The ATP Requirement for Fatty Acid Oxidation: the Early Work of Albert L. Lehninger
Year: 2005
Type: article
Abstract: The Relationship of the Adenosine Polyphosphates to Fatty Acid Oxidation in Homogenized Liver Preparations (Lehninger, A. L. (1945) J. Biol. Chem. 157, 363-382) Albert Lester Lehninger (1917-1986) was born in Bridgeport, Connecticut. In 1935 he enrolled at Wesleyan University as an English major. Although his interests soon changed to chemistry, Lehninger would later make use of his writing talents to author three classic textbooks: Biochemistry, The Mitochondrion, and Bioenergetics. Inspired by the work of Otto Warburg and Hans Krebs, Lehninger went on to graduate school at the University of Wisconsin and received his Ph.D. in 1942. His graduate research with Edgar J. Witzemann was on the metabolism of acetoacetate and the oxidation of fatty acids by disrupted liver preparations. The Journal of Biological Chemistry (JBC) Classic reprinted here concerns Lehninger's work on fatty acid oxidation. At the time, much of what was known about glycolysis and the citric acid cycle had been elucidated from minced tissue and tissue extracts. However, similar studies on fatty acid oxidation had been hampered by the fact that ruptured liver cells lost their ability to oxidize fatty acids. Luis F. Leloir and Juan M. Muñoz had some success with liver homogenates at low temperatures in the presence of oxygen, inorganic phosphate, fumarate, cytochrome c, adenylic acid, and magnesium ions (1.Muñoz J.M. Leloir L.F. Fatty acid oxidation by liver enzymes.J. Biol. Chem. 1943; 147: 355-362Abstract Full Text PDF Google Scholar), but these experiments were not always reproducible. When the reaction was carried out successfully, Leloir and Muñoz noted that there was a decrease in ATP phosphorus and phosphopyruvic acid phosphate and an increase in inorganic phosphate, indicating the reaction was somehow coupled with phosphorylation. In examining these early experiments, Lehninger realized that high concentrations of ATP or ADP might be required to activate or facilitate oxidation by the liver extracts. He came to this conclusion for a number of reasons including the fact that ATP is rapidly dephosphorylated when cells are disrupted and that the fumarate needed for the reaction might provide a substrate for oxidations capable of phosphorylating adenylic acid to ATP. In the Classic, Lehninger proves his hypothesis by adding ATP to a homogenized liver preparation and demonstrating that it consistently and reproducibly carried out fatty acid oxidation. Subsequent work would show that fatty acids are activated by the formation of a thioester linkage between the carboxyl group of the fatty acid and the sulfhydryl group of coenzyme A. This reaction is driven by ATP. With the start of the war, Lehninger abandoned his fatty acid studies and joined the wartime research effort of the Plasma Protein Fractionation Program led by Edwin Joseph Cohn, who was the author of a previous JBC Classic (2.Cohn E.J. Hendry J.L. Prentiss A.M. JBC ClassicsJ. Biol. Chem. 1925; 63 (http://www.jbc.org/cgi/content/full/277/30/e19): 721-766Abstract Full Text PDF Google Scholar). During this time, Lehninger discovered several papers on oxidative phosphorylation, and from then on the mechanisms of energy capture and transduction in cells became the central focus of his research. In 1945 Lehninger accepted a faculty position at the University of Chicago. During his 6 years in Chicago, Lehninger and two of his students would make two significant discoveries that would contribute greatly to the study of metabolism. First, Lehninger and Eugene P. Kennedy would discover that virtually all of the cell's oxidative activity occurred in the mitochondria. Second, Lehninger and Morris E. Friedkin would show that electron transport from NADH to oxygen is an immediate and direct energy source for oxidative phosphorylation. Lehninger's work with Kennedy and the latter part of his research career will be the subject of a future JBC Classic. 1All biographical information on Albert Lester Lehninger was taken from Ref. 3.Lane M.D. Talalay P. Albert Lester Lehninger 1917-1986.J. Membr. Biol. 1986; 91: 194-197PubMed Google Scholar. 1All biographical information on Albert Lester Lehninger was taken from Ref. 3.Lane M.D. Talalay P. Albert Lester Lehninger 1917-1986.J. Membr. Biol. 1986; 91: 194-197PubMed Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1542456104