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Table 3-7 shows the major classes of biomolecules in a
representative single-celled organism, Escherichia coli. Water is the most
abundant single compound in E. coli and in all other cells and organisms.
Inorganic salts and mineral elements, on the other hand, constitute only a very
small fraction of the total dry weight, but many of them are in approximate
proportion to their distribution in seawater (see Table 3-1). Nearly all of the
solid matter in all kinds of cells is organic and is present in four forms:
proteins, nucleic acids, polysaccharides, and lipids.
Proteins, long polymers of amino acids, constitute the
largest fraction (besides water) of cells. Some proteins have catalytic activity
and function as enzymes, others serve as structural elements, and still others
carry specific signals (in the case of receptors) or specific substances (in the
case of transport proteins) into or out of cells. Proteins are perhaps the most
versatile of all biomolecules. The nucleic acids, DNA and RNA,
are polymers of nucleotides. They store, transmit, and translate genetic
information. The polysaccharides, polymers of simple sugars
such as glucose, have two major functions: they serve as energy-yielding fuel
stores and as extracellular structural elements. Shorter polymers of sugars
(oligosaccharides) attached to proteins or lipids at the cell surface serve as
specific cellular signals. The lipids, greasy or oily hydrocarbon derivatives,
serve as structural components of membranes, as a storage form of energy-rich
fuel, and in other roles. These four classes of large biomolecules are all
synthesized in condensation reactions (Fig. 3-14e). In macromolecules-proteins,
nucleic acids, and polysaccharides-the number of monomeric subunits is very
large. Proteins have molecular weights in the range of 5,000 to over 1 million;
the nucleic acids have molecular weights ranging up to several billion; and
polysaccharides, such as starch, also have molecular weights into the millions.
Individual lipid molecules are much smaller (Mr 750 to 1,500), and are not
classed as macromolecules. However, when large numbers of lipid molecules
associate noncovalently, very large structures result. Cellular membranes are
built of enormous aggregates containing millions of lipid molecules.
Macromolecules Are Constructed from Monomeric Subunits
Although living organisms contain a very large number of
different proteins and different nucleic acids, a fundamental simplicity
underlies their structure (Chapter 1). The simple monomeric subunits from which
all proteins and all nucleic acids are constructed are few in number and
identical in all living species. Proteins and nucleic acids are informational
macromolecules: each protein and each nucleic acid has a characteristic
information-rich subunit sequence (Fig. 3-15).
Polysaccharides built from only a single kind of unit, or from two difl'erent
alternating units, are not informational molecules in the same
sense as are proteins and nucleic acids (Fig. 3-15). However, complex
polysaccharides made up of six or more difl'erent kinds of sugars connected in
branched chains do have the structural and stereochemical variety that enables
them to carry information recognizable by other macromolecules.
Figure 3-16 shows the structures of some monomeric units, arranged in
families. We have already seen that the most abundant polysaccharides in nature,
starch and cellulose, are constructed of repeating units of
D-glucose. The monomeric subunits of proteins are 20 different
amino acids; all have an amino group (an imino group in the case of proline) and
a carboxyl group attached to the same carbon atom, called, by convention, the a
carbon. These α-amino acids differ from each other only in their side chains
(Fig. 3-16).
The recurring structural units of all nucleic acids are eight different
nucleotides; four kinds of nucleotides are the structural units of DNA, and four
others are the units of RNA. Each nucleotide is made up of three components: (1)
a nitrogenous organic base, (2) a five-carbon sugar, and (3) phosphate (Fig.
3-16). The eight difl'erent nucleotides oi DNA and RNA are built from five
difl'erent organic bases combined with two different sugars.
Lipids also are constructed from relatively few kinds of subunits. Most lipid
molecules contain one or more long-chain fatty acids, of which palmitic acid and
oleic acid are parent compounds. Many lipids also contain an alcohol, e.g.,
glycerol, and some contain phosphate (Fig. 3-16). Thus, only three dozen
different organic compounds are the parents of most biomolecules.
