Hemoglobin Structure
`
`
`and Respiratory Transport
`
`Hemoglobin carries oxygen from the lungs to the tissues and helps
`
`
`
`to transport carbon dioxide back to the lungs. It fulfills this dual
`
`
`
`role by clicking back and forth between two alternative structures
`
`by M. F. Perutz
`
`
`
`Hemoglobin is the vital protein that
`
`solved by my colleague John C. Ken­
`
`Why grasse is greene. or why our
`
`drew and his collaborators.
`conveys oxygen from the lungs to the
`blood is red.
`
`
`tissues and facilitates the return of car­
`
`Myoglobin is the simpler of the two
`
`
`Are mysteries which none have reach' d
`
`
`bon dioxide from the tissues back to the
`
`molecules. This protein. with its 2.500
`unto.
`
`lungs. These functions and their subtle
`
`
`atoms of carbon. nitrogen. oxygen. hy­
`In this low forme. poore soule. what
`wilt thou doe? -JOHN DONNE,
`drogen and sulfur. exists for the sole
`
`interplay also make hemoglobin one of
`
`purpose of allowing its single atom of
`
`the most interesting proteins to study.
`
`
`iron to form a loose chemical bond with
`
`
`Like all proteins. it is made of the small
`"Of the Progresse of the Soule"
`of oxygen (02), Why does
`a molecule
`
`organic molecules called amino acids.
`W hen I was a student.
`nature go to so much trouble to accom­
`
`strung together in a linear sequence
`I wanted
`
`called a polypeptide chain. The amino
`
`plish what is apparently such a simple
`to solve a great problem in
`illY home town. to find
`task? Like most compounds of iron.
`
`acids are of 20 different kinds and their
`biochemistry. One day I set
`
`heme by itself combines with oxygen so
`
`sequence in the chain is genetically de­
`out from Vienna.
`
`firmly that the bond. once formed. is
`
`
`termined. A hemoglobin molecule is
`the Great Sage at Cambridge. He taught
`me that' the riddle of life was hidden in
`
`made up of four polypeptide chains. two
`
`hard to break. This happens because an
`
`
`iron atom can exist in two states of va­
`alpha chains of 1 4 1 amino acid residues
`
`
`the structure of proteins. and that X-ray
`
`
`lency: ferrous iron. carrying two posi­
`each and two beta chains of 1 46 residues
`
`crystallography was the only method
`
`tive charges. as in iron sulfate. which
`each. The alpha and beta chains have
`
`
`capable of solving it. The Sage was John
`anemic people are told to eat. and ferric
`
`
`different sequences of amino acids but
`
`Desmond Bernal. who had just discov­
`
`
`ered the rich X-ray-diffraction patterns
`
`fold up to form similar three-dimen­
`
`
`iron. carrying three.positive charges. as
`
`in iron oxide. or rust. Normally. ferrous
`
`sional structures. Each chain harbors
`
`
`given by crystalline proteins. We really
`heme reacts with oxygen irreversibly to
`one heme. which gives blood its red
`
`did call him Sage. because he knew ev­
`yield ferric heme. but when ferrous
`color. The heme consists of a ring of
`
`
`erything. and I became his disciple.
`heme is embedded in the folds of the
`
`carbon. nitrogen and hydrogen atoms
`
`In 1 9 3 7 I chose hemoglobin as the
`
`globin chain. it is protected so that its
`
`called porphyrin. with an atom of iron.
`
`protein whose structure I wanted to
`
`
`reaction with oxygen is reversible. The
`
`like a jewel. at its center. A single poly­
`
`solve. but the structure proved so much
`
`effect of the globin on the chemistry of
`peptide chain combined with a single
`more complex than any solved before
`
`the heme has been explained only re­
`heme is called a subunit of hemoglobin
`that it eluded me for more than 20 years.
`
`
`cently with the discovery that the irre­
`
`or a monomer of the molecule. In the
`
`First fulfillment of the Sage's promise
`
`
`
`versible oxidation of heme proceeds by
`complete molecule four subunits are
`
`came in 1959. when Ann F. Cullis. Hil­
`
`closely joined. as in a three-dimensional
`way of an intermediate compound in
`
`
`ary Muirhead. Michael G. Rossmann.
`which an oxygen molecule forms a
`jigsaw puzzle. to form a tetramer.
`Tony C. T. North and I first unraveled
`bridge between the iron atoms of two
`
`
`the architecture of the hemoglobin mol­
`
`hemes. In myoglobin and hemoglobin
`
`ecule in outline [see "The Hemoglobin
`
`the folds of the polypeptide chain pre­
`
`Molecule." by M. F. Perutz;
`
`
`vent the formation of such a bridge by
`In red muscle there is another protein.
`
`
`
`isolating each heme in a separate pock­
`
`
`called myoglobin. similar in constitu­
`like explorers who have discovered a
`
`
`
`et. Moreover. in the protein the iron is
`
`tion and structure to a beta subunit of
`
`new continent. but it was not the end of
`
`linked to a nitrogen atom of the amino
`
`hemoglobin but made up of only one
`the voyage. because our much-admired
`
`acid histidine. which donates negative
`
`
`polypeptide chain and one heme. Myo­
`model did not reveal its inner workings:
`
`charge that enables the iron to form a
`
`it provided no hint about the molecu­
`globin combines with the oxygen re­
`
`loose bond with oxygen.
`
`lar mechanism of respiratory transport.
`
`leased by red cells. stores it and trans­
`
`An oxygen-free solution of myoglo­
`ports it to the subcellular organelles
`
`Why not? Well-intentioned colleagues
`
`bin or hemoglobin is purple like venous
`
`called mitochondria. where the oxygen
`
`were quick to suggest that our hard-won
`blood; when oxygen is bubbled through
`
`
`generates chemical energy by the com­
`
`
`structure was merely an artifact of crys­
`
`
`such a solution. it turns scarlet like arte­
`bustion of glucose to carbon dioxide
`
`tallization and might be quite different
`
`rial blood. If these proteins are to act as
`
`and water. Myoglobin was the first
`
`
`from the structure of hemoglobin in its
`oxygen carriers. then hemoglobin must
`
`
`protein whose three-dimensional struc­
`
`living environment. which is the red
`blood cell.
`be capable of taking up oxygen in the
`
`
`ture was determined; the structure was
`
`SCIENTIFIC
`AMERICAN, November. 1 964]. We felt
`
`Hemoglobin Function
`
`92
`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 1 of 36
`
`BLUEBIRD EXHIBIT 1007
`
`

