Biochemistry Primer Part 1
What Is Biochemistry?
Simply stated, biochemistry is life. Practically stated, biochemistry
is our life: what we are and how we live. Our bodies are very busy factories,
extracting energy from the foods we eat, building cells and tissues,
and knitting everything together into a functioning unit using molecular
tools called enzymes. Creatures as distinct as bacteria, giraffes, and
people use many of the same biochemical toolsets to survive, eat, move,
and interact with their respective environments. Biochemistry underlies
our health.
Actions and Reactions
Even though you’re probably sitting down while you’re reading this, your
body is anything but static. Thousands of enzymes in your body toil away
every second of every day, breaking apart the components of the foods you
eat into energy for essential life processes. Vision, movement, memory—you
name it, there are enzymes at work behind the scenes.
Enzymes work by making it possible for chemical reactions inside your body
to take place. While that might not seem significant, consider the fact
that without the help of enzymes, the conversion of nutrients and minerals
into usable biological molecules such as proteins and nucleic
acids might take weeks, even years. Enzymes can make this happen in
minutes, sometimes seconds.
How do they do it all, and so well? Enzymes act like the accelerator pedal
of a car. But they also play the role of matchmaker, bringing together starting
materials (called substrates)
and converting them into finished materials (called reaction products).
One secret to an enzyme’s success in this endeavor is its shape. An enzyme
is shaped so that it can hug its substrate tightly. This molecular embrace
triggers chemical changes, shuffling chemical attractive forces called bonds
and producing new molecules. Only enzymes that have an exact fit with their
substrates do a decent job of speeding up chemical reactions. But things
don’t end there; reactions are not singular events. They re-occur, over
and over again. Enzymes are the key players linking up chain reactions of
the chemical events that culminate in our everyday physiology.
Much like a cascade of dominoes, the product of one chemical reaction becomes
the substrate for another. Enzymes form the core of these ordered pathways,
which themselves are the basis for metabolism. In a grand sense, metabolism
is the process any organism uses to retrieve energy from Product the environment
and use it to grow. The proper functioning of small and big body parts hinges
upon effective communication within and between pathways. That includes
everything from tiny specks of DNA that string together into all of your
genes to a complicated, multicelled organ such as the heart. By understanding
the language of physiological communication systems, scientists can devise
ways to patch the circuits when they become broken, in illness and disease.
The Motion of Life
Fish swim, birds fly, babies crawl. Enzymes, too, are constantly on
the move. The world’s smallest motor, in fact, is an enzyme found in
the powerhouse of the cell (the mitochondrion) which generates energy
in the form of a molecule called adenosine triphosphate, or ATP. Often
dubbed the energy currency of life, ATP shuttles to and fro throughout
cells, and is “traded” during chemical reactions. These molecular transactions
drive reactions forward to make a product. Several decades of work earned
three scientists—Paul Boyer of the University of California, Los
Angeles, John Walker of the Medical Research Council in the United Kingdom,
and Jens Skou of the University of Aarhus in Denmark—the Nobel
Prize for figuring out how the motor, a molecule called ATP synthase,
functions as a set of molecular levers, gears, and ratchets. Other molecular
motors include protein machines that tote DNA-laden chromosomes or protein
cargo throughout the cell. The enzyme that copies DNA does its job through
what scientists call a “sliding clamp” mechanism. As a growing DNA strand,
a future gene winds through an enzyme called DNA polymerase like a thread
through a needle. The energy source for this and all biological motor-driven
processes is ATP.
energy for the cell.
It’s a Gas!
Tediously long car trips elicit multiple rounds of word games like “20
Questions,” in which players take turns thinking of a secret object and
having their opponent ask more and more detailed questions to identify it.
In this game, the first question is always, “Animal, Vegetable, or Mineral?”
Virtually everything imaginable falls into one of those three categories.
Chemists could play such a game, in which the mystery item is a molecule—any
molecule. In this game, the first question would always be, “Solid, Liquid,
or Gas?” Looking outside the window, it’s easy to think of entries for each
of these categories: Stones are solids, dewdrops are liquids, and the atmosphere
is a blend of many different gases. But there’s a trick: In theory, any
molecule could in fact be all three, if the conditions were right. In pure
form, whether a molecule is solid, liquid, or gas depends on its environment,
namely the ambient temperature and the atmospheric pressure. Water is an
easy example. Everybody knows that below 32 degrees Fahrenheit, water is
a solid, and above 32 degrees, water is a liquid. Put a tea kettle on the
stove and witness water turn into a gas.
