Biochemistry: The Chemistry That Keeps Itself Going

Eat a piece of bread and, a few hours later, its glucose is a trickle of electrons moving along proteins inside your mitochondria. A single genetic typo in a haemoglobin gene turns one amino acid into another, and red cells bend into sickles. A medicine blocks one enzyme and a symptom eases. In each case the story can be told in molecules, in numbers, and in energy bookkeeping.

Biochemistry asks what those molecules are, how they fold and catalyse, and how a cell pays for everything. It is the bridge between the chemistry of carbon and the biology of cells, and it sits on both routes: chemists take it to see where their subject leads, and biologists take it to see what their subject is made of.

Twenty amino acids, one folded shape

Proteins are chains of amino acids, twenty kinds in the standard genetic code, joined by peptide bonds. Each kind has a different side chain: some are oily and avoid water (leucine, valine), some carry a charge (lysine is positive, aspartate negative), some can form hydrogen bonds (serine). A chain of a few hundred of these is a protein. The sequence is written in DNA, but what does the work is the shape: oily side chains bury themselves in the core, charged ones face the water, and the chain settles into helices and sheets that pack into a compact fold.

In 1961 Christian Anfinsen showed that the enzyme ribonuclease, unfolded with chemicals, refolded by itself into an active form when the chemicals were removed. The information for the shape is therefore in the sequence. He shared the 1972 Nobel Prize in Chemistry (with Stanford Moore and William Stein). It has caveats: some proteins need helper "chaperones", and some work while floppy. But it set the problem.

The sharp question is Levinthal's. A chain cannot find its shape by trying them all. Cyrus Levinthal estimated in 1969 on the order of 10³⁰⁰ possible shapes for a typical protein, yet real ones fold in milliseconds to seconds. The slider counts it your way: if each of n residues has just 3 positions, there are 3ⁿ shapes, and at a trillion tries a second the search for a 100-residue chain would last about 10²⁷ years. Proteins do not search; they slide downhill on an energy landscape shaped like a funnel.

A single change can matter enormously. In sickle-cell disease, glutamic acid at position 6 of the β-globin chain of haemoglobin is replaced by valine. That oily side chain on the surface makes haemoglobin molecules stick into fibres when they let go of oxygen, and bend the red cell. Carriers of one copy are partly protected against severe malaria, which is why the variant is common where malaria has been. Genes and environment are in conversation here, a theme of Genetics (35/46).

Enzymes: catalysts that set the pace of life

Most reactions that a cell needs would take years at body temperature. Enzymes make them take milliseconds. An enzyme does not change where a reaction ends up (the equilibrium); it lowers the barrier on the way, by holding the substrate in a pocket shaped to stabilise the transition state. Carbonic anhydrase, which interconverts carbon dioxide and bicarbonate in your blood, can turn over about a million substrate molecules per second per enzyme, among the fastest known.

In 1913 Leonor Michaelis and Maud Menten wrote down the simplest model that explains how rate depends on substrate concentration. At low [S] the enzyme is mostly empty, so the rate rises in proportion. At high [S] every enzyme is busy and the rate saturates at V_max. The K_m is the substrate concentration at which the rate is half of V_max: a small K_m means the enzyme grabs its substrate even when it is scarce.

A competitive inhibitor resembles the substrate and occupies the pocket. It does not change V_max (flood the system with substrate and you win), but it raises the apparent K_m by a factor (1 + [I]/K_i). Many drugs are inhibitors of enzymes: ibuprofen reversibly blocks the cyclooxygenase enzymes, and aspirin does it by chemically modifying them. Try the sliders.

Notice what the readout says: at [S] = K_m the rate is exactly half of maximum, and at 10 × K_m it is already 91%, so doubling the substrate again barely helps. That saturation is why a cell regulates enzymes by controlling the enzyme, not the substrate.

ATP: the energy ledger's currency

A cell cannot burn sugar like a flame; the heat would cook it. Instead it moves energy in small, controlled steps, and the common change is ATP (adenosine triphosphate). Splitting its last phosphate off to give ADP and phosphate releases energy that other reactions can borrow when they are coupled to it. Under standard biochemical conditions (1 M of everything, pH 7) the free energy change is −30.5 kJ per mole. In a living cell the concentrations are far from standard, and the free energy depends on them:

Textbooks quote about −50 to −65 kJ/mol inside cells. The reason is striking: at equilibrium ATP would be almost entirely broken down, and a cell keeps its ATP/ADP ratio many orders of magnitude above that. It is held there by constant work, and a human turns over roughly their own body weight in ATP in a day (an estimate), recycling it between ATP and ADP, not accumulating it.

Metabolism as bookkeeping: glucose to ATP

Metabolism is a set of linked reactions, and the neat way to hold it in your head is a ledger with three columns: ATP, and two electron carriers, NADH and FADH₂, which carry electrons to the cell's power plant. Glycolysis, in the cytosol, splits one glucose into two pyruvate, and pays a net 2 ATP and 2 NADH. With oxygen, pyruvate goes into the mitochondrion, giving 2 more NADH (as it becomes acetyl-CoA), and the citric acid cycle (Hans Krebs, 1937) turns the rest into carbon dioxide, with 6 NADH, 2 FADH₂ and 2 more ATP-equivalents. All that is the "earnings"; the real payout comes when the carriers deposit their electrons into the respiratory chain, which pumps protons across the inner membrane. Peter Mitchell proposed in 1961 that the resulting proton gradient, not a chemical intermediate, drives ATP synthase, a tiny rotary motor; his chemiosmotic theory won the 1978 Nobel Prize in Chemistry.

