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Henry Lardy's Contributions to Understanding the Metabolic Pathway

Year: 2005
Type: article
Abstract: The Enzymatic Synthesis of Phosphopyruvate from Pyruvate (Lardy, H. A.,and Ziegler, J. A. (1945) J. Biol. Chem. 159,343-351) The Mechanism by Which Glyceraldehyde Inhibits Glycolysis (Lardy, H. A.,Wiebelhaus, V. D., and Mann, K. M. (1950) J. Biol. Chem. 187,325-337) Oxidative Phosphorylations: Role of Inorganic Phosphate and AcceptorSystems in Control of Metabolic Rates (Lardy, H. A., and Wellman, H. (1952)J. Biol. Chem. 195,215-224) Henry Arnold Lardy (1917-) was born in Roslyn, South Dakota. He began hisscientific career at South Dakota State University in 1935, when, as afreshman, he needed money to pay his tuition and living costs and got a job inthe Dairy Department, caring for cows and rats used for vitamin D experiments.In his junior and senior years, he worked part time at the University'sExperiment Station Chemistry Laboratory, studying selenium toxicity. Lardy earned his bachelor's degree in 1939, double majoring in chemistryand dairy science. He received both his M.S. (1940) and his Ph.D. (1945) inbiochemistry from the University of Wisconsin-Madison and has remained theresince, serving as chair of a section of the Enzyme Institute from 1950 untilhis retirement in 1988. Lardy's research at Wisconsin covers a wide variety ofmetabolic phenomena, in part because he wanted his graduate students to havetheir own thesis research problems. The first Journal of Biological Chemistry (JBC) Classic reprintedhere contains Lardy's research on the regeneration of phosphopyruvate duringglycogen synthesis. Otto Meyerhof, author of a previous JBC Classic(1Meyerhof O. Junowicz-Kocholaty R. J. Biol. Chem. 1943; 149: 71-92Abstract Full Text PDF Google ScholarMeyerhof O. J. Biol. Chem. 1945; 157: 105-120Abstract Full Text PDF Google ScholarMeyerhof O. andOesper P. J. Biol. Chem. 1947; 170 (JBC Classics, (http://www.jbc.org/cgi/content/full/280/4/e3)): 1-22Abstract Full Text PDF Google Scholar), had previously reportedthat the following reaction was irreversible(2Meyerhof O. Ohlmeyer P. Gentner W. Maier-Leibnitz H. Biochem. Z. 1938; 298: 396Google Scholar). Phosphopyruvate+ADP→pyruvate+ATP However, as Lardy points out, the experiment on which Meyerhof based thisconclusion was designed to detect an exchange of high energy phosphate(∼P) between ATP and phosphopyruvate and did not depend on an accumulationof phosphopyruvate produced from pyruvate and ATP. Meyerhof acknowledged thisshortcoming by saying, “we must concede that the experimental basis forthis negative result is not too large and therefore accept it with somereservation until it is more firmly established”(3Meyerhof O. A Symposium onRespiratory Enzymes. University of Wisconsin Press, Madison1942Google Scholar). In the JBC Classic, Lardy and John Ziegler prove that the phosphopyruvatereaction is indeed reversible by using radioactive phosphorus. They found that32P, initially incorporated into ATP, is in turn incorporated intophosphopyruvate. Lardy and Ziegler also discovered that K+ isnecessary to catalyze the reaction, explaining why Meyerhof and his colleagueswere unable to demonstrate its reversibility. They carried out theirexperiments with an enzyme extract that had been dialyzed for 12 h without theaddition of any potassium salt. The second JBC Classic deals with another facet of metabolism, theinhibition of glycolysis by glyceraldehyde. Several laboratories had noticedthat adding glyceraldehyde to tumor slices inhibited the formation of lacticacid from glucose but not from polysaccharides or phosphorylated sugars.Although the conditions for glyceraldehyde inhibition had been worked out, themechanism by which the inhibition occurred was unknown. It did, however,appear that glyceraldehyde exerted its effects at the first stage of sugarmetabolism, namely by inhibiting the hexokinase responsible forphosphorylating glucose. As reported in the Classic, Lardy and his