`

`gen bound to heme iron. Suppose a solu­
`lungs, where it is plentiful, and giving it
`myoglobin, which is scarlet. The spec­
`
`
`
`tion of myoglobin is placed in a vessel
`
`up to myoglobin in the capillaries of
`
`
`troscope measures the proportion of
`
`constructed so that a large volume of
`
`muscle, where it is less plentiful; myo­
`
`
`oxymyoglobin in the solution. The in­
`gas can be mixed with it and so that its
`
`'globin in turn must pass the oxygen on
`
`jection of oxygen and the spectroscopic
`color can also be measured through a
`
`to the mitochondria, where it is still
`
`
`measurements are repeated until all the
`
`spectroscope. Without oxygen only the
`scarcer.
`
`
`myoglobin has turned scarlet. The re­
`
`purple color of deoxymyoglobin is ob­
`A simple experiment shows that myo­
`
`
`
`sults are plotted on a graph with the par­
`
`served. If a little oxygen is injected,
`
`globin and hemoglobin can accomplish
`tial pressure of oxygen on the horizontal
`
`this exchange because there is an equi­
`
`some of the oxygen combines with some
`
`axis and the percentage of oxymyoglo­
`librium between free oxygen and oxy-
`
`of the deoxymyoglobin to form oxy-
`
`bin on the vertical axis. The graph has
`
`spheres overlap. Carbon atoms are black, nitrogen atoms blue, oxygen
`
`
`HEME GROUP is the active center of the hemoglobin molecule, the
`
`
`atoms red, hydrogen atoms white and the iron atom is rust-colored.
`binding site for oxygen. The heme is a flat ring, called a porphyrin,
`
`The model shows the deoxygenated heme; oxygen binds to the lower
`
`with an iron atom at its center; it is seen here edge on and extend­
`
`side of the iron atom. The picture was generated
`
`ing horizontally across the middle of the illustration.
`of Health
`
`amino acid residues of the globin that are in contact with the heme
`from atomic coordinates determined by Giulio Fermi of the Med­
`
`
`
`are atso shown. In this computer-generated image each atom is rep­
`
`
`ical Research Council Laboratory of Molecular Biology at Cam­
`
`
`resented by a sphere into which no other atom can penetrate unless
`bridge in England. A key to the structure
`
`the atoms are chemically bonded; where two atoms are bonded the
`
`by Richard J. Feld­
`mann and Thomas K. Porter of the National Institutes
`is provided on page 95.
`93
`
`Three of the 16
`
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`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 2 of 36
`
`

