Humans and animals take in oxygen by breathing and oxidize nutrients inside their cells to make ATP; this is called cellular respiration or biological combustion. Szent-Györgyi showed that vitamin C (ascorbic acid), which he extracted in bulk from vegetables, functions as a co-enzyme that passes electrons and smooths redox reactions. He also demonstrated experimentally how enzymes catalyze the changes from succinic acid to fumaric acid and from fumaric acid to malic acid within the citric-acid cycle. By dissecting each chemical step he revealed the key to efficient energy production in cells. His findings advanced treatments for vitamin-deficiency diseases such as scurvy and improved our understanding of metabolic disorders. They became foundational material for textbooks in nutrition and medicine, and the “vitamin C” you see on food labels owes much to his work. Moreover, his research helped outline the full relay of energy from glycolysis to the TCA cycle.

In the late 1920s Szent-Györgyi crystallized a strongly reducing compound, which he called “hexuronic acid”, from oranges and paprika. Using guinea-pig experiments he proved that the substance prevents scurvy and later renamed it ascorbic acid, i.e., vitamin C. He simultaneously traced the pathway by which cells consume oxygen to synthesize ATP and quantified the electron-donating capacity of ascorbic acid as a co-enzyme. He purified the enzyme that catalyzes the reversible conversion of succinate to fumarate in muscle extracts and showed that the cycling of this redox pair governs the efficiency of energy production. These observations anticipated several steps of the TCA cycle later systematized by Hans Krebs and chemically filled in part of the citric-acid loop. Szent-Györgyi suggested that flavin and iron–sulfur centers serve as cofactors for fumarase and succinate dehydrogenase, broadening the concept of catalytic mechanism. By improving methods for measuring redox potentials he was able to monitor electron flow among metabolic intermediates in real time, a technical breakthrough. His work bridged vitamin science, metabolism, and enzyme chemistry, providing a foundation not only for treating deficiency diseases but also for identifying drug targets. Today ascorbic acid is recognized not merely as an antioxidant but also as a co-factor in collagen biosynthesis and immune modulation, and the mechanistic exploration of these roles begins with his experiments. The prize-winning research thus foreshadowed systems-biology views on how catalytic amounts of small molecules can regulate large-scale energy fluxes and pioneered the chemical dissection of metabolism.

Szent-Györgyi purified hexuronic acid by hot-ethanol extraction followed by column chromatography and determined its chemical composition (C6H8O6) and specific rotation (+23°). Using the diphenyl-oxazole method he measured the redox potential of ascorbic acid relative to the standard hydrogen electrode as +0.08 V and calculated the reversible equilibrium constant with dehydroascorbic acid. In the succinate dehydrogenase system he employed methylene blue and cytochrome b as exogenous electron acceptors to show that the succinate↔fumarate interconversion proceeds in an FAD-dependent manner. He further reported an EPR spectrum (g = 2.02) for an iron-containing fumarase within a membrane-bound enzyme complex, suggesting the presence of a [2Fe–2S] cluster. Combined with Warburg manometry, these data provided quantitative evidence that the velocity of TCA-cycle reactions correlates non-linearly with O2 partial pressure. By establishing a high-yield extraction protocol for paprika, he supplied hundreds of grams of ascorbic acid annually to European and American laboratories, accelerating scurvy-model studies. His principal results were summarized in “The Biological Role of Hexuronic Acid” (1933) and “The Catalytic Property of Fumaric Acid in Muscle” (1936). Subsequent work on flavoprotein bioenergetics and reactive-oxygen signalling often cited his data sets. Modern hypotheses that ascorbic acid serves as a co-factor for TET enzymes and HIF-hydroxylases in epigenetic regulation further highlight the prescience of his ideas. In his 1937 Nobel lecture he remarked that “a cell is not a mere furnace but a meshwork of exquisite catalysts,” signalling a paradigm shift in metabolic research.