An Interview with Professor Manuel Varela and Ann Varela: Eugene Kennedy and his good friends—lipid biosynthesis, Krebs in mitochondria, and oxidative phosphorylation

Apr 25, 2020 by

Eugene Kennedy

Michael F. Shaughnessy –

1) Eugene Kennedy—a name that is associated with many things and many discoveries—but let us discover first where and when he was born and to who and what his early education was like.

Dr. Eugene Patrick Kennedy is most famous for taking part in the discoveries that the Krebs cycle pathway, metabolic oxidation of fatty acids, and oxidative phosphorylation, all extremely vital biological processes, happen in the insides of tiny intracellular organelles called mitochondria.

Gene Kennedy, the fourth of 5 children, was born on the 4th of September 1919, in Chicago, Illinois. His parents were Irish immigrants. As a child, he was an insatiable reader and spent a lot of time in the public library, developing his love for reading. Part of his passion for reading lies with a Catholic parochial elementary school, where he first learned to read. In 1933, Kennedy enrolled in St. Philip High School, another Catholic school taught by priests of the Servite Order. Graduating from high school in 1937, he entered De Paul University in Chicago, IL, on an academic scholarship. Majoring in chemistry, Kennedy took his undergraduate degree from De Paul University in 1941.

As a college graduate, Kennedy enrolled in the Ph.D. graduate program in organic chemistry at the University of Chicago during the late summer of 1941. There he met fellow graduate student Dan Koshland, Professor Frank Westheimer of his favorite graduate course, called quantitative organic chemistry, and his teaching assistant Aaron Novick. Each of these faculty and colleagues was to become respected investigators in later years.

During graduate school, Kennedy attended courses in the mornings, and in the afternoons, he worked part-time as a chemical laboratory assistant under a newly minted Ph.D. in biochemistry, Dr. Lemuel C. Curlin, at Armour and Company. The job was Kennedy’s first lab experience with proteins. He had been trained to study and develop fractionation of serum albumin in blood plasma, for the war effort, during World War II.

While still in the Ph.D. program, Kennedy married Adelaide Majewski Kennedy in 1943; they were to have three daughters, Lisa (b. 1950), Sheila (b. 1957) and Katherine (b. 1960).

Moved to a fascination with his extracurricular work in plasma fractionation biochemistry, Kennedy thus transferred to the biochemistry department to finish his graduate thesis project in 1947. His graduate advisor was Dr. Albert Lester Lehninger, a young faculty member whose expertise was in the oxidation of fatty acids and oxidative phosphorylation.

Inspired by the pioneering work of Georg Franz Knoop with fatty acids and the “active acetate,” Kennedy investigated fatty acid breakdown by oxidation using rat liver enzymes and manometry, a technique developed by the famous Otto Warburg. Kennedy focused his attention on the intracellular mitochondria. He discovered that the oxidation of fatty acids, oxidative phosphorylation, and the Krebs cycle, all took place in the mitochondrion. These were all significant scientific findings, and Dr. Kennedy earned his Ph.D. in 1947 from the University of Chicago.

Kennedy undertook postdoctoral studies with Dr. Horace Albert Barker at Berkeley studying β-oxidation of fatty acids. In 1950, he pursued further postdoctoral studies with the famous Professor Fritz Lipmann at Massachusetts General Hospital, investigating the so-called activation of acetate by CoA. In 1951, after his postdoctoral work, Kennedy went back to the University of Chicago and joined the faculty of Charles Hugging’s Ben May Laboratories for Cancer Research. Kennedy’s new laboratory concentrated on the formation of the so-called phosphoanhydride bond between choline and phosphatidic acid to yield a new molecule of lecithin.

2) Lipid biosynthesis—what exactly did Kennedy discover, or what insights did he have?  I know lipids are of two types—but what is going on with this biosynthesis?