co-workers found that brainhexokinase was inhibited by l-glyceraldehyde but notd-glyceraldehyde. They also noticed that different hexokinasepreparations varied in their sensitivity to l-glyceraldehyde,suggesting that the compound's inhibitory action was not a direct one.Previously, Meyerhof had reported that a racemic mixture of glyceraldehydecould condense with triose phosphate to form d-fructose 1-phosphateand l-sorbose 1-phosphate(4Meyerhof O. Lohmann K. Schuster P. Biochem. Z. 1936; 286: 319Google Scholar). Thinking that one of theseesters might be the inhibitor, Lardy and his colleagues synthesized thecompounds and discovered that l-sorbose 1-phosphate strongly andconsistently inhibited brain and tumor hexokinase. Thus, the ester, and notl-glyceraldehyde, was the inhibitor of glycolysis. Becausel-sorbose 1-phosphate and the product of the hexokinase reaction,glucose 6-phosphate, shared a strong structural similarity, Lardy proposedthat, “the inhibitor combines with that portion of hexokinase which hasaffinity for glucose and prevents the substrate from combining.” In the final JBC Classic reprinted here Lardy looks at the role ofphosphate acceptors in controlling oxidation rates in metabolism. It wasbelieved that the availability of intracellular orthophosphate and phosphateacceptors was the basic factor influencing the rates of oxidation andglycolysis. Although experiments had been done to show that creatine enhancedrespiration of muscle extracts by 50 to 100%, Lardy believed these experimentswere not ideal because the tissue preparations contained active phosphatases.In this Classic, Lardy showed that adding a phosphate acceptor to rat livermitochondria enhanced the oxidation of a variety of substrates. Thisrespiration-accelerating effect could be duplicated by adding2,4-dinitrophenol, an agent that uncouples oxidative phosphorylation,preventing phosphate esterification and ATP synthesis, thus keeping the levelof ADP (a phosphate acceptor) high. Lardy concludes, “The rates ofoxidation apparently are limited by the rate of transfer or hydrolysis of highenergy phosphate compounds whose synthesis is coupled with the oxidativeelectron transport.” Although officially retired now, Lardy maintains an office at theUniversity of Wisconsin and remains a working scientist, leading a researchteam at the Enzyme Institute. In addition to the above areas of metabolicresearch, Lardy pioneered work on the preservation and storage of semen, whichhas made artificial insemination in livestock practical. Currently, hisresearch focuses on dehydroepiandrosterone (DHEA) and its metabolites. Lardy has more than 370 publications in major journals and books and hasreceived numerous awards, including the American Chemical Society's Paul LewisAward in Enzyme Chemistry (1949), the Wolf Foundation Award in Agriculture(1981), the National Award of Agricultural Excellence (1982), and the AmericanSociety of Biological Chemists' (now the American Society for Biochemistry andMolecular Biology) William C. Rose Award (1988). Lardy was also President ofthe American Society of Biological Chemists in 1964 and a member of the JBCEditorial Board from 1958 to 1964 and 1980 to 1985. He has been a member ofthe National Academy of Sciences since1958. 1All biographical information on Henry Lardy was taken from Refs.5Lardy H. Happily at work.J. Biol.Chem. 2003; 278: 3499-3509Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar and6.Matthees, D. Distinguished biochemist to lecture at SDSU Oct. 20,21, 2003. SDSU News Archives Oct2003.Google Scholar. 1All biographical information on Henry Lardy was taken from Refs.5Lardy H. Happily at work.J. Biol.Chem. 2003; 278: 3499-3509Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar and6.Matthees, D. Distinguished biochemist to lecture at SDSU Oct. 20,21, 2003. SDSU News Archives Oct2003.Google Scholar.
DOI: 10.1016/s0021-9258(20)61810-5
Language: English
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1605413738
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