Biochemistry

Biochemistry is the chemistry of living things. Almost all of it is carried out by four kinds of large molecule, built mostly from carbon, hydrogen, oxygen, nitrogen, phosphorus and sulfur, and almost all of it happens in water.

Proteins are chains of amino acids, drawn from twenty standard kinds and joined by peptide bonds. The chain folds into a shape fixed by its sequence, and the shape decides the job: catalysis, structure, transport, signalling. Nucleic acids, DNA and RNA, are chains of nucleotides that store and carry genetic information. Carbohydrates, from glucose to starch and cellulose, store energy and build cell walls. Lipids are not polymers. They are grouped together because they avoid water. Fats store energy, and phospholipids form the double-layered membrane around every cell.

Weak forces matter as much as strong ones. Hydrogen bonds hold the two strands of DNA together and keep a protein in its folded shape. They are weak enough to break and re-form at body temperature, which is what lets the molecules work.

Enzymes are catalysts, almost all of them proteins. They speed up reactions, often by factors of millions, without being used up and without changing where the reaction's equilibrium lies. They do this by lowering the activation energy. The substrate binds in a pocket called the active site, which holds it in a shape close to the transition state.

In 1913 Leonor Michaelis and Maud Menten measured how the rate of an enzyme reaction depends on the amount of substrate. At low concentrations the rate rises almost in proportion. At high concentrations every enzyme molecule is busy and the rate levels off at a maximum, Vmax. The Michaelis constant, Km, is the substrate concentration at which the rate is half that maximum. A small Km roughly means the enzyme binds its substrate tightly.

Cells control their enzymes constantly. Inhibitors can compete for the active site. Molecules binding elsewhere can change the enzyme's shape. A pathway's end product often switches off the enzyme at its first step, a form of feedback that stops the cell making more than it needs.

Adenosine triphosphate is the cell's working supply of energy. It is an adenine base and a ribose sugar with a chain of three phosphate groups. Splitting off the last phosphate to give ADP releases about 30 kilojoules per mole under standard conditions, and more under the conditions inside a cell.

Cells use that release to drive reactions that would not go on their own. They make the coupling direct: an enzyme transfers the phosphate to a substrate or a protein, changing its shape or reactivity. ATP powers muscle contraction, pumps ions across membranes and builds proteins and DNA.

ATP is not stored in bulk. Each molecule is recycled many times a day, so the body turns over roughly its own weight in ATP daily. Fritz Lipmann proposed in 1941 that phosphate bonds act as a common currency of energy in the cell.

Glycolysis splits one six-carbon glucose molecule into two three-carbon pyruvate molecules in ten enzyme steps. It happens in the cytoplasm and needs no oxygen. Two ATP are spent early on and four are made later, for a net gain of two ATP, along with two NADH, which carry electrons. Gustav Embden, Otto Meyerhof and Jakob Parnas worked out most of the pathway in the 1930s.

When oxygen is present, pyruvate enters the mitochondrion and is converted to acetyl-CoA, losing one carbon as carbon dioxide. Acetyl-CoA feeds the citric acid cycle, which Hans Krebs described in 1937. Each turn joins a two-carbon acetyl group to four-carbon oxaloacetate and releases two CO₂. Oxaloacetate is regenerated at the end of the turn. The cycle makes little ATP directly. Its main output is NADH and FADH₂.

Those carriers pass their electrons along the electron transport chain in the inner mitochondrial membrane, and oxygen is the final acceptor. The energy pumps protons across the membrane, and the protons flow back through ATP synthase, which makes ATP as they pass. Peter Mitchell proposed this chemiosmotic mechanism in 1961. Oxidative phosphorylation produces most of the roughly 30 ATP a cell gets from one glucose molecule. Without oxygen, cells fall back on fermentation and get only the two ATP from glycolysis.

DNA is a double helix of two strands running in opposite directions. Its bases pair adenine with thymine and guanine with cytosine. Because each strand fixes the sequence of the other, a cell can copy its DNA by separating the strands and building a new partner for each. Watson and Crick proposed the structure in 1953, using X-ray photographs taken by Rosalind Franklin and Raymond Gosling. Meselson and Stahl showed in 1958 that copying works this way.

In transcription, RNA polymerase reads one strand of a gene and builds a matching messenger RNA. RNA uses uracil where DNA uses thymine. In organisms with a nucleus, the message is then edited and exported from the nucleus.

In translation, a ribosome reads the messenger RNA three bases at a time. Each three-base codon specifies one amino acid or a stop signal, and transfer RNAs bring the matching amino acids. Marshall Nirenberg and Heinrich Matthaei read the first codon in 1961: UUU codes for phenylalanine. By 1966 all 64 codons were known. The code is nearly the same in every living thing, which is strong evidence that all life shares one ancestor.

Crick called this one-way flow of sequence information the central dogma (1958). Retroviruses such as HIV copy RNA back into DNA, but no known process turns a protein sequence back into nucleic acid.