What are enzymes? How cells speed up chemistry

Enzymes are proteins that speed up chemical reactions in living things, often millions of times or more, without being used up. Each one grips particular molecules, called its substrates, in a pocket shaped to fit them, and makes it easier for them to react by lowering the energy the reaction needs to get started. Without enzymes, most of the chemistry that keeps a cell alive would be far too slow to matter.

In short

• An enzyme is a catalyst: it makes a reaction happen faster but comes out unchanged, ready to do it again.
• It works by lowering the activation energy, the hump a reaction has to get over, not by changing where the reaction ends up.
• Because an enzyme's power comes from its shape, anything that bends the shape, such as heat or the wrong pH, slows it or stops it.

What does an enzyme actually do?

A chemical reaction rearranges atoms: bonds break and new ones form. Even a reaction that releases energy overall usually has to pass through an awkward, high-energy halfway state first, the transition state. The energy needed to reach it is the activation energy. A useful picture is a ball that would happily roll down into a valley, but first has to be pushed over a hill.

An enzyme lowers the hill. It holds its substrates in exactly the right positions, strains the bonds that need to break, and lends or borrows electric charges at just the right moment. More molecules then have enough energy to get over, so the reaction runs faster. Two things an enzyme does not do are worth keeping straight. It doesn't supply the energy for a reaction, and it doesn't change the balance point the reaction would eventually reach on its own; it only gets there sooner.

Most enzymes are proteins, folded into a shape with a small pocket called the active site. That wasn't obvious until 1926, when the American chemist James Sumner crystallized the enzyme urease and showed it was a pure protein; he shared the 1946 Nobel Prize in Chemistry for it. The U.S. National Library of Medicine's MedlinePlus describes enzymes as proteins found in every organ and cell, from saliva to the blood, where they help make clots. A few are made of RNA instead, the ribozymes; the most important is inside the ribosome, which joins amino acids into proteins. Enzyme names usually end in "-ase": lactase breaks down lactose, the sugar in milk, and DNA polymerase builds DNA.

Lock and key, or induced fit?

In 1894 the German chemist Emil Fischer proposed that an enzyme and its substrate fit together like a lock and a key, which explained why each enzyme acts on only one or a few molecules. In 1958 the American biochemist Daniel Koshland suggested a refinement, the induced fit: an enzyme is flexible, and its active site reshapes as the substrate binds, closing around it like a hand around a ball. Wikipedia's article on enzymes sets out both. The lock-and-key picture explains specificity, but not how the enzyme helps the reaction along. The induced fit adds part of the answer: as the active site closes, it moves the enzyme's own side chains into the positions that do the chemistry. The rest is that a working active site fits the transition state even better than it fits the substrate, so binding steadies that awkward halfway state and lowers the hill.

The steps of one cycle run like this.

1. The substrate drifts into the active site and binds.
2. The enzyme changes shape slightly, holding the substrate in a strained, reactive position.
3. The reaction happens, and the substrate becomes the product.
4. The product lets go, and the enzyme is back where it started.

How much faster, in numbers?

The speed-up can be worked out from the Arrhenius equation, which links a reaction's rate to its activation energy:

k = A × e^(−Ea / RT)

Here k is the rate, A is a factor for how often molecules meet in the right orientation, e is the number 2.718, Ea is the activation energy in joules per mole, R is the gas constant, 8.314 joules per mole per kelvin, and T is the temperature in kelvins. If an enzyme lowers the activation energy by an amount ΔEa and nothing else changes, the rate rises by a factor of e^(ΔEa / RT).

At body temperature, 37 °C or 310 kelvins, RT is 8.314 × 310 = about 2,577 joules per mole, or 2.58 kilojoules per mole. So:

Activation energy lowered by	Rate multiplied by about
10 kJ/mol	48
20 kJ/mol	2,300
30 kJ/mol	110,000
60 kJ/mol	13 billion
100 kJ/mol	70 million billion (7 × 10¹⁶)

Because the rate depends on the activation energy through an exponential, each extra step down the hill multiplies the speed rather than adding to it. Real enzymes also change the A factor and the route of the reaction, so the table is a simplified model, but it shows how such large speed-ups are possible.