I surmise the two types of lipids to which you are referring include those that constitute the membrane phospholipids. These two types are known as glycerophospholipids and sphingolipids. The process encompasses the construction of phospholipids, usually by combining a fatty acid and a head group. One of the significant discoveries by Kennedy in this area consists of his work during the early 1960s on the roles of cytidine nucleotides in the biosynthesis of the membrane phospholipids, a pathway now known as the Kennedy pathway.

In general, the biosynthesis and assembly of membrane phospholipids involve several key biochemical steps. The first is the production of its prime precursors, such as glycerol or perhaps sphingosine. The next step consists of the attachment of fatty acids to the glycerol backbone, forming so-called ester or amide chemical linkages. In the third step, a so-called headgroup is added, consisting of phosphate and one of a variety of chemical groups, forming a phosphodiester bond in the process. The last step involves a head group modification to produce the final product, the phospholipid.

In this context, Kennedy, beginning in the early 1950s, studied the third step, the attachment of the polar head groups. He had measured the rate of radioactively labeled phosphorous incorporation into the assembly during phospholipid synthesis. Kennedy observed that when he added glycerol to animal tissues, the speed of radioactive phosphorous spiked dramatically.

The finding was interpreted to mean that glycerol attached to phosphate during phospholipid synthesis in the tissues of animals. It was, thus, discovered that the new biosynthetic molecule was glycerol-3-phosphate, called at the time by Kennedy as sn-3-glycerophosphate. Kennedy’s finding led to another discovery. It was the activity for a unique enzyme that he called glycerokinase, now referred to in modern times as glycerol kinase.

The substrate of this new enzyme consisted of an important molecule called glycerol, the three-carbon backbone that was free of fatty acids and represented one of the starting points for phospholipid synthesis. The product of the new enzyme was Kennedy’s sn-3-glycerophosphate, and it harbored a radioactive phosphate at the end carbon atom of glycerol, carbon number three.

Kennedy turned his attention to one of these phosphatidic acids, called phosphatidylcholine, which is an essential part of the phospholipid membrane in all cells. Concentrating on the chemical bond, called a phosphodiester bond that connected the phosphorous and oxygens to the carbon of the glycerol backbone, he set to study the phosphatidylcholine.

Unfortunately, he experienced several false starts. In one instance, he was led astray when he had mistakenly interpreted some chromatography data to be the phosphatidylcholine. Instead, he had encountered a confounding long-chain derivative of choline, a product whose function is still a mystery to this day. Apparently, two chromatographic spots had been sitting atop each other, obfuscating the data interpretation and any convincing evidence for phosphatidylcholine.

In the meantime, Dr. Arthur Kornberg, who is the spotlight of another chapter in our book, and his colleague, William E. Pricer, Jr., managed to be the first to definitively demonstrate the production of the elusive phosphatidylcholine, publishing the work in 1952 and beating Kennedy.

https://upload.wikimedia.org/wikipedia/commons/a/ac/1-palmitoyl-2-oleoylphosphatidylcholine.svg

Figure Phosphatidylcholine

Working with the first postdoctoral fellow to enter Kennedy’s new laboratory, Dr. Samuel Weiss, in 1954, the duo directed their attention to determining what went wrong with the first failed phosphatidylcholine production failure. Kennedy and Weiss concentrated on ATP and its role in phospholipid biosynthesis. At first, they observed a spike in phosphate incorporation during phosphatidylcholine production but could not repeat the results when ATP was added from a new bottle. The new, pure ATP had no lipid-making activity. At this point, they were not convinced whether the ATP needed a co-factor or if some other nucleotide was responsible.

Thus, Weiss and Kennedy focused on other nucleotide molecules, such as cytidine triphosphate (CTP). Using CTP, the radioactive incorporation of new phosphate worked! They found the elusive phosphatidylcholine, and it had been the CTP that was responsible!

They were using Gobind Khorana’s clever technique for ATP synthesis using carbodiimide, a process that helped Khorana get the Nobel, Kennedy, and Weiss made cytidine monophosphate (CMP) and cytidine diphosphate (CDP). Then they examined the roles that these nucleotide derivatives played towards the attachment process of the head group to the glycerol backbone.

