Luis Federico Leloir and the Metabolic Pathways of Lactose

Luis Federico Leloir (1906 - 1987)

Luis Federico Leloir (1906 – 1987)

On September 6, 1906, Argentine physicist and biochemist Luis Federico Leloir was born. Leloir received the 1970 Nobel Prize in Chemistry for his discovery of the metabolic pathways in lactose, becoming only the third Argentine to receive the prestigious honor in any field. His research has led to significant progress in understanding, diagnosing and treating the congenital disease galactosemia.

“This is only one step in a much larger project. I discovered (no, not me: my team) the function of sugar nucleotides in cell metabolism. I want others to understood this, but it is not easy to explain: this is not a very noteworthy deed, and we hardly know even a little.”
[replying when asked about the significance of his Nobel prize-winning achievement.]
— Luis Federico Leloir, as quoted in John H. Exto, Crucible of Science: The Story of the Cori Laboratory (2013), 52

Luis Federico Leloir – Early Years

Leloir’s parents, Federico Leloir and Hortensia Aguirre de Leloir, both from an old and wealthy Argentinean family, traveled from Buenos Aires, Argentina, to Paris, France, in 1906 with the intention of treating Federico’s illness. However, Federico died in late August, and a week later Luis was born in Paris. After returning to Argentina in 1908, Leloir lived together with his eight siblings on their family’s estate El Tuyú along the coastline from San Clemente del Tuyú to Mar de Ajó. Leloir’s education was divided between Escuela General San Martín, Colegio Lacordaire, and for a few months at Beaumont College in England. His first stint in college ended quickly when he abandoned his architectural studies that he had begun in Paris’ École Polytechnique.

After returning again to Argentina, Leloir obtained his Argentine citizenship and joined the Department of Medicine at the University of Buenos Aires in hopes of receiving his medical doctorate. However, he got off to a rocky start, requiring four attempts to pass his anatomy exam and finally received his diploma in 1932 and began his residency in the Hospital de Clínicas and his medical internship in Ramos Mejía hospital. Leloir’s dissertation, “The Adrenal Gland and Carbohydrates,” received the 1934 School of Medicine award for the best thesis.[2]

Physiology and Salsa Golf

Leloir started his scientific career at the Institute of Physiology working with Professor Bernardo A. Houssay, who in 1947 would later win the Nobel Prize for Physiology or Medicine, on the role of the suprarenal glands and carbohydrate metabolism. The two would develop a close relationship, collaborating on various projects until Houssay’s death in 1971. It was during the 1920s that Leloir invented salsa golf (golf sauce), a peculiar combination of ketchup and mayonnaise. With the financial difficulties that later plagued Leloir’s laboratories and research, he would joke, “If I had patented that sauce, we’d have a lot more money for research right now.”

Research on Enzymes

Feeling that his knowledge in fields such as physics, mathematics, chemistry, and biology was lacking, he continued attending classes at the University as a part-time student. In 1936 he traveled to England to begin advanced studies at the University of Cambridge, under the supervision of Sir Frederick Gowland Hopkins,[6] who had obtained the Nobel prize in 1929 for his work in physiology and in revealing the critical role of vitamins in maintaining good health. Leloir’s research in the Biochemical Laboratory of Cambridge centered around enzymes, more specifically the effects of cyanide and pyrophosphate on succinic dehydrogenase. From this moment Leloir began to specialize in researching carbohydrate metabolism.

Emigration to the USA

Leloir returned to Buenos Aires in 1937. Unfortunately, Houssay had been expelled from the University of Buenos Aires for signing a public petition opposing the Nazi regime in Germany and the military government led by Pedro Pablo Ramírez. Leloir fled to the United States, where he assumed the position of associate professor in the Department of Pharmacology at Washington University in St. Louis from 1943 to 1944, collaborating with Carl Cori and Gerty Cori and thereafter worked with David E. Green at the College of Physicians and Surgeons, Columbia University as a research assistant from 1944 to 1945.