Our bodies, too, harbor an assortment of solids, liquids, and gases. But
of these three physical states, which chemists call phases, everything that
lives is largely liquid—water is the universal solvent of life. Fingernails,
hair, and bones are solids, indeed, but only the dead parts. Living cells
resident in bone and its vital bone marrow thrive in a watery environment.
Gases can also be found throughout the body; some examples include the oxygen
we breathe in and the carbon dioxide we breathe out. But inside the body,
even these gases are dissolved in liquids—mainly blood, which itself
is mostly water.
One gas, nitric oxide (whose chemical symbol is “NO”), serves the body
in a host of useful ways. Scientists were rather surprised not many years
ago when they discovered that the gas NO is a chemical messenger. Tiny and
hard to study in the laboratory, NO eluded scientists for many years. Other
molecular messengers—such as neurotransmitters and larger proteins—can
be relatively easily extracted from body fluids and studied in a test tube,
where they can remain intact for minutes or even hours at body temperatures.
NO, on the other hand, vanishes in seconds. While this property makes it
horrendously difficult to study, such volatility renders NO a molecule with
extraordinary versatility. In a snap, NO can open blood vessels, help pass
electrical signals between nerves, or fight infections.
But in addition to being a friend, NO can also be a foe—too much
or too little of this gas can be harmful. Blood vessels that have been widened
too much can lead to potentially deadly shock, a condition in which blood
pressure plunges so low that vital organs cannot get enough blood to survive.
An overactive immune response—fired up by NO—can produce a painful
syndrome called inflammatory bowel disease. With all this at stake, the
body works hard to stringently control production of this powerful gas.
The molecule that manufactures NO is an enzyme called nitric oxide
synthase (NOS). Owing to nitric oxide’s many different functions in
the body, three different versions of NOS exist, specialized for the
cardiovascular, immune, and nervous systems. In recent years, scientists
have achieved a major victory in beginning to understand how NOS works.
Thomas Poulos of the University of California, Irvine, determined the
structure, or three-dimensional shape, of one form of NOS. Since intimate
associations between an enzyme and its substrate rely on a snug fit,
probing the three-dimensional shape of an enzyme or other protein can
enable scientists to begin to understand how the protein works, predict
what other molecules it might fit, and design drugs to boost or block
its activity. After obtaining a sample of NOS protein from the laboratory
of Bettie Sue Masters of the University of Texas Health Science Center
at San Antonio, Poulos obtained a “picture” of NOS by bombarding a tiny
crystal arrangement of the protein with high-energy X rays, then piecing
together the protein’s shape by tracing the directions in which the
energy was scattered throughout the crystal. This work, years in the
making, paints a portrait of NOS consisting of two identical units.
In a cell, the two units of NOS assemble head-to-head, creating a new
landscape upon which substrates and helper molecules convene to complete
the task at hand: creating nitric oxide from an amino
acid called arginine. In the case of NOS, the helpers include iron
and a tiny molecule called a cofactor.
Enzymes like NOS are lost without these helpers.
Pulling Into Dock
Like a ship nestling into its berth, many proteins require the help
of one or more other proteins to perform their jobs well. However, unlike
ships, proteins docked together often change their shape as a result
of such an encounter. The differently shaped protein is newly and exquisitely
able to capture a substrate and carry out a chemical reaction. Akin
to rearranging seats in a room to accommodate more guests, the reshaping
of proteins (called conformational changes) can make extra room for
substrates and products to fit. Such shape changes also change the electrical
“ambience” of an enzyme’s innards, revealing differently charged portions
of the molecule that can have a big impact on molecular interactions.
Making a Protein From Scratch
Tucked away inside the DNA sequence of all of your genes are the instructions
for how to construct a unique individual. Our genetic identity is “coded”
in the sense that four building blocks, called nucleotides, string together
to spell out a biochemical message—the manufacturing instructions
for a protein. DNA’s four nucleotides, abbreviated A, T, G, and C, can
only match up in specific pairs: A links to T and G links to C. An intermediate
in this process, called mRNA (messenger ribonucleic acid), is made from
the DNA template and serves as a link to molecular machines called ribosomes.
Inside every cell, ribosomes read mRNA sequences and hook together protein
building blocks called amino acids in the order specified by the code:
Groups of three nucleotides in mRNA code for each of 20 amino acids.