`

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`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 3 of 36
`
`

`

`V. Hill. who first attempted
`
`
`
`Cooperative Effects
`
`A.
`
`C
`
`PROXIMAL
`HISTIDINE
`
`CH
`
`the shape of a rectangular hyperbola: it
`
`
`a mathe­
`the hemoglobin molecules in a solution
`
`matical analysis of the oxygen equilib­
`
`
`
`
`
`therefore follows the biblical parable of
`
`is steep at the start. when all the myoglo­
`
`rium. The normal value of Hill's coef­
`the rich and the poor: ."For unto every
`
`
`bin molecules are free. and it flattens out
`ficient is about 3 ; without heme-heme
`
`one that hath shall be given. and he shall
`at the end. when free myoglobin mole­
`cules have become so scarce that only a
`
`have abundance: but from him that hath
`
`interaction it becomes unity. The curve
`
`high pressure of oxygen can saturate
`
`ends with another line at 45 degrees to
`not shall be taken away even that which
`the axes because oxygen has now be­
`them.
`he hath." This phenomenon suggests
`
`
`To understand this equilibrium one
`
`come so abundant that only the last
`there is some kind of communication
`
`heme in each molecule is likely to be
`between the hemes in each molecule.
`
`must visualize its dynamics. Under the
`free. and all the hemes in the solution
`
`
`and physiologists have therefore called
`
`
`influence of heat the molecules in the
`
`react independently once more.
`it heme-heme interaction.
`
`solution and in the gas are whizzing
`A better picture of the underlying
`
`around erratically and are constantly
`
`
`colliding. Oxygen molecules are enter­
`
`
`
`mechanism of heme-heme interaction is
`
`ing and leaving the solution. forming
`
`
`obtained in a logarithmic graph. The
`Hill's coefficient and the oxygen affini­
`
`
`
`bonds with myoglobin molecules and
`
`equilibrium curve then begins with a
`
`ty of hemoglobin depend on the concen­
`
`breaking away from them. The number
`
`
`straight line at 45 degrees to the axes.
`
`
`
`
`tration of several chemical factors in the
`
`
`of iron-oxygen bonds that break in one
`
`because at first oxygen molecules are so
`
`red blood cell: protons (hydrogen atoms
`
`second is proportional to the number of
`scarce that only one heme in each hemo­
`
`without electrons, whose concentration
`
`oxymyoglobin molecules. The number
`
`globin molecule has a chance of catch­
`
`can be measured as pH), carbon dioxide
`
`of bonds that form in one second is pro­
`
`ing one of them. and all the hemes there­
`
`(C02), chloride ions (Cl-) and a com­
`
`
`portional to the frequency of collisions
`
`fore react independently. as in myoglo­
`
`pound of glyceric acid and phosphate
`between myoglobin and oxygen. which
`bin. As more oxygen flows in. the four
`
`called 2.3-diphosphoglycerate (DPG).
`
`is determined in turn by the product of
`
`hemes in each molecule begin to interact
`
`
`Increasing the concentration of any of
`
`their concentrations. When more oxy­
`
`and the curve steepens. The tangent to
`
`these factors shifts the oxygen equilibri­
`gen is added to the gas. more oxygen
`
`its maximum slope is known as Hill's
`coefficient (n). after the
`
`
`um curve to the right. toward lower oxy-
`
`
`molecules dissolve. collide with and
`physiologist
`
`bind to myoglobin; this raises the num­
`
`
`ber of oxymyoglobin molecules present
`
`and therefore also the number of iron­
`oxygen bonds liable to break. until the
`
`number of myoglobin molecules com­
`bining with oxygen in one second be­
`
`comes equal to the number that lose
`their oxygen in one second. When that
`
`happens. a chemical equilibrium has
`
`been established.
`
`The equilibrium is best represented
`
`by a graph in which the logarithm of the
`
`
`ratio of oxymyoglobin molecules (Y)
`to de oxymyoglobin molecules
`
`
`
`is plotted against the logarithm of the
`
`partial pressure of oxygen. The hyper­
`
`bola now becomes a straight line at 45
`
`degrees to the axes. The intercept of the
`
`
`
`line with the horizontal axis drawn at
`HEME GROUP
`um
`pressure
`constant
`
`of oxygen at which exactly half of the
`
`
`myoglobin molecules have taken up ox­
`
`ygen. The greater the affinity of the
`
`protein for oxygen. the lower the pres­
`sure needed to achieve half-saturation
`
`and the smaller the equilibrium con­
`stant. The 45-degree slope remains un­
`changed. but lower oxygen affinity shifts
`the line to the right and higher affinity
`
`shifts it to the left.
`If the same experiment is done with
`
`
`blood or with a solution of hemoglo­
`
`bin. an entirely different result is ob­
`tained. The curve rises gently at first.
`
`
`then steepens and finally flattens out as
`
`
`it approaches the myoglobin curve. This
`CHEMICAL STRUCTURE of the heme group and surrounding amino acids is shown by a
`
`
`
`strange sigmoid shape signifies that oxy­
`
`
`
`
`skeleton of lines connecting the centers of atoms. The only chemical bond between the heme
`
`
`gen-free molecules (deoxyhemoglobin)
`
`
`and the protein that enguHs it is the link between the iron atom and the amino acid at the top,
`
`are reluctant to take up the first oxygen
`
`
`
`called the proximal histidine; the two amino acids at the bottom (the distal histidine and the
`
`
`molecule but that their appetite for oxy­
`
`
`
`distal valine) touch the heme but are not bonded to it. Tbe proximal histidine is the principal
`gen grows with the eating. Conversely.
`
`path for communication between the heme and the rest of the molecule. In the deoxy state
`the loss of oxygen by some of the hemes
`
`
`
`
`sbown the iron protrudes above the porphyrin and may be hindered from returning to a cen­
`lowers the oxygen affinity of the remain­
`
`
`
`tered position by repulsion between one corner of the proximal histidine and one of the porphy­
`
`der. The distribution of oxygen among
`
`
`rin nitrogen atoms. Key was constructed with aid of a computer by R. Diamond of Cambridge.
`
`(1 - Y)
`
`o
`
`Y/(1 -Y) = 1 gives th� equilibri
`K. This is the partial
`
`o
`DISTAL VALINE \ CH �H3
`C� NH
`
`C H3
`
`CH
`
`N
`
`CH
`
`DISTAL H ISTIDINE
`
`N H
`
`95
`
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`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 4 of 36
`
`

