Part VI: Fritz Albert Lipmann, 1953 Prize in Physiology or Medicine
By Joseph Luna
From Ra to Apollo to Huitzilopochtli, the ancients were onto something by worshipping the sun. Alongside water, no other entity was as important for the agricultural harvest or for predicting the seasonal movements of wind and life-giving rain. But the precise means by which the sun can be said to nourish took over two millennia to figure out, most of it concentrated in the past 200 or so years, when chemists began to ply their trade to biological problems. Why do plants need light? What happens when a caterpillar, a cow or a human eats them? In other words, how does “food,” for any organism, really work? The answers to these questions lie in the study of metabolism, and biochemists in the late 19th and the first half of the 20th century were wild about these problems.
Fritz Lipmann was among them. Born in the east Prussian capital of Königsberg in 1899, Lipmann came of scientific age during some biochemically exciting times. After receiving an MD in 1924, Lipmann changed course and joined the laboratory of Otto Meyerhof, the discoverer of glycolysis and 1922 Nobelist, at the Kaiser-Wilhelm Institute in Berlin. In the Meyerhof lab, Lipmann worked alongside Karl Lohmann (the discoverer of adenosine tri-phosphate (ATP)) and Dean Burk (the co-discoverer of biotin). Working upstairs was Otto Warburg, who in 1931 would win a Nobel Prize for his work on cellular respiration. And in Warburg’s lab was Hans Krebs, for whom the citric acid cycle is named, and who would later share the 1953 Nobel Prize in chemistry with Lipmann.
The driving question for these biochemists at the time can be summed up succinctly: what was the chemical basis for energy production and consumption in living organisms? By the late 1920s, it was increasingly clear that ATP was a major energy currency in the cell, but the precise means by which it functioned, as both a fuel and as a building block besides how it was made in the cell, were unknown. After a year exploring this problem in P.A. Levene’s laboratory here at Rockefeller, Lipmann moved to Copenhagen to work with Albert Fischer where he studied the end product of Meyerhof’s glycolysis: pyruvic acid.
This “fiery grape” metabolite was interesting as a molecular fork in the road of sorts for an organism: in the absence of oxygen, pyruvic acid undergoes fermentation to make a limited but finite amount of energy before winding up as lactic acid. This is essentially what happens when yogurt or sauerkraut is made. But in the presence of constant oxygen, pyruvic acid does something different: it becomes oxidized and fed into the citric acid cycle to allow continuous production of ATP. In other words, energy production requires continuous breathing, or “respiration.” As a biochemical fulcrum between reactions associated with death (fermentation) or life (respiration), it’s easy to see how this molecule might’ve fascinated Lipmann in the 1930’s. Most of the above was known by then but questions remained. Lipmann noticed that in order for pyruvic acid oxidation to make ATP, some inorganic phosphate was always needed and biochemically used up. Where did this phosphate go? Using radioactive phosphate and adenylic acid, a precursor of ATP, Lipmann observed that pyruvic acid oxidation resulted in radioactive ATP. He had traced the movement of an inert phosphate to the main energy molecule in the cell. This process, now generally summarized as oxidative phosphorylation, is the means by which any organism on this planet that breathes makes energy.
But this was not why Fritz Lipmann won the Nobel Prize. The fact that Lipmann observed transfer of an energy-rich phosphate to make ATP got him thinking. When ATP is hydrolyzed to release energy, essentially the reverse to what he observed happens: ATP loses a phosphate group. These observations led Lipmann to consider the phosphate bond, its creation to make ATP, and its destruction to release energy, as the key driver for energy requiring reactions. Lipmann formally introduced this idea in a landmark review article in 1941 titled “Metabolic Generation and Utilization of Phosphate Bond Energy.” His convention, to represent the energy-rich phosphate with a squiggle (~P) has been in use ever since. What made this written synthesis all the more remarkable was that it brought up the possibility that other molecules could pass around chemical groups as co-factors of enzymes, or “co-enzymes.” It is perhaps useful to think of a co-enzyme as a runner in a relay race passing a valuable baton. In the case of ATP, that baton is an energy-rich phosphate (~P). For the vitamin riboflavin, the baton is a single electron.
The reason Lipmann accompanied Krebs to Stockholm in 1953 was for discovering the first coenzyme, named coenzyme A (CoA), whose baton is an acyl group (~Ac). As it happens, acetyl-CoA is two steps down from pyruvic acid and is the key for making the citrate needed to get the Krebs cycle going.
By the time Lipmann arrived at Rockefeller in 1957, biology was starting to move away from the biochemistry of metabolism and into the new molecular frontier of DNA. Lipmann maintained an active laboratory at Rockefeller studying topics as diverse as protein synthesis and antibiotic production, well after his retirement in 1970. By then, scientific understanding of photosynthesis in the chloroplasts of plants and oxidative phosphorylation in the mitochondria of animals would allow him to trace how a photon emitted from the sun would spark a chain reaction of flowing electrons, phosphates, acyl groups and the like to create life. It must’ve been a slow and proud realization for one of the 20th century’s great biochemists: metabolism rules all.
