Biochemistry 1937

The Role of Citric Acid in Intermediate Metabolism in Animal Tissues

Hans Krebs & William Johnson

How a cell burns its fuel: a self-renewing ring of reactions that turns food into CO₂ and usable energy.

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In depth · the introduction

Every breath you take feeds a tiny chemical merry-go-round inside your cells — a ring of reactions that burns your food and never runs down.

The big idea

Your cells get their energy by burning food with the oxygen you breathe. Hans Krebs discovered that the burning isn't a straight assembly line but a loop. A small fragment of food joins a carrier, travels around a ring of eight steps, sheds its carbon as the CO₂ you breathe out, and hands off energy along the way — then the carrier is rebuilt, ready to grab the next fragment.

The ring turns over and over. Because each lap rebuilds its own starting material, only a tiny amount of the ring's chemicals is ever needed — they are machinery, not fuel. That self-renewing loop is the citric acid cycle, also called the Krebs cycle.

How it came about

Krebs was a German-born biochemist who had been forced out of Germany in 1933 and rebuilt his career in England. Working with minced pigeon breast muscle — a tissue that breathes hard — he noticed something strange: adding a pinch of citric acid made the muscle consume far more oxygen than that pinch could possibly account for. The citric acid was being used and remade, not burned up.

Piecing together clues from other chemists, Krebs realized the acids form a self-renewing circle. He sent the result to the leading journal Nature — which turned it down. It was published instead in a smaller journal, Enzymologia. Sixteen years later, in 1953, the same work won him the Nobel Prize.

Why it mattered

The cycle is how nearly every living thing that uses oxygen — a bacterium, a tree, you — pulls energy out of food. It is the great junction box of metabolism: sugar, fat, and protein all funnel into the same ring to be burned. Mapping it turned the chemistry of life from a tangle of separate reactions into a single, comprehensible system — one that medicine and biology still rely on every day.

A way to picture it

Think of a waterwheel. The stream — your food — pours onto the wheel; the wheel turns and does work, capturing energy; the spent water spills off as it leaves, like the CO₂ you breathe out. The crucial part is that the wheel itself isn't used up — it comes right back to the top, ready for the next splash. The cycle's acids are the wheel; only a little is needed, because it keeps coming around.

Where it sits

The cycle is the middle act of how cells make energy: before it, food is broken into small fragments; after it, the energy carriers it fills (NADH and its kin) drive the cell's main power plant. It stands alongside other discoveries in this Library about the molecules of life — from Hodgkin and Huxley's electrical nerve to the DNA of Watson and Crick — as part of the twentieth century's project to read life as chemistry.

The original document

Original source text

H. A. Krebs & W. A. Johnson · Enzymologia 4 (1937): 148–156 · University of Sheffield

The paper sets out to explain how animal tissues oxidize carbohydrate all the way to carbon dioxide and water. The experimental material is minced pigeon breast muscle — a tissue chosen for its exceptionally vigorous respiration — suspended in a manometer that reads its uptake of oxygen as small amounts of various organic acids are added.

The decisive observation is that the effect of citrate is catalytic. Adding a small, sub-stoichiometric amount of citric acid raises the muscle's total oxygen consumption by far more than the oxidation of that citrate alone could account for. The citrate is therefore not consumed but regenerated — it cycles. The same catalytic potency had been seen for a family of di- and tricarboxylic acids (succinate, fumarate, malate, oxaloacetate, α-ketoglutarate, citrate) that earlier workers had each studied separately.

Krebs's synthesis is to close these fragments into a single ring. A substance derived from carbohydrate condenses with the four-carbon oxaloacetate to form six-carbon citric acid; through a sequence of oxidations and two losses of CO₂ the molecule is whittled back down to oxaloacetate, which is then free to condense again. Because oxaloacetate is continuously regenerated, only a catalytic trace is needed — exactly matching the experiment.

[ … ]

The note is the cycle's first full statement, not its finished biochemistry: the identity of the two-carbon unit that actually enters the ring — the acetyl group carried by coenzyme A — was unknown in 1937 and was established only after Lipmann's later discovery of coenzyme A. Submitted first to the journal Nature, the manuscript was declined, and appeared instead in Enzymologia.

University of Sheffield · 1937