`

`eOOH
`
`why it is so toxic. In heavy smokers up to
`
`20 percent of the oxygen combining
`sites can be blocked by carbon monox­
`
`ide. so that less oxygen is carried by the
`blood. In addition carbon monoxide has
`
`an even more sinister effect. The combi­
`nation of one of the four hemes in any
`
`
`hemoglobin molecule with carbon mon­
`oxide raises the oxygen affinity of the
`
`remaining three hemes by heme-heme
`
`interaction. The oxygen equilibrium
`
`
`curve is therefore shifted to the left.
`
`
`which diminishes the fraction of the
`
`
`oxygen carried that can be released to
`the tissues.
`If protons lower the affinity of hemo­
`
`
`globin for oxygen. then the laws of ac­
`
`tion and reaction demand that oxygen
`
`
`lower the affinity of hemoglobin for pro­
`
`tons. Liberation of oxygen causes hemo­
`
`globin to combine with protons and vice
`versa; about two protons are taken up
`
`for every four molecules of oxygen re­
`leased. and two protons are liberated
`
`again when four molecules of oxygen
`
`are taken up. This reciprocal action is
`known as the Bohr effect and is the key
`
`to the mechanism of carbon dioxide
`
`
`transport. The carbon dioxide released
`
`
`
`by respiring tissues is too insoluble to be
`
`transported as such. but it can be ren­
`
`dered more soluble by combining with
`enfo.lded in a po.lypeptide
`
`water to form a bicarbonate ion and a
`
`
`
`proton. The chemical reaction is written
`
`SUBUNIT OF HEMOGLOBIN co.nsists o.f a heme gro.up (color)
`is a linear sequence o.f amino. acid residues, each o.f which is represent­
`
`chain. The po.lypeptide
`ed here by a single do.t, marking the po.sitio.n o.f the central (alpha) carbon ato.m. The chain be­
`gins with an amino. gro.up (NBs) and ends with a carboxyl group (COOH). Most o.f the po.ly­
`
`peptide is Co.i1ed up to. fo.rm helical segments but there-are also. no.nhelical regio.ns. The co.mput­
`
`er-generated diagram o.f a ho.rse-hemo.glo.bin subunit was prepared by Feldmllnn and Po.rter.
`
`In the absence of hemoglobin this reac­
`
`tion would soon be brought to a halt by
`gen affinity. and makes it more sigmoid.
`
`greater the fraction of oxygen that can
`
`
`
`the excess of protons produced. like a
`
`
`
`Increased temperature also shifts the
`
`
`
`
`be released. Several factors conspire to
`
`fire going out when the chimney is
`
`curve to the right. but it makes it less
`
`
`
`that purpose. Oxidation of nutrients by
`
`blocked. Deoxyhemoglobin acts as a
`
`
`sigmoid. Strangely. none of these fac­
`
`
`the tissues liberates lactic acid and car­
`
`buffer. mopping up the protons and tip­
`
`
`tors. with the exception of temperature.
`bonic acid; these acids in turn liberate
`ping the balance toward the ,formation
`
`
`influences the oxygen equilibrium curve
`
`protons. which shift the curve to the
`
`
`of soluble bicarbonate. In the lungs the
`
`of myoglobin. even though the chemis­
`
`right. toward lower oxygen affinity. and
`process is reversed. There. as oxygen
`
`try and structure of myoglobin are re­
`
`make it more sigmoid. Another impor­
`
`binds to hemoglobin. protons are cast