Connector molecules called tRNA (transfer RNA)
aid in this process. Ultimately, the string of amino acids folds upon
itself, adopting the unique shape that is the signature of that particular
protein.
Building Blocks
So the case is made that enzymes, and all proteins, are extremely important
in the body. Where do these important molecules come from? Do they last
forever?
Proteins are synthesized continually throughout life. Stockpiles of proteins
are not passed on from generation to generation, but their molecular instruction
guides—our genetic material, DNA—are. After reading the DNA
“letters” in our genes, specialized molecular machines (groups of enzymes
working side by side inside the cell) copy the DNA, then other machines
use this genetic template to churn out proteins. To do this, enzymes mix
and match a set of 20 different amino acids, the building blocks of proteins.
Hooking together these amino acids, the body constructs thousands of different
protein types. Theoretically, millions of proteins could be formed through
all the possible linkages between amino acids. It is not surprising, then,
that every one of these amino acids must be readily available at all times
for protein synthesis.
Dire consequences may result if one or more of these amino acids is either
absent or overabundant. For instance, a genetic disorder called phenylketonuria
(PKU) is caused by the body’s inability to get rid of extra phenylalanine,
an amino acid abbreviated “Phe.” PKU is an “autosomal recessive” disorder,
meaning that the only way to get the disease is if both of your parents
carry a version of a gene linked with this disease. If only one parent has
the gene linked to PKU, his or her children cannot develop the disease.
Children who have PKU are born without the enzyme that breaks down the Phe
amino acid. Extremely high levels of Phe accumulate and are very toxic,
especially to the brain. As a result, PKU causes mental retardation. Yet
Phe is an essential amino acid—your body cannot do without it. Both
diet and genes contribute to causing PKU, and so any means to control the
supply of Phe in the body can prevent the disease.
A thin silver lining to the PKU story is that the disorder can be diagnosed
simply—in fact, since the 1960s, nearly every baby born in the United
States has received a tiny needle stick in his or her heel to retrieve a
droplet of blood to test for levels of the Phe-chewing enzyme. If caught
early enough and treated in the first year of life, PKU can be controlled.
In 150 million infants tested since the early 1970s, 10,000 cases of PKU
have been detected and treated. At present, doctors treat children with
PKU by prescribing a life-long restrictive diet; certain foods, such as
milk and diet sodas containing the artificial sweetener aspartame (NutraSweet®),
are rich sources of Phe. The diet is rigid, requiring children to avoid
those and many other foods, such as meat and fish, dairy products, bread,
nuts, and even some vegetables. As a result, people with PKU have to take
a special Phe-free vitamin/mineral supplement to ensure that they receive
adequate amounts of all of the other essential amino acids bountiful in
those foods. People used to think that once a child with PKU reached the
teens, he or she could go off the diet, which can be expensive because of
the supplement. However, current guidelines recommend that people with PKU
remain on the restrictive diet throughout life.
To get around the difficulty and inconvenience of maintaining a highly
specialized diet and taking a dietary supplement for life, a better solution
might be to provide the Phe-digesting enzyme to people whose bodies lack
it. But while replacing the missing enzyme that breaks down Phe (abbreviated
“PAH”) may seem a simple plan, this is much easier said than done. The PAH
enzyme has many parts and cofactors. What’s more, delivering the enzyme
requires a liver transplant, a procedure that itself carries significant
risks. An alternative approach would be to supply people with PKU with an
enzyme that will get rid of Phe and that can be safely administered by mouth.
Such an enzyme, called “PAL,” abounds in nature—plants, yeast, and
a variety of other organisms have it, and scientists can produce it in the
lab using genetic
engineering strategies. Recently, researchers have succeeded in treating
an experimental strain of mice who develop a PKU-like syndrome with lab-made
PAL. Clinical studies in people will determine for sure whether this strategy
offers hope for people with the disease.
A Special Bond
to make molecules. Dots represent electrons taking part in chemical
bonding.
You may be surprised to learn that at the heart of chemistry is physics—the
study of attracting and repelling forces that link up the building blocks
of life. Chemical bonds are those physical forces that keep atoms together,
and they come in a few varieties (see drawing/illustration at right).
