Microbiology and Immunology

WORLD OF MICROBIOLOGY AND IMMUNOLOGY Krebs cycle

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various ions matched their concentrations within the body, a

technique which eventually was adopted in almost all bio-

chemical, physiological, and pharmacological studies.

Working with a medical student named Kurt Henseleit,

Krebs systematically investigated which substances most

influenced the rate at which urea—the main solid component

of mammalian urine—forms in liver slices. Krebs noticed that

the rate of urea synthesis increased dramatically in the pres-

ence of ornithine, an amino acid present during urine produc-

tion. Inverting the reaction, he speculated that the same

ornithine produced in this synthesis underwent a cycle of con-

version and synthesis, eventually to yield more ornithine and

urea. Scientific recognition of his work followed almost

immediately, and at the end of 1932—less than a year and a

half after he began his research—Krebs found himself

appointed as a Privatdozentat the University of Freiburg. He

immediately embarked on the more ambitious project of iden-

tifying the intermediate steps in the metabolic breakdown of

carbohydrates and fatty acids.

Krebs was not to enjoy his new position in Germany for

long. In the spring of 1933, along with many other German sci-

entists, he found himself dismissed from his job because of

Nazi purging. Although Krebs had renounced the Jewish faith

twelve years earlier at the urging of his patriotic father, who

believed wholeheartedly in the assimilation of all German

Jews, this legal declaration proved insufficiently strong for the

Nazis. In June of 1933, he sailed for England to work in the

biochemistrylab of Sir Frederick Gowland Hopkins of the

Cambridge School of Biochemistry. Supported by a fellowship

from the Rockefeller Foundation, Krebs resumed his research

in the British laboratory. The following year, he augmented his

research duties with the position of demonstrator in biochem-

istry. Laboratory space in Cambridge was cramped, however,

and in 1935 Krebs was lured to the post of lecturer in the

University of Sheffield’s Department of Pharmacology by the

prospect of more lab space, a semi-permanent appointment,

and a salary almost double the one Cambridge was paying him.

His Sheffield laboratory established, Krebs returned to a

problem that had long preoccupied him: how the body pro-

duced the essential amino acids that play such an important

role in the metabolic process. By 1936, Krebs had begun to

suspect that citric acid played an essential role in the oxidative

metabolism by which the carbohydrate pyruvic acid is broken

down so as to release energy. Together with his first Sheffield

graduate student, William Arthur Johnson, Krebs observed a

process akin to that in urea formation. The two researchers

showed that even a small amount of citric acid could increase

the oxygen absorption rate of living tissue. Because the

amount of oxygen absorbed was greater than that needed to

completely oxidize the citric acid, Krebs concluded that citric

acid has a catalytic effect on the process of pyruvic acid con-

version. He was also able to establish that the process is cycli-

cal, citric acid being regenerated and replenished in a

subsequent step. Although Krebs spent many more years refin-

ing the understanding of intermediary metabolism, these early

results provided the key to the chemistry that sustains life

processes. In June of 1937, he sent a letter to Naturereporting

these preliminary findings. Within a week, the editor notified

him that his paper could not be published without a delay.

Undaunted, Krebs revised and expanded the paper and sent it

to the new Dutch journal Enzymologia,which he knew would

rapidly publicize this significant finding.

In 1938, Krebs married Margaret Fieldhouse, a teacher

of domestic science in Sheffield. The couple eventually had

three children. In the winter of 1939, the university named him

lecturer in biochemistry and asked him to head their new

department in the field. Married to an Englishwoman, Krebs

became a naturalized English citizen in September, 1939,

three days after World War II began.

The war affected Krebs’s work minimally. He con-

ducted experiments on vitamin deficiencies in conscientious

objectors, while maintaining his own research on metabolic

cycles. In 1944, the Medical Research Council asked him to

head a new department of biological chemistry. Krebs refined

his earlier discoveries throughout the war, particularly trying

to determine how universal the Krebs cycle is among living

organisms. He was ultimately able to establish that all organ-

isms, even microorganisms, are sustained by the same chemi-

cal processes. These findings later prompted Krebs to

speculate on the role of the metabolic cycle in evolution.

In 1953, Krebs received the Nobel Prize in physiology

and medicine, which he shared with Fritz Lipmann, the dis-

coverer of co-enzyme A. The following year, Oxford

University offered him the Whitley professorship in biochem-

istry and the chair of its substantial department in that field.

Once Krebs had ascertained that he could transfer his meta-

bolic research unit to Oxford, he consented to the appoint-

ment. Throughout the next two decades, Krebs continued

research into intermediary metabolism. He established how

fatty acids are drawn into the metabolic cycle and studied the

regulatory mechanism of intermediary metabolism. Research

at the end of his life was focused on establishing that the meta-

bolic cycle is the most efficient mechanism by which an

organism can convert food to energy. When Krebs reached

Oxford’s mandatory retirement age of sixty-seven, he refused

to end his research and made arrangements to move his

research team to a laboratory established for him at the

Radcliffe Hospital. Krebs died at the age of eighty-one.

See alsoCell cycle and cell division; Cell membrane transport

KKrebs cycleREBS CYCLE

The Krebs cycle is a set of biochemical reactions that occur in

the mitochondria. The Krebs cycle is the final common path-

way for the oxidation of food molecules such as sugars and

fatty acids. It is also the source of intermediates in biosynthetic

pathways, providing carbon skeletons for the synthesis of

amino acids, nucleotides, and other key molecules in the cell.

The Krebs cycle is also known as the citric acid cycle, and the

tricarboxylic acid cycle. The Krebs cycle is a cycle because,

during its course, it regenerates one of its key reactants.

To enter the Krebs cycle, a food molecule must first be

broken into two- carbon fragments known as acetyl groups,

which are then joined to the carrier molecule coenzyme A

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