`
`lated closely to those of the individual
`
`tant regulator of the oxygen affinity is
`
`
`off. driving carbon dioxide out of solu­
`chains of hemoglobin.
`
`
`DPG. The number of DPG molecules in
`
`tion so that it can be exhaled. The reac­
`What is the purpose of these extraor­
`the red cell is about the same as the
`
`tion between carbon dioxide and water
`dinary effects? Why is it not good
`
`number of hemoglobin molecules. 280
`
`
`is catalyzed by carbonic anhydrase. an
`
`
`enough for the red cell to contain a sim­
`
`million. and probably remains fairly
`
`enzyme in the red cells. The enzyme
`
`ple oxygen carrier such as myoglobin?
`
`
`constant during circulation; a shortage
`
`speeds up the reaction to a rate of about
`
`Such a carrier would not allow enough
`
`of oxygen. however. causes more DPG
`
`
`half a million molecules per second. one
`of the oxygen in the red cell to be un­
`
`
`to be made. which helps to release more
`
`of the fastest of all known biological
`
`loaded to the tissues. nor would it allow
`
`oxygen. With a typical sigmoid curve
`reactions.
`
`enough carbon dioxide to be carried
`
`nearly half of the oxygen carried can be
`There is a second but less important
`to the lungs by the blood plasma. The
`
`
`released to the tissues. The human fetus
`
`
`mechanism for transporting carbon di­
`
`partial pressure of oxygen in the lungs
`
`
`has a hemoglobin with the same alpha
`
`oxide. The gas binds more readily to de­
`
`is about 1 00 millimeters of mercury.
`
`chains as the hemoglobin of the human
`
`oxyhemoglobin than it does to oxyhe­
`
`
`which is sufficient to saturate hemoglo­
`
`
`adult but different beta chains. resulting
`
`moglobin. so that it tends to be taken
`bin with oxygen whether the equilibri­
`in a lower affinity for DPG. This gives
`
`up when oxygen is liberated and cast off
`
`um curve is sigmoid or hyperbolic. In
`
`fetal hemoglobin a higher oxygen affini­
`when oxygen is bound. The two mecha­
`
`
`ty and facilitates the transfer of oxygen
`venous blood the pressure is about 35
`
`nisms of carbon dioxide transport are
`
`
`from the maternal circulation to the fe­
`
`millimeters of mercury; if the curve
`
`
`antagonistic: for each molecule of car­
`tal circulation.
`
`
`
`were hyperbolic. less than 10 percent of
`
`bon dioxide bound to deoxyhemoglobin
`
`
`the oxygen carried would be released at
`Carbon monoxide (CO) combines
`either one or two protons are released.
`that pressure. so that a man would as­
`
`
`with the heme iron at the same site as
`
`which oppose the conversion of oth­
`
`oxygen. but its affinity for that site is 1 50
`
`
`phyxiate even if he breathed normally.
`
`er molecules of carbon dioxide to bi­
`
`times greater; carbon monoxide there­
`
`The more pronounced the sigmoid
`
`carbonate. Positively charged protons
`
`shape of the equilibrium curve is. the
`
`fore displaces oxygen. which explains
`
`entering the red cell draw negatively
`
`96
`
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`© 1978 SCIENTIFIC AMERICAN, INC
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`Page 5 of 36
`
`