Fortunately, they made use of newly available radioactive phosphocholine and commercially pure CMP to do critical experiments. First, they synthesized CDP-choline and used it to measure the rate of phosphatidylcholine, and it proved to be the key ingredient!

One unusual incident occurred in the middle of these experiments.  Kennedy’s home caught fire! With critical CMP preparation experiments languishing on ice, Kennedy raced home to find his family standing outside of their house with fire trucks in front. Thankfully, no one was harmed, but a basement furnace overheated, and the fire was quickly put out.  Glad his family was safe. Kennedy had to return to the lab to complete the radioactive cytidine nucleotide solutions.

We know today that the CDP molecule is involved in the synthesis of other phospholipids, such as cardiolipin, phosphatidylinositol, or phosphatidylethanolamine. These CDP-based intermediates are referred to generally as CDP-diacylglycerols. The CDP attachments serve to activate the hydroxyl (–OH) groups of the glycerol backbone, to make them ready for the head group attachment. We also know that when these intermediates are produced, CMP comes off the CDP-diacylglycerols to make glycerophospholipids, complete with their phosphate head groups firmly attached.

The discovery of this Kennedy pathway of phospholipid synthesis led to his induction into all good textbooks of biochemistry, especially that of Lehninger’s famous text, where Kennedy is specifically given due credit.

3) Krebs in mitochondria is another association—but how do these two words relate? And can you review both for learning scholars?

The Krebs cycle is a central pathway that occurs inside the mitochondrion, which is a cellular organelle found in eukaryotic cells that generates the biological energy for these living systems. The Krebs cycle is a metabolic pathway named after its discoverer professor and Nobel Laureate Sir Hans Adolf Krebs. In the middle of the twentieth century, Drs. Albert Lehninger and Eugene Kennedy discovered that the enzymes of the Krebs cycle reside inside the mitochondria.

It is widely believed that the modern mitochondria in eukaryotic cells arose evolutionarily after an ancient infection of sorts of a primordial cell with an ancient prokaryote. This historic prokaryotic infection event, called endosymbiosis, then served to produce needed energy for the primordial cell, which took the pressure off these cells to acquire power externally. Without that infective process, which presumably occurred billions of years ago, eukaryotic life, including those of humans and all other animals, would be virtually impossible.

Figure Eukaryotic cell with its intracellular organelles, including mitochondria

These mitochondria play an essential role in cellular respiration. The overall process of cellular respiration can be envisaged in three distinct stages. The first stage involves glycolysis and the production of acetyl-CoA, a central metabolite. The second stage involves the Krebs cycle, and the final phase involves the respiratory chain.

The machinery of cellular respiration is present in the plasma membrane of prokaryotes and in the inner membrane of the mitochondria. Mitochondria possess two distinctive membranes, an outer and an inner membrane. The inner membrane is folded into convoluted structures called cristae, which serve to enhance the surface area, making more room for molecules.

These mitochondrial organelles function by making ATP molecules, using the energy stored in the electrochemical gradients, such as those of protons or perhaps sodium, to shuttle electrons from food breakdown to oxygen. When organisms acquire food, they oxidatively break them down via glycolysis. Glycolysis occurs in the cytoplasm of both prokaryotes and eukaryotes, converting foods into smaller energized metabolites such as pyruvate. In addition to ATP and phosphoenolpyruvate, the pyruvate metabolite can be transported into the inner matrix of the mitochondrion. Inside the organelle, certain enzymes reside, such as pyruvate dehydrogenase, which then converts pyruvate into acetyl CoA. The newly generated acetyl CoA can proceed with entry into the Krebs cycle.

Furthermore, the Krebs cycle, the electron transport process, fatty acid oxidation, and oxidative phosphorylation occur inside the mitochondrial matrix. During the oxidative breakdown of foods, the electrons are removed by NAD+ to make NADH. The electrons from the glycolytic-derived NADH molecules in the cytoplasm are shuttled into the mitochondrion. On the other hand, the electrons are removed from Krebs cycle intermediates, generating NADH and FADH2 and are already in the mitochondrial matrix.