Each of the compounds in Figure 3-16 has multiple functions in living
organisms (Fig. 3-17). Amino acids are not only the monomeric subunits of
proteins; some also act as neurotransmitters and as precursors of hormones and
toxins. Adenine serves both as a subunit in the structure of nucleic acids and
of ATP, and as a neurotransmitter. Fatty acids serve as components of complex
membrane lipids, energy-rich fuel-storage fats, and the protective waxy coats on
leaves and fruits. n-Glucose is the monomeric subunit of starch and cellulose,
and also is the precursor of other sugars such as n-mannose and sucrose.
It is extremely improbable that amino acids in a mixture would
spontaneously condense into a protein with a unique sequence. This would
represent increased order in a population of molecules; but according to the
second law of thermodynamics (Chapter 13) the tendency is toward ever-greater
disorder in the universe. To bring about the synthesis of macromolecules from
their monomeric subunits, free energy must be supplied to the system (the cell).
The randomness of the components of a chemical system is expressed as
entropy, symbolized S. Any change in randomness of the system is the entropy
change, ΔS, which has a positive value when randomness increases. J. Willard
Gibbs, who developed the theory of energy changes during chemical reactions,
showed that the freeenergy content (G; recall Chapter 1) of any isolated system
can be defined in terms of three quantities: enthalpy (H) (reflecting the number
and kinds of bonds; see p. 66), entropy (S), and T, the absolute temperature
(Kelvin). The definition of free energy is: G = H - TS. When a chemical reaction
occurs at constant temperature, the free-energy change is determined by ΔH,
reflecting the kinds and numbers of chemical bonds and noncovalent interactions
broken and formed, and ΔS, the change in the system's randomness:
ΔG = ΔH - ΔS
Recall from Chapter 1 that a process tends to occur spontaneously only if ΔG
is negative. How, then, can cells synthesize polymers such as proteins and
nucleic acids, if the free-energy change for polymerizing subunits is positive?
They couple these thermodynamically unfavorable (endergonic) reactions to other
cellular reactions that liberate free energy (exergonic reactions), so that the
sum of the free-energy changes is negative:
| Amino acids |
![]() |
Proteins |
ΔG1>0 (endergonic) |
| ATP |
![]() |
AMP + 2 PO43- |
ΔG2<0 (exergonic) |
| sum: Amino acids + ATP |
![]() |
Proteins + AMP + 2
PO43- |
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There Is a Hierarchy in Cell Structure
The monomeric subunits in Figure 3-16 are very small compared with biological
macromolecules. An amino acid molecule such as alanine is less than 0.5 nm long.
Hemoglobin, the oxygen-carrying protein of erythrocytes, consists of nearly 600
amino acid units covalently linked into four long chains, which are folded into
globular shapes and associated in a tetrameric structure with a diameter of 5.5
nm. Protein molecules in turn are small compared with ribosomes (about 20 nm in
diameter), which contain about 70 different proteins and several different RNA
molecules. Ribosomes, in their turn, are much smaller than organelles such as
mitochondria, typically 1,000 nm in diameter. It is a long jump from the simple
biomolecules to the larger cellular structures that can be seen with the light
microscope. Figure 3-18 illustrates the structural hierarchy in cellular
organization.
In proteins, nucleic acids, and polysaccharides, the individual subunits are
joined by covalent bonds. By contrast, in supramolecular complexes, the
different macromolecules are held together by noncovalent interactions-much
weaker, individually, than covalent bonds. Among these are hydrogen bonds
(between polar groups), ionic interactions (between charged groups), hydrophobic
interactions (between nonpolar groups), and van der Waals interactions, all of
which have energies of only a few kilojoules, compared with covalent bonds,
which have bond energies of 200 to 900 kJ/mol (see Table 3-5). The nature of
these noncovalent interactions will be described in the next chapter.
The large numbers of weak interactions between macromolecules in
supramolecular complexes stabilize the resulting noncovalent structures.