`

`97
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`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 6 of 36
`
`

`

`charged chloride ions in with them. and
`
`these ions too are bound more readily
`
`by deoxyhemoglobin than by oxyhemo­
`
`
`globin. DPG is synthesized in the red
`
`cell itself and cannot leak out through
`
`the cell membrane. It is strongly bound
`
`by deoxyhemoglobin and only very
`weakly bound by oxyhemoglobin.
`
`Heme-heme interaction and the inter­
`
`play between oxygen and the other four
`
`
`ligands are known collectively as the co­
`
`operative effects of hemoglobin. Their
`
`discovery by a succession of able physi­
`
`
`ologists and biochemists took more than
`half a century and aroused many con­
`
`troversies. In 1 93 8 Felix Haurowitz of
`
`the Charles University in Prague made
`
`
`another vital observation. He discov­
`
`
`ered that deoxyhemoglobin and oxy­
`
`
`
`hemoglobin form different crystals. as
`
`though they were different chemical
`substances. which implied that hemo­
`globin is not an oxygen tank but a mo­
`
`
`lecular lung because it changes its struc­
`ture every time it takes up oxygen or
`
`releases it.
`
`Theory of Allostery
`
`The discovery of an interaction
`
`among the four hemes made it obvious
`
`that they must be touching. but in sci­
`ence what is obvious is not necessarily
`
`true. When the structure of hemoglo­
`bin was finally solved. the hemes were
`
`found to lie in isolated pockets on the
`
`surface of the subunits. Without contact
`between them how could one of them
`sense whether the others had combined
`with oxygen? And how could as hetero­
`
`
`geneous a collection of chemical agents
`
`
`as protons. chloride ions. carbon dioxide
`
`
`and diphosphoglycerate influence the
`
`oxygen equilibrium curve in a similar
`
`way? It did not seem plausible that any
`
`of them could bind directly to the
`hemes. that all of them could bind at
`
`any other common site. although there
`
`again it turned out we were wrong. To
`add to the mystery. none of these agents
`
`affected the oxygen equilibrium of my­
`
`
`oglobin or of isolated subunits of hemo­
`
`globin. We now know that all the coop­
`
`
`erative effects disappear if the hemo­
`
`globin molecule is merely split in half.
`but this vital clue was missed. Like Aga­
`tha Christie. nature kept it to the last to
`make the story more exciting.
`
`There are two ways out of an impasse
`
`in science: to experiment or to think. By
`
`
`temperament. perhaps. I experimented.
`
`whereas Jacques Monod thought. In the
`end our paths converged.
`
`Monod's scientific life had been de­
`voted to finding out what regulates the
`
`growth of bacteria. The key to this prob­
`
`
`lem appeared to be regulation of the
`
`
`
`synthesis and catalytic activity of en­
`each of which con·
`COMPLETE MOLECULE of hemoglobin
`
`zymes. Monod and Fran<;ois Jacob had
`
`
`
`sists of one polypeptide chain and one heme. There are two kinds of subunit, designated alpha
`
`discovered that the activity of certain
`
`
`which have different sequences of amino acid residues but similar
`
`
`enzymes is controlled by switching their
`
`
`three-dimensional structures. The beta chain also has one short extra helix. The four subunits,
`
`synthesis on and off at the gene; they and
`
`seen here in two views, are arranged at the vertexes of a tetrahedron around an axis of two­
`others then found a second mode of reg-
`fold symmetry.
`
`lies in a separate pocket at the surface of the molecule.
`
`(white)
`and beta (gray),
`
`is made up of four subunits,
`
`Each heme (color)
`
`98
`
`(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0) (cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 7 of 36
`
`

