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Leloir, Luis Federico

LELOIR, LUIS FEDERICO

(b. Paris, France, 6 September 1906; d. Buenos Aires, Argentina, 2 December 1987),

biochemistry, nucleotide sugars, oligoand polysaccharide synthesis.

Leloir received the 1970 Nobel Prize in Chemistry for his discovery of nucleotide sugars and the role of those compounds in the interconversion of monosaccharides and as precursors in the synthesis of oligo- and polysaccharides. His many contributions to biochemistry also include the first description of fatty acid oxidation in a cell-free system, of angiotensinogen and its conversion to angiotensin upon incubation with rennin, and the role of lipid-bound saccharides as intermediates in protein glycosylation.

Medical and Biochemical Training . Luis F. Leloir was born in Paris, France. His Argentine parents had traveled to the French capital seeking medical treatment for the father, a lawyer who never practiced his trade. Two years later his mother (his father died before Leloir’s birth) took him to Buenos Aires. He studied medicine at the University of Buenos Aires, becoming a medical doctor in 1932. From 1932–1934 he was an internist at the University Hospital while doing the experimental work for his doctoral thesis under the supervision of Bernardo A. Houssay. Houssay was director of the Institute of Physiology of the University of Buenos Aires and had performed remarkable studies on the role of the hypophysis on carbohydrate metabolism for which he received the Nobel Prize in Physiology or Medicine in 1947. Leloir’s dissertation, “The Adrenal Gland and Carbohydrates,” received the 1934 School of Medicine award for the best thesis. In 1935 Leloir went to Sir Frederick Gowland Hopkins’s Biochemical Laboratory at the University of Cambridge for postdoctoral training in biochemistry. In the United Kingdom, Leloir became familiar with current biochemical techniques.

Fatty Acid Oxidation and Hypertension . Back in Buenos Aires, Leloir resumed his work at the Institute of Physiology and tackled two projects (fatty acid oxidation and hypertension) in the years from 1937 to 1942. With Juan M. Muñoz he studied the metabolism of ethanol and fatty acids. In a series of papers, they reported that a particulate fraction obtained from liver homogenates, if supplemented with a tetracarbon dicarboxylic acid, cytochrome C, and adenosine monophosphate, was able to sustain oxidation of fatty acids. This was a remarkable contribution, as until then it had been believed that the process required cell integrity. The lack of a refrigerated centrifuge nearly frustrated the successful preparation of the particulate fraction, but Leloir’s craftsmanship, one of his strengths, provided an ingenious and money-saving solution to the obstacle as he wrapped several car inner tubes filled with freezing mixture around an old pulley-driven centrifuge. His practical ingenuity was extremely useful in a country such as Argentina, where research funds were often scarce.

The second problem tackled by Leloir in those years was that of malignant renal hypertension. His study of it was carried on in collaboration with Muñoz, Eduardo Braun Menendez, and Juan C. Fasciolo. It was then known that constriction of the renal artery of dogs resulted in permanent hypertension. Fasciolo then showed that an increase in blood pressure also resulted from grafting a constricted kidney into a normal dog, thus indicating that the effect was due to a substance that the treated kidney secreted to the blood. One early finding of the group was that an aqueous acetone extract of a constricted kidney was able to produce a transient increase in blood pressure. The aqueous acetone-soluble substance was different from renin, an already-known pressor substance that could also be extracted from kidneys. Leloir and coworkers found then that incubation of renin (a protease) with blood plasma (that contained what is now called angiotensinogen) produced the pressor substance soluble in aqueous acetone (now called angiotensin). Leloir’s knowledge of biochemistry was fundamental in these findings.

Nucleotide Sugars . Argentina experienced a military coup d’état in Argentina in 1943. Soon after, Houssay, together with many other important personalities, sent a public letter to the authorities demanding a return to “constitutional normality, effective democracy, and American solidarity.” “American solidarity” was a euphemism for siding Argentina with the Allies in World War II. The new government, which had a certain sympathy with the Axis, reacted by dismissing all signers that were public employees. Houssay, as a university professor, fell into this category. His dismissal was followed by the resignation of most of the scientific staff of the Institute of Physiology,

Leloir among them, in solidarity with Houssay. Leloir then traveled to the United States, where he first worked with Ed Hunter on the formation of citric acid at Carl and Gerty Coris’s laboratory at Washington University in St. Louis and then with David Green (with whom he had already worked in Cambridge) at Columbia University in New York City on the separation of aminotransferases. In 1943 Leloir married Amelia Zuberbuhler. The outcomes of this happy marriage were a daughter and nine grandchildren.