File:Animal mitochondrion diagram en (edit).svg

https://commons.wikimedia.org/wiki/File:Animal_mitochondrion_diagram_en_(edit).svg

Figure The mitochondrion

The Krebs cycle is a central metabolic pathway that is shared by all living cells, from bacteria to humans. In prokaryotes, we know that the Krebs cycle occurs in the cytoplasm. However, in 1948, Kennedy and his graduate thesis advisor, Dr. Albert Lehninger, who is also featured in this book, discovered that the reactions of the Krebs cycle occur inside the mitochondrion, rather than the cytoplasm. This was a notable scientific discovery, worthy of permanent inclusion in the biological and biochemical textbooks.

The Krebs cycle is also known as the tricarboxylic acid cycle (TCA) and the citric acid cycle (CAC). The TCA designation refers to the fact that many of the biochemicals in the pathway have three carboxyl groups (—COO) attached to them (see the figure on the Krebs cycle). The CAC description refers to the first metabolite in the pathway, citric acid, or citrate if considering its condition under physiological conditions inside a cell.

File:Citric acid cycle noi.JPG

https://en.wikipedia.org/wiki/File:Citric_acid_cycle_noi.JPG

Figure Krebs cycle

The reactions of the Krebs cycle fall into several biochemical categories (see figure on the Krebs cycle). One such reaction type, called anabolism, involves the conversion of acetyl CoA into citrate. A second category is an isomerization, in which citrate is rearranged to isocitrate. Another group consists of a process called oxidative-reduction (redox) reactions in which NADH and FADH2 are produced after the electrons are moved from the Krebs cycle intermediates. One reaction type is decarboxylation. Here carbon dioxide is removed from two of the intermediates, namely, isocitrate and α-ketoglutarate. The CO2 is then expired from the eukaryotic host or excreted by the prokaryote. In terms of respiration, breathing oxygen in and carbon dioxide out, these biochemical reactions play a part in the exhalation. Another critical reaction is called substrate-level phosphorylation, in which GTP is produced where the source of the phosphate is the substrate, which in this case, is succinyl CoA. Lastly, hydration, the addition of water, occurs to make malate. The endpoint of Krebs, oxaloacetate, completes the cycle by condensing with acetyl CoA, to create a new molecule of citrate and begin the cycle again.

4) Oxidative phosphorylation—why is this important, and what was Kennedy’s relationship here?

Between 1948 and 1950, Kennedy and Lehninger discovered that oxidative phosphorylation occurs within mitochondria.

The processes of glycolysis and Krebs cycle take electrons from our food and bring them to NADH and FADH2. These carriers of electrons then take them to the electron transport chain, wherein aerobic organisms, like humans, oxygen receives the electrons that had been extracted previously during glycolysis and Krebs. During this electron transport process, a gradient of ions, like protons (H+) or sodium ions (Na+) accumulate on one side of the plasma membrane in prokaryotes or the inner mitochondrial membrane of eukaryotes, generating a force of energy, called the electrochemical gradient of ions (H+ or Na+). The concentrations of these ions are high on one side of the membrane and low on the other side. Such differences in ion concentrations are known as gradients, and they are often termed as proton-motive force (PMF) or sodium-motive force (SMF).

These ion gradients are another form of potential biological energy, and they are used to make ATP. Thus, oxidative phosphorylation can be defined as the oxidation-reduction transfer of electrons along the respiratory chain where the electrons end up at molecular oxygen, the resulting generation of the PMF or SMF, the energy of which is then used to phosphorylate ADP to make ATP. The oxidative part refers to the loss of electrons as they move along the respiratory chain, and the phosphorylation part indicates that ADP has received a phosphate to produce ATP.