`

`A aUND
`DlSTlu.aD IN IR&LAIID BY
`IRISH W HISKEY
`,!//y,�� I LIMITED
`BOW EET DISTILLERY
`110 ....... PLQZ.) •• I'IIOOP
`DUBLIN
`
`If he likes fine Scotch, he'll love light, Chances are, as a dedicated
`
`Scotch drinker,
`
`imported Jameson Irish.
`
`
`he will instantly appreciate this flavor
`
`Let him try a glass of}ameson Irish Whiskey difference.
`Though it may take a little time for him to
`
`
`the way he would his favorite Scotch.
`
`get used to saying, "Jameson Irish on the rocks,
`
`He'll notice how much it tastes like fine
`
`Scotch -only lighter and more delicate. please:'
`
`
`
`Jameson. World's largest-selling Irish Whiskey.
`
`(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0) (cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 8 of 36
`
`

`

`Polaroid introduces Sonar
`
`
`focusing.
`automatic
`
`What you do.
`
`(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0) (cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 9 of 36
`
`

`

`
`
`<Ct978 Polaroid Corporation. "Polaroid:' "SX-70" and "Pronto:'
`
`
`
`1. It sends sound waves to the sub­
`3. The lens automatically
`rotates to
`ject. Press one button on Polaroid's
`
`With sonar automat­
`precise focus.
`
`ic focusing, you'll get those candid,
`
`revolutionary Sonar OneStep Land
`cameras. I naudible sound waves dart
`unposed pictures you might have
`missed before. No more precious
`
`from the transducer (shown here),
`bou n c e o f f y o u r
`ti me wasted tryi ng to
`11:Ff:?>··
`subject and re­
`f ocus t he cam e r a
`' �
`you rself. The Sonar
`
`tu rn to the cam­
`....... r:'>\ . . , ....•. . ,.
`OneStep does it for
`e r a . The l e n s
`"z, �< -£,y�, .,'
`.� . ¥
`
`you accurately in just
`whips into precise
`
`a fraction of a second.
`focus -automatically.
`What the camera does.
`
`rI., ,. -.' '';'; �I� .. •
`
`2. These ultrasonic
`4. You can get sharp, precisely
`waves bounce
`focused pictures every time. Sonar
`back in a split second. They meas-
`focusing works in dim light or even
`
`darkness. You'll get precisely focused
`
`flash pictures, too. At the press of one
`button, the Sonar OneStep focuses
`
`automatically, sets the shutter speed
`
`istance to your subject, giv­
`
`and lens aperture, makes the expo­
`
`precisely focused pictures.
`sure, and hands you the developing
`
`
`picture. All in as little as a second and
`a half. Never before has such accu­
`
`rate pictu re taki ng been so easy.
`
`The Sonar OneSteps from $9995*
`OneSteps.The Worlds Simplest Cameras.
`
`'Suggested list Pronto SONAROneStep.
`
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`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 10 of 36
`
`

`

`INTRODUCING THE 1979 PLYMOUTH SAPPORO.
`-EPA estimates based on 1.6 litre
`engine with manual transmis­
`sion. Your mileage may vary
`-Plgmoulli
`depending on how and where
`headrests and adjustable lumbar sup­
`
`Imagine that you've just settled into
`you drive, your car's condition
`ports. Luxury surrounds you, by virtue
`the cockpit of a unique and very
`and its optional equipment.
`of Sapporo's many standard features.
`
`sophisticated automobile. You're
`MCA-Jn ENGINE
`looking at full Rallye Instrumentation
`WITH SILENT SHAFT.
`... tach, oil and amp gauges ... all
`perfectly placed. Overhead you find a
`1.6 litre Silent Shaft engine (2.6 litre
`At Sapporo's heart, beats a standard
`console and your digital chronometer.
`Before you reach for the standard
`available), perhaps the smoothest and
`
`5-speed, you adjust the power sport
`
`quietest 4-cylinder powerplant avail­
`mirrors. And now ... you buckle up
`able anywhere. Also standard ... the
`and turn the key.
`
`MeA-Jet system, an air injection
`
`If you like the daydream, you'll love
`the car. It's called Sapporo ...
`great performance. Sapporo, a very
`Plymouth Sapporo. And it offers much
`
`sophisticated machine that offers more
`
`more than the sophisticated instru­
`than you might have imagined. And
`mentation just described.
`there's only one way to satisfy your
`WXURr 10 STIR THE IMAGlNAT.
`
`imagination. Experience Sapporo.
`Sapporo adjusts to you. With reclining
`bucket seats, concealed adjustable
`
`system that delivers great mileage and
`
`(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0) (cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`© 1978 SCIENTIFIC AMERICAN, INC
`
`Page 11 of 36
`
`

