The 1997 Nobel Prize in chemistry recognizes work carried out over the last four decades, and acknowledges the modern, broadened view of chemistry that includes research at the chemistry-biology interface. The prize was shared by three scientists. Half of it was shared by Paul D. Boyer, Professor Emeritus of Chemistry and Biochemistry at the University of California, Los Angeles, and John Walker, Senior Scientist at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, for their work in understanding how cells produce the “high-energy” molecule adenosine triphosphate (ATP). Physiologist Jens C. Skou, Professor of Biophysics, Aarhus University, Denmark, received the other half of the Nobel Prize for work dating back to 1957 that addresses how the body uses ATP as an energy source to pump ions across membranes.

ATP is an example of what is called a nucleoside triphosphate. A nucleoside triphosphate can be thought of as the chemical combination of a carbon-nitrogen ring system, called a base (adenine in the case of ATP), a sugar (D-ribose in the case of ATP), and three phosphoric acid molecules, with loss of four water molecules. (This is not how ATP is made biologically, but rather how the parts can be assembled conceptually.)

Like the phosphoric acid molecules from which nucleoside triphosphates are derived, the phosphate groups are strong acids, and are ionized at cellular pH values. In many cases they are complexed with metals ions, such as Mg²⁺. For simplicity, however, we show these in their un-ionized forms.

To understand the significance of the award-winning work, we have to learn about one reaction of ATP and the central importance of this reaction as a source of energy for the cell. ATP can undergo hydrolysis to give one molecule of a closely related molecule, adenosine diphosphate (ADP), and one molecule of phosphoric acid.

(Again for simplicity we show phosphoric acid in its un-ionized form, but under the cellular conditions it exists as a mixture of HPO₄^2- and H₂PO₄^-.) The standard free-energy change for this reaction under conditions similar to those in the cell is -30 to -31 kJ mol^-1, the exact value depending on the exact conditions. In effect, ATP serves as a reservoir of 30 kJ mol^-1 of energy for the cell. When the cell needs energy, ATP hydrolysis is used to provide it. We can think of ATP as the cell’s ultimate fuel.

ATP is synthesized in the cell by the reverse of the reaction shown above: that is, by the combination of ATP and phosphoric acid. This reaction is catalyzed by an enzyme called ATP synthase. As catalysts, enzymes simply speed up the reaction; they can’t change the laws of thermodynamics and create energy. In other words, because ATP hydrolysis liberates energy, the formation of ATP requires energy. (The cells of a typical human synthesize multikilogram quantities of ATP each day!) The energy to form ATP ultimately comes from the foods we eat, such as sugars. The million-dollar question to be answered was how ATP synthase somehow harnesses the energy released in the breakdown of foods to drive ATP synthesis. Boyer and Walker received their share of the 1997 Nobel Prize for figuring out how ATP synthase works, and the resulting picture is remarkable.

If ATP is the cell’s fuel, then the place in which it is synthesized, the mitochondrion, is the cell’s power plant. Mitochondria are membrane-enclosed structures within cells. They contain an outer membrane, and an inner membrane that folds back on itself. Between the two membranes is an aqueous region called the intermembrane space. The region inside the inner membrane is called the mitochondrial matrix.

Many ATP synthase molecules are anchored to the matrix side of the inner membrane, and each molecule projects as a stalk-like structure into the matrix. (See magnification in above figure.) In 1961, British biochemist Peter Mitchell proposed that the oxidation of glucose–the series of reactions by which glucose is utilized as a food–ultimately results in the pumping of protons from the mitochondrial matrix into the intermembrane space. For this chemiosmotic hypothesis, Mitchell received the Nobel Prize in 1978. We can think of proton pumping as we might think of blowing up a balloon, except in this case protons are used to “blow up” the intermembrane space. (The expansion of the intermembrane space can be seen quite clearly in electron-microscope pictures.) The pumped protons are like the air in a blown-up balloon, or like water behind a dam: there is potential energy waiting to be released when the air in the balloon or water behind the dam is allowed to flow. (Mitchell called this potential energy a protonmotive force.) Boyer showed that ATP synthase is the dynamo through which the protons flow back into the matrix. The protons, as they flow through the dynamo, cause a mechanical force to be exerted within the ATPase that in effect enables the enzyme to “ram together” ATP and phosphoric acid to form an ATP molecule.

Boyer and Walker received the Nobel Prize for providing many of the details of how the ATP synthase works. How exactly the flow of protons exerts the force on parts of the enzyme is not yet known. Perhaps the researchers who answer this question will garner a future Nobel Prize.

The second half of the Nobel Prize was awarded to Jens Skou for his work, first published in 1957, on a nerve-cell enzyme that hydrolyzes ATP. This enzyme is called the sodium-potassium pump. To understand the significance of this work, we first have to know a little more biology. Most cells maintain a low internal concentration of sodium ions (Na⁺)–about 0.010 molar–while the concentration of these ions outside the cell is more than ten times as great–about 0.140 molar. Potassium ions (K⁺), on the other hand, are at a relatively low concentration outside the cell–about 0.005 molar–while the concentration of K⁺ inside the cell is relatively high–about 0.100 molar. These differences are essential for proper functioning of the cell. When a nerve is stimulated, sodium ions pour into the nerve cell. The low-sodium condition must then be restored by pumping sodium out of the cell, against the concentration gradient. This requires energy, and the energy is supplied by the hydrolysis of ATP, which, as we have seen, releases 30-31 kJ mol^-1. Skou showed clearly that the pumping of Na⁺ out of the cell, and of K⁺ into the cell, is coupled to the hydrolysis of ATP by an ATP-hydrolyzing protein embedded in the cell membrane; this enzyme came to be known as the sodium-potassium pump. In effect, the Na⁺-K⁺ pump is an engine driven by the energy derived from ATP hydrolysis. The hydrolysis of each molecule of ATP causes changes in the protein that result in the internalization of three potassium ions and the externalization of two sodium ions.

Since Skou’s work, many other enzymes have been discovered that use the energy derived from ATP hydrolysis to drive transport of ions and nutrients across cell membranes. Such energy-requiring transport against a concentration gradient is called active transport. Some cells expend 30-50% of their ATP in providing energy that supports active transport! Skou’s work was the seminal contribution that opened up the entire field of active transport to a new level of understanding.

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