Before Kennedy’s foray into the field of oxidative phosphorylation studies, his Ph.D. advisor Lehninger and his graduate student assistant Morris Friedkin had found several intriguing pieces to the puzzle. They had demonstrated that the conversion of ADP to ATP required the presence of NADH. They also knew that the phosphates of ATP could later be found in other molecules, such as phospholipids, nucleic acids, and interestingly, other proteins. A third fact was Lehninger’s keen insight that his oxidative phosphorylation and Kennedy’s work on phospholipid biosynthesis shared possible linkages. Another fascinating point was the finding by Otto Warburg that the energetics of metabolism in tumors occurred under anaerobic conditions. These new captivating elements of biochemistry set the stage for Kennedy to explore the parameters of oxidative phosphorylation.

Working with Guy Williams-Ashman, Kennedy obtained livers and tumors and made cellular extracts out of these animal tissues. Next, they measured oxidative phosphorylation activities of these cell extracts and observed them as highly active, especially the tumor tissues that were quite malignant. Then, by studying the incorporation of radioactive phosphorous into proteins of the cell extracts, Kennedy and Williams-Ashman observed high phosphate incorporation levels into proteins, nucleic acids, and lipids of these tumors. They became intrigued by the phosphorylated proteins.

Focusing on these so-called phosphoproteins, Kennedy and collaborator George Burnett began a search for the enzymes that mediated such phosphorylating activities. When they managed to purify the catalyst, it turned out to be the first case of a protein kinase! Burnett and Kennedy published this groundbreaking kinase discovery in 1954.

While a graduate student in Lehninger’s laboratory, Kennedy had been studying enzymes involved in phospholipid biosynthesis. The first step in his enzyme preparation studies involved the generation of ATP after the addition of radioactively labeled phosphate-32, denoted as 32P, to cellular-derived mitochondria. First, however, the mitochondria had to be obtained in pure form. To do these organellar isolations, Kennedy adopted the laboratory technique of Dr. George Palade, who would earn the Nobel for his efforts towards purifying microsomes, now known as ribosomes, which at the time were laden with RNA and inaccurately thought to have been part of the mitochondria. We know today that the mitochondrion and the ribosome are different entities.

Palade had used the method called density-gradient centrifugation to purify the microsomes. It was an arduous process requiring lots of time and extremely high-speed centrifuges. A tiny mistake in precisely weighing the test tubes would unbalance the centrifuge’s rotor and cause catastrophic destruction of not only the centrifuge but also of a laboratory, should the rotor come loose from the machine.

Using Palade’s method, Kennedy isolated the mitochondria out of the recesses of laboratory rat liver cells and measured their oxidative phosphorylation activities. He found them highly active! These experiments definitively demonstrated that oxidative phosphorylation occurred within the mitochondria. It was a significant finding!

5) From 1959—to 1993—he worked at taught at Harvard Medical School—an incredibly long and illustrious career—is there any way to summarize his impact and his discoveries during that time?

In 1959, Dr. Kennedy moved from the University of Chicago to become the endowed Hamilton Kuhn professor and head of the biological chemistry department at Harvard’s Medical School.

Some of his first studies at Harvard consisted of examining the synthesis of a phospholipid called phosphatidylserine. It had been a stubborn molecule to study, and it resisted his efforts to learn of its synthesis. Instead, he found an enzyme that broke it down rather than built it up. He called it phosphoserine phosphatase, which removed phosphate from the phospholipid.

His search for a phosphoserine pathway also led to the discovery of another degrading enzyme, this one called phosphatidylserine decarboxylase, which removed a carboxyl moiety from phosphatidylserine to liberate serine and ethanolamine. Kennedy’s group and other laboratories did manage, however, to ultimately elucidate a complete pathway scheme for the biosynthesis of several phospholipids, including phosphatidylserine and others such as triacylglycerol. In most of these and other cases, Kennedy’s CDP-diacylglycerols were important requisite intermediates for the biosynthesis of phospholipids in animals.

