutations that occur in certain genes during the course ofour lives contribute to formation of various human cancers.The normal, wild-type forms of such “cancer-causing” genesgenerally encode proteins that help regulate cell proliferationor death (Chapter 23). We also can inherit from our parentsmutant copies of genes that cause all manner of genetic diseases, such as cystic fibrosis, muscular dystrophy, sickle cellanemia, and Huntington’s disease.
Happily we can also inherit genes that make us robustly resist disease. A remarkablenumber of genes associated with cancer and other humandiseases are present in evolutionarily distant animals. For example, a recent study shows that more than three-quarters ofthe known human disease genes are related to genes found inthe fruit fly Drosophila.With the identification of human disease genes in otherorganisms, experimental studies in experimentally tractableorganisms should lead to rapid progress in understandingthe normal functions of the disease-related genes and whatoccurs when things go awry. Conversely, the disease statesthemselves constitute a genetic analysis with well-studiedphenotypes. All the genes that can be altered to cause a certain disease may encode a group of functionally relatedproteins.
Thus clues about the normal cellular functions ofproteins come from human diseases and can be used toguide initial research into mechanism. For instance, genesinitially identified because of their link to cancer in humanscan be studied in the context of normal development in various model organisms, providing further insight about thefunctions of their protein products.2CHEMICALFOUNDATIONSPolysaccharide chains on the surface of cellulose visualized byatomic force microscopy. [Courtesy of M. Miles from A.
A. Baker etal., 2000, Biophys J. 79:1139–1145.]The life of a cell depends on thousands of chemical interactions and reactions exquisitely coordinated withone another in time and space and under the influenceof the cell’s genetic instructions and its environment. Howdoes a cell extract critical nutrients and information from itsenvironment? How does a cell convert the energy storedin nutrients into work (movement, synthesis of critical components)? How does a cell transform nutrients into the fundamental structures required for its survival (cell wall,nucleus, nucleic acids, proteins, cytoskeleton)? How does acell link itself to other cells to form a tissue? How do cellscommunicate with one another so that the organism asa whole can function? One of the goals of molecular cell biology is to answer such questions about the structure andfunction of cells and organisms in terms of the properties ofindividual molecules and ions.Life first arose in a watery environment, and the properties of this ubiquitous substance have a profound influenceon the chemistry of life.
Constituting 70–80 percent byweight of most cells, water is the most abundant moleculein biological systems. About 7 percent of the weight of living matter is composed of inorganic ions and small moleculessuch as amino acids (the building blocks of proteins), nucleotides (the building blocks of DNA and RNA), lipids (thebuilding blocks of biomembranes), and sugars (the buildingblocks of starches and cellulose), the remainder being themacromolecules and macromolecular aggregates composedof these building blocks.Many biomolecules (e.g., sugars) readily dissolve inwater; these water-liking molecules are described as hydrophilic. Other biomolecules (e.g., fats like triacylglycerols)shun water; these are said to be hydrophobic (water-fearing).Still other biomolecules (e.g., phospholipids), referred to asamphipathic, are a bit schizophrenic, containing both hydrophilic and hydrophobic regions.
These are used to buildthe membranes that surround cells and their internal organelles (Chapter 5). The smooth functioning of cells, tissues, and organisms depends on all these molecules, from thesmallest to the largest. Indeed, the chemistry of the simpleproton (H) with a mass of 1 dalton (Da) can be as important to the survival of a human cell as that of each giganticDNA molecule with a mass as large as 8.6 1010 Da (single strand of DNA from human chromosome 1).A relatively small number of principles and facts of chemistry are essential for understanding cellular processes at themolecular level (Figure 2-1). In this chapter we review someof these key principles and facts, beginning with the covalent bonds that connect atoms into a molecule and the noncovalent forces that stabilize groups of atoms within andbetween molecules.
We then consider the key properties ofthe basic building blocks of cellular structures. After reviewing those aspects of chemical equilibrium that are most relevant to biological systems, we end the chapter with basicOUTLINE2.1Atomic Bonds and Molecular Interactions2.2Chemical Building Blocks of Cells2.3Chemical Equilibrium2.4Biochemical Energetics29CHAPTER 2 • Chemical Foundations(a)(b)Protein AOHO−+CH3NHCH3CH3CH3CH3OCCH3+ +_ _CHO30ONoncovalentinteractionsCProtein BSmall moleculesubunits(c)Macromolecule(d)γ"High-energy"phosphoanhydridebondsβkfαkrkeq =kfkr▲ FIGURE 2-1 Chemistry of life: key concepts. (a) Covalent andnoncovalent interactions lie at the heart of all biomolecules, aswhen two proteins with complementary shapes and chemicalproperties come together to form a tightly bound complex.
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