Ionic bonds,
in which positively charged atoms are attracted to negatively charged
atoms, are the strongest of the bond types. Covalent
bonds are more subtle, and occur when neighboring atoms (such as
hydrogen) share electrons from within their respective halos of swirling
particles. Chemists refer to both ionic and covalent bonds as “intramolecular”
forces. Other important forces are called “intermolecular” forces—those
holding different molecules together. These types of forces form the
basis for liquids and solids, which are really just collections of molecules
arranged in a precise pattern in space. Intermolecular forces are also
called van
der Waals forces, named for the Dutch physicist who first discovered
them. Hydrogen bonds are a type of van der Waals force, and represent
an important bond in biochemistry.
From Mice to…Bacteria?
A favorite experimental tool of many scientists is the laboratory mouse,
which can be bred “to order” with characteristics useful for addressing
specific research questions. While rodents differ from people in important
and obvious respects, believe it or not mice and rats share many of the
same genes with humans. In some cases, upwards of 80 percent of the nucleotides
in a mouse gene may be identical to a similar one—its “homologue”—in
humans. Nature is economical: Very important genes (those that code for
key metabolic enzymes, for instance) are conserved throughout evolution,
varying little between species. For researchers, that’s a good thing. Mice
and a slew of other so-called model
organisms—such as bacteria, yeast, and even plants—are the
workhorses of many biochemical laboratories. But in addition to these often
striking similarities, there are significant differences in the biochemistry
of model organisms, especially in the most primitive of species like bacteria.
Scientists can exploit these differences to fight disease, targeting enzymes
or other molecular parts that are common to microorganisms but are absent
from your body.
A Killer’s Strategy
Drug-sensitive bacteria are killed when vancomycin
attaches to an Alanine-Alanine strand of the bacterium’s growing cell
wall (top), preventing the protective cell wall from forming at all.
Vancomycin cannot attach to the slightly different, Alanine- Lactate
strand of the drug-resistant bacteria (bottom). As a result, the resistant
bacteria are able to make their tough cell wall and survive in the presence
of the antibiotic drug.
Chemical Biology in Action: Chemistry to the Rescue
Arguably many of the most important medical advances this century relate
to the development of powerful antibiotics and vaccines to treat infectious
diseases caused by bacteria, viruses, and parasites. But those breakthroughs
have come with a cost—the microbes have learned how to fight back,
and with a vengeance. The misuse of antibiotics—these drugs are
overprescribed by doctors and people often fail to finish a full prescription—is
the most common reason why antibiotic resistance is coming so rapidly
to the fore.
When you take an antibiotic, the drug treats infection by knocking
out hundreds of strains of “sensitive” bacteria in your body. But it
also leaves behind scores of “resistant” strains—slightly altered
versions of the sensitive variety. The resistant microbes, with no stops
in place, repopulate themselves rapidly. To make matters worse, these
lingering resistant organisms hang out not only in your body, but they
can spread to your family and friends—worsening the problem for
everyone.
Bacteria are not inherently malicious. In the human body, many different
types of bacteria reside within the large intestine, where they perform
vital roles in processing food. Trillions of microorganisms break down
undigested carbohydrates, common components of vegetables and other
foods like beans. In the wrong place, however, these normally innocuous
bacteria—called enterococci—can do the body great harm.
In disease, such microbes can seep from the relatively safe harbor of
the intestines into other regions of the body, such as burned skin,
the heart, or the urinary tract. There, the bacteria can multiply rampantly,
especially when the immune system is already strained. Enterococci
are stubbornly resistant to most antibiotic drugs. Until recently, an
antibiotic called vancomycin fairly effectively put the brakes on enterococcal
infections. However, in recent years the incidence of enterococcal resistance
to vancomycin has been on a disturbing rise.
Fortunately, chemists are hot on the heels of enterococci. Christopher
T.Walsh and Daniel Kahne, both of Harvard Medical School in Boston,
Massachusetts, have traced the roots of vancomycin resistance to a single,
errant chemical link. Vancomycin normally kills enterococci by getting
in the bacterium’s way while it tries to manufacture a protective cell
wall for itself. Vancomycin prevents the molecular “bricks” of this
cell wall from melding together, leaving the bacterium susceptible to
the harsh environment and destructive enzymes in the cells of its host’s
body. Walsh, Kahne, and their coworkers unearthed a set of just five
genes that enable enterococci to get past the antibiotic drug vancomycin’s
action by using a slightly different method to build a cell wall. The
researchers’ detective work points to promising avenues for future antibiotic
drug development, based on the strategy of interrupting enzymes that
rearrange the cell wall precursors.
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