Returning to Argentina, Leloir in 1945 affiliated with the Institute of Experimental Biology and Medicine, which had been recently inaugurated in Buenos Aires to host Houssay and most of the former members of the Institute of Physiology. Leloir then started recruiting collaborators, the first of which was Ranwel Caputto, a medical doctor who, like Leloir, had received postdoctoral training in biochemistry with Malcolm Dixon at the University of Cambridge. Raúl Trucco, a microbiologist, was invited next, as the intention was to study fatty acid oxidation in bacteria. Carlos Cardini and Alejandro Paladini soon joined the group. At that time Jaime Campomar, a textile industrialist, had decided to fund a new institution dedicated to biochemical research and approached Houssay for advice on choosing its director. Houssay quickly suggested Leloir for the job, and the latter was to be the director of the Instituto de Investigaciones Bioquímicas Fundación Campomar (Institute for Biochemical Research Campomar Foundation; now called the Fundación Instituto Leloir [Leloir Institute Foundation]) for the rest of his life. The institute was inaugurated in November 1947 in a small, one-story, and rather old house that was adjacent to the institute directed by Houssay. Figure 1 depicts the initial research group at the central patio of the institute.

Because experiments on fatty acid oxidation produced dubious results, the group decided to switch its efforts to studying the synthesis of lactose (a disaccharide composed of galactose plus glucose, Gal and Glc, respectively). Caputto claimed that during his thesis work he had been able to synthesize the disaccharide on incubating glycogen (see below) with a mammary gland extract. As those results could not be repeated, Leloir suggested studying instead lactose degradation, as this process might

provide information about the synthetic pathway. This prediction proved to be correct. In hindsight, it may be speculated that what Caputto had observed was probably the formation of maltose (another disaccharide but containing two glucoses) by amylolytic degradation of the polysaccharide. Identification of disaccharides was at that time based on unreliable methods, as the morphology of the crystals of derivatives formed upon reaction with phenylhydrazine (osazones).

For the planned research, the group decided to use a cell-free extract derived from a yeast (Saccharomyces fragilis) adapted to grow on lactose as a carbon source. The scientists first detected a lactase that degraded the disaccharide to its monosaccharide constituents and then a galactokinase that phosphorylated galactose to galactose 1-phosphate (Gal 1-P). Conversion of the last compound to glucose 6-P (Glc 6-P) required two unknown thermostable factors: glucose 1,6 diphosphate (Glc 1,6 diP) for the conversion of glucose 1-P (Glc 1-P) to Glc 6-P, and uridine diphosphate glucose (UDP-Glc) for the conversion of Gal 1-P to Glc 1-P. Determining the structure of UDP-Glc was a real tour de force, given the minimum amounts of reagents and equipment available. They determined that the compound had one Glc residue per two phosphates and that it absorbed in the ultraviolet light, but the absorption spectrum was that of an unknown substance (only spectra of adenosine-containing compounds were known by then). One day Caputto came to the institute in an excited state, carrying the last issue of the Journal of Biological Chemistry depicting in one of the articles the spectrum of uridine, which coincided with that of the new substance. Figure 2 is a cartoon drawn by Leloir showing the mood of the group before solving the structure of UDP-Glc.

The so-called Leloir’s Pathway may be then represented as:

Gal + ATP → Gal 1-P + ADP

Gal 1-P + UDP-Glc → UDP-Gal + Glc 1-P

UDP-Gal ← UDP-Glc

Glc 1-P → Glc 6-P

where UDP-Gal stands for uridine diphosphate galactose.

UDP-Glc was the first nucleotide sugar to be described, and the pathway shows the first role of these novel compounds, that of being involved in monosaccharide interconversion. In the case described above, conversion of UDP-Gal to UDP-Glc was shown to require NAD (nicotinamide adenine dinucleotide) as inversion of the OH group in C4 proceeds by an oxidoreduction reaction. Furthermore, description of the pathway provided a full explanation of galactosemia, a human congenital disease that is characterized by the inability to metabolize galactose. Most patients are deficient in the enzyme involved in the second reaction depicted above, whereas in a milder form of the disease, galactokinase is the deficient enzyme.

As reported also by Leloir and collaborators, the general pathway for nucleotide sugar synthesis can be represented as:

NTP + monosaccharide 1-P → NDP- monosaccharide + PP

where NTP stands for nucleoside triphosphates (ATP, UTP, GTP, and CTP) and PP for pyrophosphate. Of the nearly one hundred nucleotide sugars now known, several of them (GDP-Man, UDP-GlcNAc, UDP-GalNAc, and ADP-Glc) were first described by Leloir and co-workers.