`

`Changeux of the Pasteur Institute in
`
`
`Paris. together with Jeffries Wyman of
`
`
`the University of Rome. recognized that
`the enzymes in the latter class have cer­
`tain features in common with hemoglo­
`bin. They are all made of several sub­
`units. so that each molecule includes
`
`several sites with the same catalytic ac­
`
`tivity. just as hemoglobin includes sev­
`eral hemes that bind oxygen. and they
`
`all show similar cooperative effects.
`
`Monod and his colleagues knew that
`
`deoxyhemoglobin and oxyhemoglobin
`
`have different structures. which made
`them suspect that the enzymes too may
`exist in two (or at least two) structures.
`
`They postulated that these structures
`
`should be distinguished by the arrange­
`EQUILmRIUM CURVES measure the affinity for oxygen of hemoglobin and of the simpler
`myoglobin molecule. Myoglobin, a protein of muscle, has just one heme group and one poly­
`ment of the subunits and by the number
`
`peptide chain and resembles a single subunit of hemoglobin. The vertical axis gives the amount
`
`and strength of the bonds between them.
`
`
`of oxygen bound to one of these proteins, expressed as a percentage of the total amount that
`with which the solution is allowed to reach equilibrium.
`
`If there are only two alternative struc­
`
`can be bound. The horizontal axis measures the partial pressure of oxygen in a mixture of gases
`curve is hyperbolic.
`For myoglobin (black)
`tures. the one with fewer and weaker
`the equilibrium
`
`is sigmoid: initially hemoglobin is reluctant
`bonds between the subunits would be
`
`Myoglobin absorbs oxygen readily but becomes saturated at a low pres­
`gen, but its affinity increases with oxygen uptake. At arterial oxygen pressure both molecules
`sure. The hemoglobin curve (color)
`
`free to develop its full catalytic activity
`to take up oxy­
`
`(or oxygen affinity); this structure has
`its oxygen, whereas hemoglobin releases roughly half.
`
`therefore been labeled R.
`are nearly saturated, but at venous pressure myoglobin would give up only about 10 percent of
`
`The activity would be damped in the
`At any partial pressure myoglobin has a
`
`higher affinity than hemoglobin, which allows oxygen to be transferred from blood to muscle.
`
`structure with more and stronger bonds
`
`between the subunits; this form is called
`�� �� �O
`T, for "tense." In either of these struc-
`
`
`tures the catalytic activity (or oxygen
`g,<I. :$-/.
`V r�"
`
`affinity) of all the subunits in one mole­
`" " " "
`/
`"':J,,"
`" / " "
`cule should always remain equal. This
`postulate of symmetry allowed the
`/ " " "
`
`
`properties of allosteric enzymes to be
`
`
`described by a neat mathematical theo­
`
`ry with only three independent varia­
`
`(/) Q. :J o II: C!)
`bles: KR and KT• which in hemoglobin w 10
`con-15
`stants of the R and T structures
`respec-;:
`and L. which stands for the num- �
`ber of molecules in the T structure
`vided by the number in the R structure. �
`the ratio being measured in the absence (/)
`di- �
`.01
`was coined because the regula-C!)
`
`(from the' g, of oxygen. The term allostery
`w ::; w :r >-
`a?
`Greek roots alios. "other." and stereos,
`"solid")
`tor molecule that switches the activity
`of the enzyme on or off has a structure
`� LL o o
`.1
`different from that of the molecule
`
`whose chemical transformation the en­
`zyme catalyzes.
`� II:
`This ingenious theory simplified the
`
`
`interpretation of the cooperative effects
`
`
`enormously. The progressive increase in
`.011--__
`
`oxygen affinity illustrated by the parable
`of the rich and the poor now arises not
`
`from any direct interaction between the
`SIGMOID SHAPE of the oxygen equilibrium curve appears more pronounced when the frac­
`
`
`hemes but from the switchover from the
`
`
`tional saturation and partial pressure of oxygen are plotted on logarithmic scales. On such a
`T structure
`
`graph the equilibrium curve for myoglobin becomes a straight
`
`structure with high affinity. This trans­
`The hemoglobin curve begins and ends with straight lines, called asymptotes, at the same a