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Luis F. Leloir and the Biosynthesis of Saccharides

2005; Elsevier BV; Volume: 280; Issue: 19 Linguagem: Inglês

10.1016/s0021-9258(20)67598-6

1083-351X

Nicole Kresge, Robert Simoni, Robert L. Hill,

Chemical synthesis and alkaloids

Isolation of the Coenzyme of the Galactose Phosphate-Glucose PhosphateTransformation (Caputto, R., Leloir, L. F., Cardini, C. E., and Paladini, A.C. (1950) J. Biol. Chem. 184,333-350) Uridine Diphosphate Acetylglucosamine (Cabib, E., Leloir, L. F., andCardini, C. E. (1953) J. Biol. Chem. 203,1055-1070) Guanosine Diphosphate Mannose (Cabib, E., and Leloir, L. F. (1954)J. Biol. Chem. 206,779-790) Luis Federico Leloir (1906-1987) was born in Paris but moved to BuenosAires with his Argentine parents when he was 2 years old. He attended theUniversity of Buenos Aires and graduated with an M.D. in 1932. Leloir got ajob at the University hospital but left the bedside for the bench 2 yearslater. As he recalled, “When I practiced medicine, except for surgery,digitalis, and a few other active remedies, we could do little for ourpatients. Antibiotics, psychoactive drugs, and all the new therapeutic agentswere unknown. It was therefore not strange in 1932 that a young doctor such asI should try to join efforts with those who were trying to advance medicalknowledge”(1Leloir L.F. Far away and long ago.Annu. Rev. Biochem. 1983; 52: 1-15Crossref PubMed Scopus (5) Google Scholar). 1All biographical information on Luis F. Leloir was taken from Refs.1Leloir L.F. Far away and long ago.Annu. Rev. Biochem. 1983; 52: 1-15Crossref PubMed Scopus (5) Google Scholar and8Leloir L.F. Two decades of research on thebiosynthesis of saccharides.Science. 1971; 172: 1299-1302Crossref PubMed Scopus (136) Google Scholar. We thank Armando J. Parodi,Ph.D., of the Fundacion Instituto Leloir, for helpful comments in thepreparation of this JBC Classic Introduction.1All biographical information on Luis F. Leloir was taken from Refs.1Leloir L.F. Far away and long ago.Annu. Rev. Biochem. 1983; 52: 1-15Crossref PubMed Scopus (5) Google Scholar and8Leloir L.F. Two decades of research on thebiosynthesis of saccharides.Science. 1971; 172: 1299-1302Crossref PubMed Scopus (136) Google Scholar. We thank Armando J. Parodi,Ph.D., of the Fundacion Instituto Leloir, for helpful comments in thepreparation of this JBC Classic Introduction. The most active research laboratory in town was run by Bernardo A. Houssay,who would later be awarded the Nobel Prize with Carl and Gerty Cori for theirwork on the role of the pituitary gland in carbohydrate metabolism. Leloirjoined Houssay's laboratory as a graduate student and studied the role of theadrenals in carbohydrate metabolism. After Leloir finished his thesis work, Houssay advised him to study abroad.So, in 1936 Leloir moved to England to work at the Biochemical Laboratory ofCambridge University. There, he collaborated with Malcolm Dixon on the effectof cyanide and pyrophosphate on succinic acid dehydrogenase, Norman L. Edsonon ketogenesis using liver slices, and David E. Green on the purification andproperties of β-hydroxybutyrate dehydrogenase. Leloir returned to Buenos Aires after his time at Cambridge and startedinvestigating the oxidation of fatty acids in the liver with J. M.Muñoz. They managed to produce an active cell-free system, which was anaccomplishment since at that time it was thought that oxidation could onlyoccur in intact cells. Leloir also worked with E. Braun Menéndez, JuanCarlos Fasciolo, and A. C. Taquini on the mechanism of renal hypertension andthe formation of angiotensin. In 1944, Leloir left Buenos Aires again. This time he went to WashingtonUniversity in St. Louis to work with Carl and Gerty Cori, who were featured ina previous Journal of Biological Chemistry (JBC) Classic(2Cori C.F. Cori G.T. J. Biol. Chem. 1928; 79: 321-341Abstract Full Text PDF Google ScholarCori G.T. Colowick S.P. Cori C.F. J. Biol. Chem. 1938; 124: 543-555Abstract Full Text PDF Google ScholarCori G.T. Colowick S.P. Cori C.F. J. Biol. Chem. 1939; 127: 771-782Abstract Full Text PDF Google ScholarGreen A.A. Cori G.T. J. Biol. Chem. 1943; 151: 21-29Abstract Full Text PDF Google ScholarCori G.T. Green A.A. J. Biol. Chem. 1943; 151 (JBC Classics, (http://www.jbc.org/cgi/content/full/277/29/e18)): 31-38Abstract Full Text PDF Google Scholar). While in the States,Leloir reunited with Green and spent some time at the College of