The question as to whether UDP-Glc had an additional role beside that of being involved in monosaccha-ride interconversion was raised because UDP-Glc was detected also in yeast strains unable to use galactose for growth. The method then used for UDP-Glc quantification (acceleration of Gal 1-P to Glc 1-P transformation) provided evidence for a second role of nucleotide sugars, that of being intermediates in monosaccharide transfer reactions. The disappearance of UDP-Glc incubated with a yeast extract proceeded at a higher rate in the presence of added Glc 6-P. This effect was quickly traced by Leloir and a new collaborator, Enrico Cabib, to the formation of treahalose 6-P. (Trehalose is a disaccharide composed of two glucoses, different from maltose.) The reaction can be described then as:

UDP-Glc + glucose 6-P → trehalose 6-P + UDP

Similarly, soon after Leloir described the synthesis of sucrose 6-P (sucrose is a sophisticated name for our daily sugar, composed of two monosaccharides, Glc and fructose), using wheat germ extracts:

UDP-Glc + fructose 6-P → sucrose 6-P + UDP.

Curiously, synthesis of lactose, which was the first aim of the project, was described not by Leloir and his coworkers but in 1961 by Winifred M. Watkins and W. Z. Hassid, working with mammary gland extracts (“The Synthesis of Lactose by Particulate Enzyme Preparations from Guinea Pig and Bovine Mammary Glands”). It proceeds as follows:

UDP-Gal + Glc → lactose + UDP

Glycogen is a reserve polysaccharide constituted by many glucose units present in a variety of organisms, from bacteria to mammals. Plants have, additionally, another polysaccharide (starch) structurally closely related to glycogen. In the late 1930s and early 1940s, Carl and Gerty Cori, in a series of articles, described the incubation of Glc 1-P with a mammalian cell extract resulting in glycogen synthesis according to the following (reversible) reaction:

Glc 1-P + (Glc)n ← (Glc)n+1 + P

where (Glc)n stands for glycogen containing n Glc molecules. The participating enzyme (glycogen phosphorylase) was crystallized. For many years this was taken as the pathway of glycogen synthesis, although some conflicting reports soon appeared. For instance, the application of adrenaline to animals, which resulted in phosphorylase activation, led to glycogen degradation, not to glycogen synthesis. Moreover, the P levels in live tissues suggested that the equilibrium was displaced from right to left in the above equation. In 1957 Leloir and Cardini reported in “Biosynthesis of Glycogen from Uridine Diphosphate Glucose” that incubation of UDP-Glc with a mammalian cell extract resulted in the synthesis of glycogen. The synthetic reaction was then:

UDP-Glc + (Glc)n → (Glc)n+1 + UDP.

The activity of the enzyme involved (glycogen synthetase) was found to be highly regulated to allow accumulation of the polymer in times of plenty and its degradation in times of need.

Changing Times: 1958–1970 . Jaime Campomar died in 1956, and as his heirs decided to discontinue funding the institute, Leloir almost decided to close it for good. Fortunately, however, a series of events helped to dissuade Leloir from taking such a drastic decision. First, Leloir applied for and received a generous grant from the National Institutes of Health in the United States. Second, the government of General Juan Peron, which was not friendly to higher education and research, was deposed in 1955. The new government reinstated the autonomy of public universities and created the National Research Council, an institution that provided funds for research and full-time positions. Houssay became its first president and held that post until his death in 1971. The building that housed Leloir’s institute was almost completely dilapidated. (He had constructed with his own hands a series of interior channels to prevent leaking rainwater from damaging journals and books in the library.) The post-Peronist government, however, offered Leloir a much larger building (a former nun’s school), and both he and Houssay moved their institutes into it. In addition, a fruitful association between Leloir’s Instituto de Investigaciones Bioquímicas Fundación Campomar and the School of Sciences of the University of Buenos Aires was initiated in 1958. Leloir was designated research professor of the university’s School of Sciences.

Leloir devoted the first years in the new building to the study of the regulation of glycogen synthetase by metabolites (mainly by Glc 6-P) and by interconversion between active and inactive forms triggered by phosphorylation and dephosphorylation. He also determined that the precursor in the synthesis of starch was not UDP-Glc but a new nucleotide sugar, adenosine diphosphate glucose (ADP-Glc). As UDP-Glc showed a poor incorporation of glucose into the polysaccharide in cell-free assays, he tried several synthetic nucleotide sugars and found that ADP-Glc was by far the best precursor. He then isolated the compound from natural sources (sweet corn). Another problem that caught Leloir’s attention was the synthesis of high molecular weight (particulate) glycogen. He found that the polysaccharide synthesized in the test tube either by glycogen phosphorylase from Glc 1-P or by glycogen synthetase from UDP-Glc was differentially decomposed by a series of physical and chemical treatments. The fact that the polysaccharide formed by the synthetase from UDP-Glc in the test tube showed decomposition features identical with those of the native molecules was a definitive demonstration that UDP-Glc was the true glycogen precursor in vivo.