Real enzymes reach the far end of that table. An enzyme called OMP decarboxylase, which helps make a building block of DNA and RNA, speeds up its reaction by a factor of about 10¹⁷. Without it, the reaction would take 78 million years to convert half its starting material; with it, about 18 milliseconds, according to a 2000 paper from Richard Wolfenden's lab in the Proceedings of the National Academy of Sciences. The ratio of those two times, about 2.5 × 10¹⁵ seconds against 0.018 seconds, is that 10¹⁷. Speed per molecule is impressive too. Catalase, which breaks down hydrogen peroxide (2 H₂O₂ into 2 H₂O and O₂), has one of the highest turnover numbers of any enzyme: one catalase molecule can convert millions of peroxide molecules each second. That is the fizz when hydrogen peroxide meets a cut, as catalase from damaged cells releases oxygen.

Why do heat and pH change how enzymes work?

An enzyme works only while it keeps its shape, and its shape is held by many weak bonds.

Temperature cuts both ways. Warmth makes molecules move faster and collide more, so activity rises with temperature at first. But beyond a point, the weak bonds give way and the enzyme unfolds, or denatures, and activity collapses. Human enzymes generally work best near body temperature. Enzymes from organisms that live in hot springs are built to hold together in the heat: the DNA polymerase from the bacterium Thermus aquaticus, called Taq, works best at 75 to 80 °C, according to Wikipedia's entry on Taq polymerase, which is why it is used to copy DNA in the PCR test, where samples are heated to separate DNA strands over and over.

pH, a measure of how acidic a solution is, changes the electric charges on an enzyme's side chains, which changes both its shape and its grip on the substrate. Each enzyme has a pH it prefers, matched to where it works. Pepsin, which digests protein in the stomach, is most active between pH 1.5 and 2.5, and is inactive at 6.5 and above, according to Wikipedia's entry on pepsin. Trypsin, which carries on digesting protein in the small intestine, works best in slightly alkaline conditions around pH 8.

Cooling usually just slows an enzyme down, and warming it again brings it back. Heat that denatures it is often permanent, for the same reason that a boiled egg white, which is mostly protein, can't be unboiled.

Where do enzymes show up?

Everywhere chemistry happens in a body. Each step of digestion, of turning food into usable energy, and of building new cells is run by its own enzyme, often in long chains where one enzyme's product is the next one's substrate. All of those reactions together make up metabolism, and cells control them largely by switching enzymes on and off or making more or fewer of them.

Many medicines work by blocking an enzyme. Aspirin and ibuprofen block cyclooxygenase enzymes involved in pain and inflammation, and statins block an enzyme in the liver's cholesterol-making chain. Some poisons work the same way, and so do many antibiotics, which jam enzymes that bacteria have and humans lack.

A common misconception is that enzymes are something to take as a supplement to "help" the body. Most enzymes swallowed as food or pills are proteins like any other, and the stomach's acid and enzymes break them down. People with specific conditions, such as lactose intolerance or a pancreas that makes too few digestive enzymes, can be prescribed particular enzymes; this note explains the biology and isn't medical advice. Enzymes are one of the features shared by everything on the checklist of life.

Check yourself

• Without looking back, explain what activation energy is and what an enzyme does to it.
• Why does lowering the activation energy by twice as much speed a reaction up far more than twice as much?
• Explain why a fever that is too high, or a stomach enzyme moved to the intestine, can stop an enzyme working.

Sources

• Enzyme — MedlinePlus, U.S. National Library of Medicine
• The Nobel Prize in Chemistry 1946 — Nobel Prize Outreach
• Enzyme — Wikipedia
• Anatomy of a proficient enzyme: the structure of orotidine 5′-monophosphate decarboxylase — Miller and colleagues, Proceedings of the National Academy of Sciences, 2000
• Catalase — Wikipedia
• Pepsin — Wikipedia