Although the monomeric subunits of macromolecules are so much smaller than
cells and organelles, they influence the shape and function of these much larger
structures. In sickle-cell anemia, a hereditary human disorder, the hemoglobin
molecule is defective. In the two β chains of hemoglobin from healthy
individuals, a glutamic acid residue occurs at position 6. In people with
sickle-cell anemia, a valine residue occurs at position 6. This single
difference in the sequence of the 146 amino acids of the β chain affects only a
tiny portion of the molecule, yet it causes the hemoglobin to form large
aggregates within the erythrocytes, which become deformed (sickled) and function
abnormally.
Prebiotic Evolution
Because all biological macromolecules are made from the same three dozen
subunits, it seems likely that all living organisms descended from a single
primordial cell line. These subunits are proposed to have had, singly and
collectively, the most successful combination of chemical and physical
properties for their function as the raw materials of biological macromolecules
and for carrying out the basic energy-transforming and self replicating features
of a living cell. These primordial organic compounds may have been retained
during biological evolution over billions of years because of their unique
fitness.
Biomolecules First Arose by Chemical Evolution
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We come now to a puzzle. Apart from their occurrence in living
organisms, organic compounds, including the basic biomolecules, occur only in
trace amounts in the earth's crust, the sea, and the atmosphere. How did the
first living organisms acquire their characteristic organic building blocks? In
1922, the biochemist Aleksandr I. Oparin proposed a theory for the origin of
life early in the history of the earth, postulating that the atmosphere was once
very different from that of today. Rich in methane, ammonia, and water, and
essentially devoid of oxygen, it was a reducing atmosphere, in contrast to the
oxidizing environment of our era. In Oparin's theory, electrical energy of
lightning discharges or heat energy from volcanoes (Fig. 3-19) caused ammonia,
methane, water vapor, and other components of the primitive atmosphere to react,
forming simple organic compounds. These compounds then dissolved in the ancient
seas, which over many millenia became enriched with a large variety of simple
organic compounds. In this warm solution (the "primordial soup") some organic
molecules had a greater tendency than others to associate into larger complexes.
Over millions of years, these in turn assembled spontaneously to form membranes
and catalysts (enzymes), which came together to become precursors of the first
primitive cells. For many years, Oparin's views remained speculative and
appeared untestable.
A classic experiment on the abiotic (nonbiological) origin of
organic biomolecules was carried out in 1953 by Stanley Miller in the laboratory
of Harold Urey. Miller subjected gaseous mixtures of
NH3, CH4, water vapor, and
H2to electrical sparks produced across a pair of
electrodes (to simulate lightning) for periods of a week or more (Fig. 3-20),
then analyzed the contents of the closed reaction vessel. The gas phase of the
resulting mixture contained CO and CO2, as well as the
starting materials. The water phase contained a variety of organic compounds,
including some amino acids, hydroxy acids, aldehydes, and hydrogen cyanide
(HCN). This experiment established the possibility of abiotic production of
biomolecules in relatively short times under relatively mild conditions.
Several developments have allowed more refined studies of the type pioneered
by Miller and Urey, and have yielded strong evidence that a wide variety of
biomolecules, including proteins and nucleic acids, could have been produced
spontaneously from simple starting materials probably present on the earth at
the time life arose.
Modern extensions of the Miller experiments have employed "atmospheres" that
include C02 and HCN, and much improved technology for
identifying small quantities of products. The formation of hundreds of organic
compounds has been demonstrated (Table 3-8). These compounds include more than
ten of the common amino acids, a variety of mono-, di-, and tricarboxylic acids,
fatty acids, adenine, and formaldehyde. Under certain conditions, formaldehyde
polymerizes to form sugars containing three, four, five, and six carbons. The
sources of energy that are effective in bringing about the formation of these
compounds include heat, visible and ultraviolet (UV) light, x rays, gamma
radiation, ultrasound and shock waves, and alpha and beta particles.
In addition to the many monomers that form in these experiments, polymers of
nucleotides (nucleic acids) and of amino acids (proteins) also form. Some of the
products of the self condensation of HCN are effective promoters of such
polymerization reactions (Fig. 3-21), and inorganic ions present in the earth's
crust (Cu2+, Ni2+, and
Zn2+) also enhance the rate of polymerization.