In the next two decades, starting in 1960, the Kennedy laboratory at Harvard Medical School would study the biosynthesis of membranes in microbes, definitively demonstrating the requirement for cytidine nucleotides for membrane biogenesis in Escherichia coli. It was a very productive time for Kennedy. During the decade of the 1960s, for example, Kennedy worked with colleagues Marilyn Rumley, Julian Kanfer, Ying-Ying Chan, Jim Carter, and Ron Pieringer.

In the 1970s, Kennedy studied microbial membrane biochemistry with Bill Dowhan, Chris Raetz, Martin Snider, Gayle Snider, Michel Satre, Carlos Hirschberg, Ed Hawrot, Keith Langley, Richard Tyhach, and Bill Wickner. Many of these collaborators went on to illustrious scientific careers on their own.

During this time, another focus of the Kennedy laboratory involved his interest in the translocation of phospholipids. Kennedy and co-authors George F. Wilgram and Edward A. Dennis studied the distribution of integral membrane proteins that were discovered to play essential roles in microbial membrane biosynthesis. During the 1970s and 80s, Kennedy, Langley, James Rothman, and Michael Yaffe discovered that membranes are synthesized by enzymes that reside at their integral sites within the membranes. That is, the membrane machinery was constructed on location, rather than elsewhere and transported to the end location.

These results predicted the necessity for a microbial protein that mediated translocation of phospholipids through the membrane in order to deliver the mandatory phospholipid types to their proper locations in the membrane. Indeed, such a phospholipid translocation protein was discovered by Dowhan and others in the early 1990s when they isolated a yeast protein called SEC14p that conferred transfer of specific phospholipids in the Golgi apparatus. It was a significant discovery.

In the mid-1960s, Kennedy studied one of my favorite proteins, called the lactose permease, from Escherichia coli. It is a famous member of the well-known lac operon, which you will recall was discovered by Nobel Laureates François Jacob and Jacques Monod, both of whom are featured in an earlier book of ours. The work of Hiroshi Nikaido, who was housed in the laboratory of Herman Kalckar at the Massachusetts General Hospital in Boston, inspired Kennedy.

Thus, he focused on the idea that sugar transport activity of the lactose permease was somehow related to the radioactive incorporation of labeled phosphate into membrane phospholipids. The phenomenon was referred to as the “phospholipid effect.” While the study of this phenomenon led nowhere, as no specific phospholipids were necessary for lactose transport per se, it nonetheless led to other fruitful studies.

The mechanism of sugar translocation across the bacterial membrane was studied by Kennedy and C. Fred Fox. At the time, it was not entirely clear whether a transporter protein was required for sugar transport. Thus, Kennedy and Fox attempted to locate the protein in the membrane by labeling it with an indicator, a sugar derivative called p-aminophenyl-β-galactoside. But the chemical indicator instead turned out to inhibit the sugar transport property of the permease. Thus, it was challenging to determine whether the permease was functional.

Then, an astute insight occurred to Kennedy as he took a road trip from Woods Hole, MA, to his home in Brookline. The idea was to grow two batches of Escherichia coli cells, one that was uninduced and the other that was induced for the lactose permease. The uninduced cells had no permease, while the induced cells harbored the putative permease. The experiment was then conducted in two stages.

The first stage was to grow both batches of cells (uninduced versus induced) in the presence of a sulfhydryl-based chemical called N-ethylmaleimide (NEM), which could bind proteins in the bacteria, and combine the NEM with high amounts of sugar—a substrate for the permease. In this stage, NEM bound all proteins, except the lactose permease in the induced cells because the permease was protected by the sugar substrate. Then Fox and Kennedy washed the cells to remove the sugar. In the cells without the permease, most proteins were bound to NEM. In cells with the permease, most proteins were also attached to NEM, except the permease, as they had been protected from NEM binding because the sugar prevented the NEM binding.

The second stage involved exposing the induced cells (harboring the lactose permease) to NEM that was labeled with the radioactive isotope of carbon-14 (14C) but without any sugar present.

Thus, the permease had radioactive 14C-labeled NEM!