The old textbooks said one glucose gives 36 to 38 ATP. Newer measurements put it at about 30 to 32, because a proton-driven motor does not pay in whole molecules. The ledger lets you see why the range exists.

Without oxygen, the cell stops after glycolysis and must recycle its NADH by making lactate or, in yeast, ethanol: two ATP per glucose instead of about thirty. That is the arithmetic behind a sprinter's burning legs and a baker's rising dough, and it is why oxygen matters.

Lipids, sugars and membranes: fuel, walls and labels

Three more families fill out the picture.

Family	Built from	Roles
Carbohydrates	sugars (glucose, fructose) joined in chains	quick fuel (starch, glycogen); structure (cellulose); labels on cell surfaces
Lipids	fatty acids, glycerol, cholesterol	dense energy store; membranes; signals (steroid hormones)
Proteins	amino acids	catalysis, structure, transport, signalling

The small difference in how sugar units are joined has large effects: starch and cellulose are both glucose polymers, but the link is shaped differently in each, so humans digest starch and cannot digest cellulose. Fats carry about 37 kJ per gram (9 kcal) against about 17 kJ (4 kcal) for carbohydrate and protein, because a fat is more reduced, with more electrons to hand to the respiratory chain. That is why animals store energy as fat.

Membranes come from a simpler fact: a phospholipid has a water-loving head and two oily tails. In water such molecules assemble themselves into a double layer, tails inward, about 5 nanometres thick, which is the same physics that lets soap form droplets around grease. Proteins embedded in that layer do the transport and sensing; see Cell Biology (35/44).

Nucleic acids as molecules

DNA and RNA are chains of nucleotides: a sugar, a phosphate and a base. The backbone is sugar–phosphate; the bases (A, C, G, T in DNA; U replaces T in RNA) stick out. In 1953 James Watson and Francis Crick proposed the double helix, using X-ray data from Rosalind Franklin's group and Maurice Wilkins's; the 1962 Nobel Prize went to Watson, Crick and Wilkins. The key chemistry is complementary pairing: A binds T with two hydrogen bonds, and G binds C with three. Erwin Chargaff had found the matching counts of A with T, and G with C, years earlier. How the code is read is the job of Molecular Biology (35/45); here the point is simpler: a G–C pair holds more tightly than an A–T pair.

For a short DNA piece, a rule of thumb (the Wallace rule) puts the melting temperature at about 2 °C for each A or T and 4 °C for each G or C. Longer pieces and real salt conditions need more careful models, which is why labs use calculators.

AlphaFold and the protein-structure problem

Knowing a protein's sequence is not the same as knowing its shape. For decades the only way to get a shape was experiment: X-ray crystallography, NMR, and more recently cryo-electron microscopy, each a long project. The Protein Data Bank, started in 1971, now holds well over 200,000 experimental structures, but known protein sequences number in the hundreds of millions.

Predicting the shape from the sequence became a competition, CASP, held every two years. In November 2020 DeepMind's AlphaFold 2 reached accuracy in CASP14 that was comparable to experimental structures for many targets, a result the organisers called a breakthrough. The method was published in 2021 (Jumper and colleagues) and in 2022 predictions for about 200 million proteins were released in a public database. The 2024 Nobel Prize in Chemistry went half to David Baker for computational protein design and half to Demis Hassabis and John Jumper for structure prediction.

What it did not do is end the subject. A prediction is a model with a confidence score, not a measurement. It does not by itself explain how a chain folds (Levinthal's question), how a protein moves or how it behaves when it binds a drug or another protein, and it is less certain for floppy regions and rare folds. Experimental structures still check it, and they train it. Treat it as a very good map, drawn from the territory that experiments surveyed.

What a graduate just sees

• A protein's job is set by its shape, and its shape is set by its sequence and by water.
• One amino acid out of hundreds can change everything, and effects depend on environment.
• Enzymes lower barriers and never move the equilibrium; rates saturate at V_max.
• Cells keep ATP enormously far from equilibrium, and that distance is the energy they spend.
• Metabolism is a ledger: sugar becomes carriers (NADH, FADH₂), carriers become a proton gradient, the gradient becomes ATP.
• Fat is dense fuel because it is more reduced than sugar.
• Membranes assemble themselves from molecules with a wet head and an oily tail.
• G–C pairs are stronger than A–T pairs: three hydrogen bonds against two.
• A predicted structure is a model with a confidence level, not a measurement.

Where it shows up next

• Molecular Biology (35/45): how DNA is copied and read, and how cells control which genes are on.
• Physiology (35/49): hormones, muscle and the fuel switches between fed and fasting states.
• Microbiology (35/50): bacteria differ chiefly in which metabolism they run, with or without oxygen.
• Plant Biology (35/53): photosynthesis is respiration in reverse, with light paying the bill.
• In the world: drug design, enzyme-based detergents and diagnostics, brewing and baking, sports science and diabetes care.

If you want to go deeper

• 📘 Textbook. David Nelson and Michael Cox, Lehninger Principles of Biochemistry (Macmillan / W. H. Freeman, 8th edition). The standard in many courses; strong on energetics.
• 📘 Textbook. Jeremy Berg, John Tymoczko, Gregory Gatto and Lubert Stryer, Biochemistry (Macmillan / W. H. Freeman, 9th edition). Known for clear diagrams and for connecting to medicine.
• 📘 Gentler. Nick Lane, Power, Sex, Suicide: Mitochondria and the Meaning of Life (Oxford University Press, 2005; 2nd ed. 2018). A popular account of energy in cells.
• 🌐 Free course. MIT OpenCourseWare 7.05 General Biochemistry. Also the free OpenStax Biology 2e.