In short, laboratory experiments on the spontaneous formation of
biomolecules under prebiotic conditions have provided good evidence that many of
the chemical components of living cells, including proteins and RNA, can form
under these conditions. Short polymers of RNA can act as catalysts in
biologically significant reactions (Chapter 25), and it seems likely that RNA
played a crucial role in prebiotic evolution, both as catalyst and as
information repository.
RNA Molecular May Have Been the Firrst and Catalysts
In modern organisms, nucleic acids encode the genetic information that
specifies the structure of enzymes, and enzymes have the ability to catalyze the
replication and repair of nucleic acids. The mutual dependence of these two
classes of biomolecules poses the perplexing question: which came first, DNA or
protein?
The answer may be: neither. The discovery that RNA molecules can
act as catalysts in their own formation suggests that RNA may have been the
first gene and the first catalyst. According to this scenario (Fig. 3-22), one
of the earliest stages of biological evolution was the chance formation, in the
primordial soup, of an RNA molecule that had the ability to catalyze the
formation of other RNA molecules of the same sequence-a self replicating, self
perpetuating RNA. The concentration of a self replicating RNA molecule would
increase exponentially, as one molecule formed two, two formed four, and so on.
The fidelity of self replication was presumably less than perfect, so the
process would generate variants of the RNA, some of which might be even better
able to self replicate. In the competition for nucleotides, the most efficient
of the self replicating sequences would win, and less efficient replicators
would fade from the population.
The division of function between DNA (genetic information storage) and
protein (catalysis) was, according to the "RNA world" hypothesis, a later
development (Fig. 3-22). New variants of self replicating RNA molecules
developed, with the additional ability to catalyze the condensation of amino
acids into peptides. Occasionally, the peptide(s) thus formed would reinforce
the self replicating ability of the RNA, and the pair-RNA molecule and helping
peptide-could undergo further modifications in sequence, generating even more
efficient self replicating systems. Sometime after the evolution of this
primitive protein-synthesizing system, there was a further development: DNA
molecules with sequences complementary to the self replicating RNA molecules
took over the function of conserving the "genetic" information, and RNA
molecules evolved to play roles in protein synthesis. Proteins proved to be
versatile catalysts, and over time, assumed that function. Lipidlike compounds
in the primordial soup formed relatively impermeable layers surrounding self
replicating collections of molecules. The concentration of proteins and nucleic
acids within these lipid enclosures favored the molecular interactions required
in self replication.
This "RNA world" hypothesis is plausible but by no means universally
accepted. The hypothesis does make testable predictions, and to the extent that
experimental tests are possible within finite times (less than or equal to the
life span of a scientist!), the hypothesis will be tested and refined.
Biological Evolution Began More Than Three Billion Years Ago
The earth was formed about 4.5 billion years ago, and the first definitive
evidence of life dates to about 3.5 billion years ago. An international group of
scientists showed in 1980 that certain ancient rock formations (stromatolites;
Fig. 3-23) in western Australia contained fossils of primitive microorganisms.
Somewhere on earth during that first billion-year period, there arose the first
simple orga.nism, capable
of replicating its own structure from a template (RNA?) that was the first
genetic material. Because the terrestrial atmosphere at the dawn of life was
nearly devoid of oxygen, and because there were few microorganisms to scavenge
organic compounds formed by natural processes, these compounds were relatively
stable. Given this stability and eons of time, the improbable became inevitable:
the organic compounds were incorporated into evolving cells to produce more and
more effective self reproducing catalysts. The process of biological evolution
had begun. Organisms developed mechanisms for harnessing the energy of sunlight
through photosynthesis, to make sugars and other organic molecules from carbon
dioxide, and to convert molecular nitrogen from the atmosphere into nitrogenous
biomolecules such as amino acids. By developing their own capacities to
synthesize biomolecules, cells became independent of the random processes by
which such compounds had first appeared on earth. As evolution proceeded,
organisms began to interact and to derive mutual benefits from each other's
products, forming increasingly complex ecological systems.
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