For the uninduced cells (without lactose permease), they were exposed to radioactive hydrogen (3H, tritium)-NEM, while another batch of but exposed to the isotope of carbon, 14C. The ingenious idea manifested itself in that for the uninduced cells, and any observed tritium would label proteins that were not the lactose permease, while the carbon-14-labeled NEM precisely marked the elusive sugar transporter itself! The lactose permease had finally been detected, and it was such an elegant experiment! It became famous as the “double-labeled” experiment. The work was published in 1965 in the prestigious Proceedings of the National Academy of Sciences.

Unfortunately, repeated attempts to purify the lactose permease, by Kennedy and investigators from many laboratories, failed. The first successful attempt was performed by Michael Newman and Thomas Hastings Wilson at Harvard, who published their groundbreaking work in 1981.

In the late 1970s, Kennedy worked with Rothman and Langley to study the movement of individual phospholipid molecules from one side of the membrane bilayer to the other layer. This sort of phospholipid movement became known as the “flip-flop” mechanism, and the search was on for a Flippase enzyme that meditated these flipping and flopping interchanges. This field of study is still an ongoing area.

In 1990, Kennedy worked with his postdoctoral fellow, Dr. Mark Platt, who purified an acyl carrier protein, encoded by a gene called nodF, which was essential for the production of lipid molecules that were necessary for cellular growth of the Gram-negative bacterium Rhizobium meliloti (known nowadays as Sinorhizobium meliloti). It was a significant discovery with exciting ramifications for cellular signalling mechanisms and growth.

6)  Al Lehninger, Fritz Lipmann, and Eugene Kennedy were supposedly known as “The Gods of Biochemistry,” and students and scientists apparently knew this.  What kind of concluding remark can you make about Kennedy and his colleagues?

Dr. Albert Lehninger was Kennedy’s graduate advisor at the University of Chicago. Lehninger is highlighted in another chapter of this book. Briefly, Lehninger and Kennedy discovered that various critical biological activities were performed in the mitochondrion. These living processes included the Krebs cycle, oxidative phosphorylation, and fatty acid metabolism and transport.

Dr. Fritz Lipmann was featured prominently in chapter 23 of our first book. His significant contribution to biochemistry, among many, was the elucidation of the pyruvate dehydrogenase complex reaction, in which pyruvate is converted to acetyl CoA. The carbons of sugars and other biochemical building blocks go through this central metabolite to enter the Krebs cycle.

As a postdoctoral fellow, in 1950, Kennedy joined the Lippman laboratory, which was housed at Mass General in Boston. Kennedy would write in later years that Lipmann was an influential force in guiding both his philosophical and methodological approaches to scientific research. Fritz A. Lipmann would go on to earn the Nobel, sharing it with Hans A. Krebs in 1953.

7) One of Kennedy’s colleagues honored him with the attachment below—which is a tribute to his contributions not just to the field—but to science. Your thoughts?

I think one legacy left behind by Kennedy is the long list of appreciative students.

Cleary, Kennedy left a lasting impression upon those who knew him well. The above tribute was written by one of his grateful graduate students, Dr. Christopher Raetz, and included in a memorial to Kennedy published by William (Bill) T. Wickner in the Proceedings of the National Academy of Sciences, on the 29th of November, 2011, two months after the death of Kennedy on the 22nd of September of that year. Kennedy was 92 years old.

I once had the privilege of meeting Kennedy when I was still a postdoctoral fellow in the mid-1990s. He was introduced to me by Dr. Thomas H. Wilson, who was a professor at Harvard Medical School and my postdoctoral advisor at the time. I had already known of Kennedy’s prominence in the field of biochemistry, and I was deeply honored to meet him personally. I specifically chose to go to Harvard as a postdoc because of Wilson’s work with salt bridges of the lactose permease.

After my arrival in Wilson’s laboratory, I learned that it was Kennedy who inspired him to pick up the study of the famous lactose permease. Thus, had it not been for Kennedy’s pioneering work with lactose transport, I never would have gone to Harvard.

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