The Nobel Prize and Afterward . On 20 October 1970 the Swedish Academy of Sciences announced the awarding of the Nobel Prize in Chemistry to Luis F. Leloir for his discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates. By then he had already begun what was going to be his last great contribution to biochemistry.

Phillips Robbins at the Massachusetts Institute of Technology and Jack Strominger at Harvard University had, in the mid-1960s, determined that lipid bound mono- and oligosaccharides behaved as biosynthetic intermediates between nucleotide sugars and several polysaccharide components of the bacterial cell wall. The lipid moiety was identified as a polyprenol (undecaprenol) phosphate. Leloir then described how the incubation of rat liver membranes with UDP-Glc resulted in the formation of dolichol-P-Glc, dolichol being a polyprenol containing 20-21 isoprene units in mammalian cells. Further incubation of dolichol-P-Glc led to the transfer of the monosaccharide to a compound tentatively identified as dolichol-P-P-oligosaccharide (later shown to be GlcNAc2 Man9 Glc3). Further incubation of this last lipid derivative with the membranes resulted in the transfer of the whole oligosaccharide to proteins. Leloir thus established the basis of the pathway leading to the synthesis of glycoproteins in eukaryotic cells and also provided the first evidence indicating that the protein-linked oligosaccharide was processed (i.e., that monosaccharides were both removed from it and added to it).

In 1978 the mayor of the city of Buenos Aires donated land and formed and presided over a committee to gather funds for constructing a new building. At the end, equal amounts of public and private funds were received. The move to the new premises took place in December 1983. Leloir was to continue doing research there for four years.

Leloir the Man . Leloir belonged to an old and wealthy Argentinean family, a circumstance that allowed him fully to devote his time to basic research when funding for such endeavors was almost nonexistent in the country. He personally covered funds for most subscriptions of scientific journals received at the Institute’s library and fully donated his salary as research professor of the University of Buenos Aires to the Institute. Leloir had a low profile personality; he shunned public exposure and displayed an extremely subtle and exquisite sense of humor. Leloir was a hard worker who, until a few years before passing away, had continued working at the bench. Research was for him the best of hobbies. (He never had a private office, instead receiving visitors and doing institute paperwork at the laboratory.) He was extremely courteous and treated everybody, independently of their social position, in the same unassuming way. He had a calm personality and showed a degree of discomfort only when somebody behaved rudely or showed bad manners. Leloir’s personality greatly contributed to the substantial pleasure of working in his group or his institute.

BIBLIOGRAPHY

WORKS BY LELOIR

With Carlos E. Cardini. “Biosynthesis of Glycogen from Uridine Diphosphate Glucose.” Journal of the American Chemical Society 79 (1957): 6340-6341.

“Two Decades of Research on the Biosynthesis of Saccharides.” Science 172 (25 June 1971): 1299–1303. The text of Leloir’s Nobel lecture.

“Biosynthesis of Polysaccharides Seen from Buenos Aires.” In Biochemistry of the Glycosidic Linkage, edited by Romano Piras and Horacio G. Pontis. New York: Academic Press, 1972.

“Far Away and Long Ago.” Annual Review of Biochemistry 52 (1983): 1–15.

OTHER SOURCES

Cabib, Enrico. “Research on Sugar Nucleotides Brings Honor to Argentinian Biochemist.” Science 170 (6 November 1970): 608–609.

Cori, Carl F.; Gerty T. Cori; and Albert H. Hegnauer. “Resynthesis of Muscle Glycogen from Hexosemonophosphate.” Journal of Biological Chemistry 120 (1937): 193-202.

Cori, Gerty T.; Carl F. Cori; and Gerhard Schmidt. “The Role of Glucose-1-Phosphate in the Formation of Blood Sugar and Synthesis of Glycogen in the Liver.” The Journal of Biological Chemistry 129 (1939): 629-639.

Cori, Gerty T., and Carl F. Cori. “Crystalline Muscle Phosphorylase: IV. Formation of Glycogen.” Journal of Biological Chemistry 151 (1943): 57-63.

Kresge, Nicole; Robert D. Simoni; and Robert L. Hill. “Luis F. Leloir and the Biosynthesis of Saccharides.” Journal of Biological Chemistry 280 (13 May 2005): 158-160.

Myrbäck, Karl. “Presentation Speech of the Nobel Prize in Chemistry 1970.” In Les Prix Nobel en 1970, edited by Wilhelm Odelberg. Stockholm, Sweden: Nobel Foundation, 1971.

Parodi, Armando J. “Leloir, su Vida y su Ciencia.” Ciencia Hoy 16 (August-September 2006): 23-30.

Watkins, Winifred M., and William Z. Hassid. “The Synthesis of Lactose by Particulate Enzyme Preparations from Guinea Pig and Bovine Mammary Glands.” Journal of Biological Chemistry 237 (1962): 1432-1440.

Armando J. Parodi

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