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Daniel Edward Atkinson, professor emeritus of chemistry and biochemistry at UCLA, and a major figure in 20th century biochemistry, died at the age of 102 on Feb. 2, 2024, in Medford, Oregon. He is known internationally for two major contributions to metabolic biochemistry: the concept of “energy charge” and the understanding of the physiological role of the urea cycle.

Penny Jennings

Although he retired as a full professor in 1991, Daniel Atkinson remained active at UCLA until moving to Oregon in 2011. He’s pictured here in 2007.

In 1952, Atkinson began his independent career as an assistant professor at UCLA. He rose through the ranks, retiring as a full professor in 1991, but kept active at UCLA until moving to Oregon in 2011. His laboratory trained more than 30 Ph.D. students and more than 20 postdoctoral fellows and visiting faculty, publishing 80 papers including 20 in the Journal of Biological Chemistry.

Atkinson's research pioneered the field of metabolic regulation. This work allowed for the development of the concept of energy charge, now a main topic of biochemistry textbooks and a fundamental bridgehead for researchers. He was also responsible for our present understanding of the biological role of the urea cycle in pH regulation. UCLA biochemistry majors are still delighted to hear how his findings, initially challenged by the old guard, made their way into mainstream biochemistry.

UCLA

Daniel Atkinson at his UCLA desk as an Assistant Professor in 1952.

His classic 1977 monograph published by Academic Press, "Cellular Energy Metabolism and its Regulation," presented a global view of the logic of metabolism and is still widely read and acclaimed.

Energy charge

Atkinson’s studies on enzymes of the central metabolic pathway led to our understanding of the control of anabolic and catabolic reactions by the ratios of cellular adenosine mono-, di- and triphosphate, known as AMP, ADP and ATP. ATP is the near universal chemical energy source that drives metabolism, transport and movement.

Steven Clarke

The cover of Daniel Atkinson’s 1977 monograph.

In Atkinson’s concept of energy charge, the fraction of the total adenylate pool as ATP equivalents (ATP plus half the amount of ADP) / (sum of ATP, ADP and AMP) represents the energy storage balance of the cell — values near 0.9 indicate a high energy balance and values below 0.5 indicate that cells are lacking energy resources. Atkinson discovered that key regulatory enzymes possessed allosteric binding sites for AMP, ADP and ATP that enabled them to respond appropriately to cellular energy charge.

Grahame Hardie, a professor at Dundee University and discoverer of the AMP-activated protein kinase, or AMPK, believes Atkinson’s energy charge hypothesis is a fundamental concept of the field.

“In the 1990s I was trying to understand the physiological role of AMPK, a protein kinase we had defined that was activated by AMP and inhibited by high ATP,” Hardie wrote. “I was toying with the idea that it was a kind of energy sensor that might control the balance between catabolism and anabolism, but others were sceptical (one well-known metabolic biochemist even told me that AMPK couldn’t be important, because ATP levels in cells never varied!).

“Then I read the book by Daniel Atkinson, in which he drew the analogy between AMP, ADP and ATP and the chemicals in an electrical cell or battery, and introduced the concept of energy charge. I discovered his 1964 paper on the regulation of phosphofructokinase in the Journal of Biological Chemistry where he wrote in the discussion: ‘These indications that the level of AMP, or the AMP to ATP ratio, may regulate the metabolic direction (toward energy release or toward energy storage) … suggest that AMP may function more generally as a mediator of energy metabolism. Similar effects of AMP or ADP on enzymes involved at other branch points between biosynthesis and degradation seem likely.’

“Reading this, suddenly everything clicked into place. Atkinson’s prediction from 1964 was indeed correct, the only thing he had not anticipated being that the sensing of AMP and ATP would often be done by an upstream signalling protein (AMPK), rather than by the metabolic enzymes themselves.”

