| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 283, Issue 18, 10, May 2, 2008
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Classics
Purine Metabolism of a Diaminopurine-resistant Strain of Lactobacillus casei
(Elion, G. B., Vanderwerff, H., Hitchings, G. H., Balis, M. E., Levin, D. H., and Brown, G. B. (1953) J. Biol. Chem. 200, 7–16)
The Purine Metabolism of a 6-Mercaptopurine-resistant Lactobacillus casei
(Elion, G. B., Singer, S., and Hitchings, G. H. (1953) J. Biol. Chem. 204, 35–41)
George Herbert Hitchings (1905–1998) was born in Hoquiam, Washington. After losing his father to illness when he was 12 years old, Hitchings decided to become a doctor. He entered the University of Washington as a premedical student in 1923, but by the end of his freshman year he decided to become a chemistry major. He graduated in 1927 and stayed on to earn a master's degree in 1928.
|
In 1942 Hitchings joined the Burroughs Wellcome Research Laboratories (now known as GlaxoSmithKline) to head the biochemistry department. Two years later, he hired Gertrude Elion as a laboratory assistant and began a life-long collaboration on drug development. Elion will be featured in an upcoming JBC Classic.
The recent development of sulfa drugs led Hitchings to wonder if other substances that interfered with microbe metabolism could also be used as drugs. He began examining the nucleic acids and assigned Elion to investigate purines. They soon discovered that bacterial cells were unable to produce nucleic acids unless certain purines were present and started to work on synthesizing compounds that would inhibit the incorporation of these purines into nucleic acids, which is the subject of the two JBC Classics reprinted here. By 1950 they discovered two compounds, diaminopurine and thioguanine, which inhibited the incorporation of adenine and guanine (respectively) into nucleic acids. The methods they used would eventually come to be known as "rational" drug design, and Hitchings and Elion would be regarded as pioneers in the field.
The first JBC Classic reports Hitchings' confirmation that diaminopurine is an adenine antagonist. Using a mutant of Lactobacillus casei that grew in a folic acid-containing medium with high concentrations of 2,6-diaminopurine, he looked at the differences between the mutant and wild-type metabolic pathways. Hitchings and his colleagues discovered that the mutant bacteria displayed a decreased incorporation of adenine and diaminopurine into pentose nucleic acid purines and an increased ability to utilize the diaminopurine riboside. These differences confirmed that diaminopurine is a competitive antagonist of adenine. Thus, Hitchings concluded that "diaminopurine and adenine are metabolized via the same primary pathway in the wild strain, and that it is the alteration or elimination of this mechanism which accounts for the resistance of the mutant to diaminopurine."
Their success with diaminopurine and thioguanine led Elion to substitute an oxygen with a sulfur atom on a purine molecule, producing 6-mercaptopurine, a molecule closely related to thioguanine. The second JBC Classic reprinted here details Hitchings investigations into 6-mercaptopurine action using a strain of L. casei that was resistant to the compound. He found that the mutant grew well in the presence of xanthine and guanine but grew poorly on adenine and adenylic acid b and scarcely at all on hypoxanthine. The mutant was also sensitive to adenine antagonists, but these effects could be counteracted by adenine. These results suggested to Hitchings that two distinct routes were involved in adenine metabolism and that a hypoxanthine-containing metabolite might be an intermediate in the conversion of adenine to guanine in L. casei, with its transformation to a guanine-containing substance being a possible site of action for 6-mercaptopurine.
As a result of this research, diaminopurine, thioguanine, and 6-mercaptopurine have been used to treat leukemia due to their ability to block DNA synthesis in white blood cells. Elion and Hitchings also developed a number of additional drugs including azathioprine, a less toxic form of 6-mercaptopurine used to suppress the immune system after organ transplants, and allopurinol, a drug used to treat gout that blocks uric acid production by competing for xanthine oxidase, an enzyme that converts purines to uric acid. In recognition of their contributions to drug discovery, Hitchings and Elion shared the 1988 Nobel Prize in Physiology or Medicine with Sir James W. Black.
As a result of these overwhelming successes, Hitchings was promoted to Vice President in Charge of Research in 1967. He remained in this position until 1976 when he became Scientist Emeritus.
In addition to research, Hitchings was heavily involved in philanthropy. He became Director of The Burroughs Wellcome Fund in 1968 and President of the Fund in 1971. In 1983, he founded what is now the Greater Triangle Community Foundation. Hitchings was also Director and Vice President of United Way, Director and Committee Chairman of the American Red Cross, and Director, President, and Chairman of the Foundation for Better Health of Durham.
In addition to the Nobel Prize, Hitchings received numerous awards, including the Gregor Mendel Medal from the Czechoslovakian Academy of Science in 1968 and the Albert Schweitzer International Prize for Medicine in 1989. He was awarded 11 honorary degrees and was a member of the National Academy of Sciences.
REFERENCES
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