Return to Argentina

In 1945 Leloir returned to Argentina to work under Houssay again at the Instituto de Investigaciones Bioquímicas de la Fundación Campomar, which Leloir would direct from its creation in 1947. Initially, the institute was composed of five rooms, a bathroom, central hall, patio, kitchen, and changing room. During the final years of the 1940s, although lacking financial resources and operating with very low-cost teams, Leloir’s successful experiments would reveal the chemical origins of sugar synthesis in yeast as well as the oxidation of fatty acids in the liver. Together with J. M. Munoz, he produced an active cell-free system, a first in scientific research. It had initially been assumed that in order to study a cell, scientists could not separate it from its host organism, as oxidation could only occur in intact cells. By 1947 he had formed a team that included Caputo, Enrico Cabib, Raúl Trucco, Alejandro Paladini, Carlos Cardini and José Luis Reissig, with whom he investigated and discovered why a malfunctioning kidney and angiotensin helped cause hypertension. That same year, his colleague Rawell Caputo, in his investigations of the mammary gland, made discoveries regarding carbohydrate storage and its subsequent transformation into a reserve energy form in organisms.

The Leloir Pathway

Before Leloir did his groundbreaking research into the transformation of one sugar into another, combustion was well-understood, but synthesis remained a mysterious, largely guessed-at phenomenon. By isolating a new class of substances called sugar nucleotides, Leloir found the key to deciphering this voluminous backlog of unsolved metabolic reactions.[4] In 1948, Leloir and his team identified the sugar nucleotides that were fundamental to the metabolism of carbohydrates, turning the Instituo Campomar into a biochemistry institution well known throughout the world. Immediately thereafter, Leloir received the Argentine Scientific Society Prize, one of the many awards he would receive both in Argentina and internationally. During this time, his team dedicated itself to the study of glycoproteins. Leloir and his colleagues elucidated the primary mechanisms of galactose metabolism (now coined the Leloir pathway) and determined the cause of galactosemia, a serious genetic disorder that resulted in lactose intolerance.

Academic Career

The following year, he reached an agreement with Roland Garcia, dean of the Department of Natural Sciences at UBA, which named Leloir, Carlos Eugenio Cardini and Enrico Cabib as titular professors in the University’s newly founded Biochemical Institute. Following the death of their institute’s sponsor Jaime Campomar in 1957, his heirs decided to discontinue funding the institute. Leloir and his team applied to the National Institutes of Health in the United States desperate for funding, and surprisingly was accepted. In 1958, the Institute found a new home in a former all-girls school, a donation from the Argentine government. As Leloir and his research gained greater prominence, further research came from the Argentine Research Council, and the Institute become associated with the University of Buenos Aires in 1958.

The Nobel Prize for Chemistry

On December 2, 1970, Leloir received the Nobel Prize for Chemistry for his discovery of the metabolic pathways in lactose, becoming only the third Argentine to receive the prestigious honor in any field. In his acceptance speech at Stockholm, he borrowed from Winston Churchill‘s famous 1940 speech to the House of Commons and remarked, “never have I received so much for so little“.

Leloir published a short autobiography, entitled “Long Ago and Far Away” in the 1983 Annual Review of Biochemistry. In 1983, Leloir became one of the founding members of the Third World Academy of Sciences, later renamed the TWAS. Luis Federico Leloirs’s articles and books include “Suprarrenales y Metabolismo de los hidratos de carbon (1934)”, “Farmacologia de la hipertensia (1940)”, “Hipertension arterial nefrogena (1943)”, “Invitro Synthesis of Particulate Glycogen“, “Properties of synthetic and native liver glycogen” and others.

Luis Federico Leloir passed away on December 2, 1987, aged 81.

Fructose and Galactose Breakdown Pathways, AK Lectures [6]

References and Further Reading:

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