Atkinson’s analogy of cellular energy charge with the charge on a battery came from his deep understanding of electricity and mechanics. His students also remember him comparing an allosteric enzyme with the automatic transmission of a car: Both need an output (gear selection for the transmission; catalytic activity for the enzyme) dependent upon integrating multiple inputs (speed, torque and accelerator position for the transmission; binding of small molecules and covalent posttranslational modifications for the enzyme). One of these students commented that Atkinson’s biochemical analogies made them understand for the first time how a battery or a transmission actually works.

Urea cycle

By 1982, Atkinson had embarked on a second major field of study: urea biosynthesis. Before Atkinson put his mind to the issue, most researchers believed the function of the urea cycle was to prevent the accumulation of ammonium ion. He noticed that the catabolism of excess amino acids to carbon dioxide, water and ammonium ion was accompanied by the release of base in the form of bicarbonate anion in almost equal molar amounts as ammonium ion.

While there was little to suggest significant toxicity from ammonium ion, the production of bicarbonate would be expected to raise the pH of the organism to levels incompatible with life. This led Atkinson to realize that the urea production neatly solves this problem by converting exactly equal amounts of ammonium ion and bicarbonate into the neutral products urea, carbon dioxide and water, all readily excreted.

Atkinson’s urea hypothesis was confirmed by a study of freshwater tilapia fish that live in lakes at pH 7.1 or related species that live in alkaline soda lakes where the pH is 9.6– 10. While fish species in lakes at neutral pH lack enzymes of the urea cycle, like almost all fish that excrete ammonium ion and bicarbonate directly into the environment, the species in the alkaline environment had a full complement of enzymes to make urea and keep their internal pH close to neutral. Other fish are able to turn on the synthesis of urea in response to alkaline environments.

ATP and metabolism

Reginald Garrett, professor emeritus at the University of Virginia and co-author with Charles Grisham of the widely used text Biochemistry, now in its seventh edition, notes that Atkinson not only created the new paradigms of energy charge and the role of the urea cycle as a mechanism for pH regulation; he also made the major contribution explicating the role of ATP in achieving thermodynamic favorability.

“Essentially any metabolic sequence, catabolic or anabolic, is rendered thermodynamically favorable by the involvement of ATP,” Garrett wrote. “Exergonic catabolic metabolism drives ATP synthesis; ATP hydrolysis then fuels the endergonic processes of anabolism. Atkinson invented the term “ATP coupling coefficient”to describe the number of ATP equivalents produced by a catabolic sequence (+) or consumed in an anabolic sequence (-).

UCLA

Attending the UCLA biochemists’ dinner at the 1962 Pacific Slope Biochemistry Conference in Seattle were, clockwise from left, Charles West, Margaret Holzer, Garth Reith, Atsuko Fujimoto, Leland Shannon, Roberts Smith, Daniel Atkinson, Joseph Pinto and Audree Fowler.

“The use of ATP equivalents to describe how thermodynamic favorability is achieved in metabolism pairs with the paradigm of energy charge, where adenine nucleotides determine the kinetic regulation of metabolism, thus uniting thermodynamics and kinetics, the two key features of any chemical reaction, under the aegis of ATP.”

Atkinson received his BSc degree in agronomy and chemistry from the University of Nebraska in 1942. He did his Ph.D. thesis work with Sidney Fox at Iowa State University. After receiving his degree in 1949, he did brief postdoctoral work at Cal Tech and the Argonne National Laboratory before joining the UCLA chemistry faculty in 1952. Francis Blacet wrote in his history of the department that Atkinson inherited the mantle of Max Dunn, the only biochemist in the department during the previous 30 years.
Atkinson was a member of the 91ÑÇÉ«´«Ã½ for 67 years, serving as a Council member from 1979 to 1982, as a member of the editorial board of the JBC from 1966 to 1971 and as a JBC associate editor from 1972 to 1977.

In 2016, the UCLA Department of Chemistry and Biochemistry established the in Metabolic Biochemistry to be presented to undergraduate and graduate students in their honor.