Physiciansand Surgeons at Columbia University working on the purification ofaminotransferases. After his stay in the United States, Leloir returned to the Institute ofPhysiology in Buenos Aires. He worked there for a time and then left for aprivate institution recently created, the Instituto de InvestigacionesBioquimicas Fundacion Campomar (now Fundacion Instituto Leloir), where heremained until his death. In collaboration with Ranwel Caputto, Carlos E.Cardini, Raúl Trucco, and Alejandro C. Paladini, Leloir started to workon the metabolism of galactose. The project was initiated when Caputtopresented some preliminary results that indicated that mammary glandhomogenates could produce lactose when incubated with glycogen. The groupperformed many experiments with mammary gland extracts but generally gotambiguous results, mainly due to their lack of a reliable method for lactosedetection. Discouraged, they decided to focus on the breakdown of lactose bySaccharomyces fragilis, hoping that this would give them informationon the mechanism of lactose synthesis. Leloir and his colleagues isolated lactase from the yeast and determinedthat galactose was phosphorylated to produce galactose 1-phosphate. Theysynthesized glucose 1-phosphate and galactose 1-phosphate and observed thatthe esters were used when incubated with enzymes from galactose-adapted yeast.At first they thought that only one factor was required for this reaction, butsoon realized that two factors were involved: one for the conversion ofgalactose 1-phosphate into glucose 1-phosphate and another for the formationof glucose 6-phosphate, as shown in the following reaction. Galactose 1-phosphate→glucose 1-phosphate→glucose 6-phosphate Factor 1 Factor 2 The group first concentrated on finding Factor 2 and eventually determinedthat it was glucose 1,6-diphosphate(3Cardini C.E. Paladini A.C. Caputto R. Leloir L.F. Trucco R.E. Arch. Biochem. 1949; 22: 87PubMed Google Scholar). Next, they turned theirattention to identifying Factor 1. The purified factor absorbed light at 260nm and had a spectrum similar to that of adenosine, with some differences.They were stumped on the identity of this factor for quite some time untilCaputto came in one morning with an issue of the JBC that showed aspectrum identical to theirs. The spectrum was that of uridine. The grouppublished their results in a preliminary communication in Nature(4Cardini C.E. Paladini A.C. Caputto R. Leloir L.F. Uridine diphosphate glucose: the coenzyme of thegalactose-glucose phosphate isomerization.Nature. 1950; 165: 191-193Crossref Scopus (34) Google Scholar) and then in theJBC, which is the first classic reprinted here. In addition touridine, the co-factor was found to contain glucose and two phosphates andhence was named uridine diphosphate glucose (UDPG). The presence of uridine ina co-factor was rather novel as, until then, all known factors (ATP, NAD, FAD)only contained the nucleotide adenosine. The occurrence of a sugar derivativecombined with a nucleoside was also novel. Eventually, Leloir determined thatUDPG acts as a glucose donor in the synthesis of trehalose(5Leloir L.F. Cabib E. The enzymicsynthesis of trehalose phosphate.J. Am. Chem. Soc. 1953; 75: 5445-5446Crossref Scopus (20) Google Scholar), sucrose(6Cardini C.E. Leloir L.F. Chiriboga J. The biosynthesis of sucrose.J. Biol.Chem. 1955; 214: 149-155Abstract Full Text PDF PubMed Google Scholar), and glycogen(7Leloir L.F. Cardini C.E. Biosynthesisof glycogen from uridine diphosphate glucose.J. Am. Chem.Soc. 1957; 79: 6340Crossref Scopus (78) Google Scholar). Another result of the discovery of UDPG was the isolation andcharacterization of the sugar nucleotides UDP-N-acetylglucosamine(UDPAG) and guanosine diphosphate mannose (GDPM), which are the subjects ofthe remaining two JBC Classics reprinted here. UDPAG was originallydetected as an impurity in UDPG concentrates and was called UDP-X until Leloirwas able to identify the sugar moiety as N-acetylglucosamine.Similarly, GDPM was first detected by paper chromatography of UDPGpreparations that were purified by anion exchange. UDPAG and GDPM are nowknown to be involved in the biosynthesis of numerous glycoconjugates. Leloir's extensive work on sugar nucleotides and his contributions tobiochemistry received the recognition they deserved when he was awarded theNobel Prize in Chemistry in 1970, “for his discovery of sugarnucleotides and their role in the biosynthesis of carbohydrates.”